Emerging Antibiotic in ICU Ahmed elmenshawy MD Alexandria University
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Emerging Antibiotic in ICU
Ahmed elmenshawy MD
Alexandria University
Disclosure
bull No Conflict of interest
Increasing resistance
Problem
Solutions
Conclusions
Problem
Classification of Drug resistance
bull XDR+
bull Polymixin
Pan
PDR
bull MDR+
carbapenem
Extensive
XDR
bull Cephalosporins
bull B-lactamB-lactamasesinhibitor
bull Aminoglycosides
bull Fluroquinolones
Multi
MDR
At least 3
ESKAPE pathogens
bull Enterococcus faecium hellipVRE
bull Staphylococcus aureus MRSA VISAVRSA
bull Klebsiella pneumoniae
bull Acinetobacter baumanii
bull Pseudomonas aeruginosa
bull Enterobacteriaceae
Gram NegativeESBL carbepamase
Gram Positive
Acientobacter resistance to antibiotics
Journal of thoracic disease
Staphylococcus auresus sensitivity to Vancomycin
100 100
90
100 100 100
100 100
100
84
86
88
90
92
94
96
98
100
102
2008 2009 2010 2011 2012 2013 2014 2015 2016
Vancomycin
Alexandria Critical Care Department
Klebsiella pneumonia sensitivity to carbapenem
100 100 100
846
718
52163 615
59 58
45
50
974895
621
736 73711 73
50
86
0
20
40
60
80
100
120
0
20
40
60
80
100
120
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Pseudomonas aeruginosasensitivity to carbapenems
42
325
413 476
306
45
5153
35
49
388408
481
249
285
41
57
31
0
10
20
30
40
50
60
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Acinetobacter baumaniisensitivity to carbanems
221
176141
38
84
65
29
9 83
396
345
167
118 136
2229
96
0
5
10
15
20
25
30
35
40
45
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Solutions
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Disclosure
bull No Conflict of interest
Increasing resistance
Problem
Solutions
Conclusions
Problem
Classification of Drug resistance
bull XDR+
bull Polymixin
Pan
PDR
bull MDR+
carbapenem
Extensive
XDR
bull Cephalosporins
bull B-lactamB-lactamasesinhibitor
bull Aminoglycosides
bull Fluroquinolones
Multi
MDR
At least 3
ESKAPE pathogens
bull Enterococcus faecium hellipVRE
bull Staphylococcus aureus MRSA VISAVRSA
bull Klebsiella pneumoniae
bull Acinetobacter baumanii
bull Pseudomonas aeruginosa
bull Enterobacteriaceae
Gram NegativeESBL carbepamase
Gram Positive
Acientobacter resistance to antibiotics
Journal of thoracic disease
Staphylococcus auresus sensitivity to Vancomycin
100 100
90
100 100 100
100 100
100
84
86
88
90
92
94
96
98
100
102
2008 2009 2010 2011 2012 2013 2014 2015 2016
Vancomycin
Alexandria Critical Care Department
Klebsiella pneumonia sensitivity to carbapenem
100 100 100
846
718
52163 615
59 58
45
50
974895
621
736 73711 73
50
86
0
20
40
60
80
100
120
0
20
40
60
80
100
120
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Pseudomonas aeruginosasensitivity to carbapenems
42
325
413 476
306
45
5153
35
49
388408
481
249
285
41
57
31
0
10
20
30
40
50
60
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Acinetobacter baumaniisensitivity to carbanems
221
176141
38
84
65
29
9 83
396
345
167
118 136
2229
96
0
5
10
15
20
25
30
35
40
45
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Solutions
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Increasing resistance
Problem
Solutions
Conclusions
Problem
Classification of Drug resistance
bull XDR+
bull Polymixin
Pan
PDR
bull MDR+
carbapenem
Extensive
XDR
bull Cephalosporins
bull B-lactamB-lactamasesinhibitor
bull Aminoglycosides
bull Fluroquinolones
Multi
MDR
At least 3
ESKAPE pathogens
bull Enterococcus faecium hellipVRE
bull Staphylococcus aureus MRSA VISAVRSA
bull Klebsiella pneumoniae
bull Acinetobacter baumanii
bull Pseudomonas aeruginosa
bull Enterobacteriaceae
Gram NegativeESBL carbepamase
Gram Positive
Acientobacter resistance to antibiotics
Journal of thoracic disease
Staphylococcus auresus sensitivity to Vancomycin
100 100
90
100 100 100
100 100
100
84
86
88
90
92
94
96
98
100
102
2008 2009 2010 2011 2012 2013 2014 2015 2016
Vancomycin
Alexandria Critical Care Department
Klebsiella pneumonia sensitivity to carbapenem
100 100 100
846
718
52163 615
59 58
45
50
974895
621
736 73711 73
50
86
0
20
40
60
80
100
120
0
20
40
60
80
100
120
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Pseudomonas aeruginosasensitivity to carbapenems
42
325
413 476
306
45
5153
35
49
388408
481
249
285
41
57
31
0
10
20
30
40
50
60
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Acinetobacter baumaniisensitivity to carbanems
221
176141
38
84
65
29
9 83
396
345
167
118 136
2229
96
0
5
10
15
20
25
30
35
40
45
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Solutions
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Problem
Classification of Drug resistance
bull XDR+
bull Polymixin
Pan
PDR
bull MDR+
carbapenem
Extensive
XDR
bull Cephalosporins
bull B-lactamB-lactamasesinhibitor
bull Aminoglycosides
bull Fluroquinolones
Multi
MDR
At least 3
ESKAPE pathogens
bull Enterococcus faecium hellipVRE
bull Staphylococcus aureus MRSA VISAVRSA
bull Klebsiella pneumoniae
bull Acinetobacter baumanii
bull Pseudomonas aeruginosa
bull Enterobacteriaceae
Gram NegativeESBL carbepamase
Gram Positive
Acientobacter resistance to antibiotics
Journal of thoracic disease
Staphylococcus auresus sensitivity to Vancomycin
100 100
90
100 100 100
100 100
100
84
86
88
90
92
94
96
98
100
102
2008 2009 2010 2011 2012 2013 2014 2015 2016
Vancomycin
Alexandria Critical Care Department
Klebsiella pneumonia sensitivity to carbapenem
100 100 100
846
718
52163 615
59 58
45
50
974895
621
736 73711 73
50
86
0
20
40
60
80
100
120
0
20
40
60
80
100
120
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Pseudomonas aeruginosasensitivity to carbapenems
42
325
413 476
306
45
5153
35
49
388408
481
249
285
41
57
31
0
10
20
30
40
50
60
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Acinetobacter baumaniisensitivity to carbanems
221
176141
38
84
65
29
9 83
396
345
167
118 136
2229
96
0
5
10
15
20
25
30
35
40
45
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Solutions
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Classification of Drug resistance
bull XDR+
bull Polymixin
Pan
PDR
bull MDR+
carbapenem
Extensive
XDR
bull Cephalosporins
bull B-lactamB-lactamasesinhibitor
bull Aminoglycosides
bull Fluroquinolones
Multi
MDR
At least 3
ESKAPE pathogens
bull Enterococcus faecium hellipVRE
bull Staphylococcus aureus MRSA VISAVRSA
bull Klebsiella pneumoniae
bull Acinetobacter baumanii
bull Pseudomonas aeruginosa
bull Enterobacteriaceae
Gram NegativeESBL carbepamase
Gram Positive
Acientobacter resistance to antibiotics
Journal of thoracic disease
Staphylococcus auresus sensitivity to Vancomycin
100 100
90
100 100 100
100 100
100
84
86
88
90
92
94
96
98
100
102
2008 2009 2010 2011 2012 2013 2014 2015 2016
Vancomycin
Alexandria Critical Care Department
Klebsiella pneumonia sensitivity to carbapenem
100 100 100
846
718
52163 615
59 58
45
50
974895
621
736 73711 73
50
86
0
20
40
60
80
100
120
0
20
40
60
80
100
120
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Pseudomonas aeruginosasensitivity to carbapenems
42
325
413 476
306
45
5153
35
49
388408
481
249
285
41
57
31
0
10
20
30
40
50
60
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Acinetobacter baumaniisensitivity to carbanems
221
176141
38
84
65
29
9 83
396
345
167
118 136
2229
96
0
5
10
15
20
25
30
35
40
45
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Solutions
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
ESKAPE pathogens
bull Enterococcus faecium hellipVRE
bull Staphylococcus aureus MRSA VISAVRSA
bull Klebsiella pneumoniae
bull Acinetobacter baumanii
bull Pseudomonas aeruginosa
bull Enterobacteriaceae
Gram NegativeESBL carbepamase
Gram Positive
Acientobacter resistance to antibiotics
Journal of thoracic disease
Staphylococcus auresus sensitivity to Vancomycin
100 100
90
100 100 100
100 100
100
84
86
88
90
92
94
96
98
100
102
2008 2009 2010 2011 2012 2013 2014 2015 2016
Vancomycin
Alexandria Critical Care Department
Klebsiella pneumonia sensitivity to carbapenem
100 100 100
846
718
52163 615
59 58
45
50
974895
621
736 73711 73
50
86
0
20
40
60
80
100
120
0
20
40
60
80
100
120
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Pseudomonas aeruginosasensitivity to carbapenems
42
325
413 476
306
45
5153
35
49
388408
481
249
285
41
57
31
0
10
20
30
40
50
60
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Acinetobacter baumaniisensitivity to carbanems
221
176141
38
84
65
29
9 83
396
345
167
118 136
2229
96
0
5
10
15
20
25
30
35
40
45
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Solutions
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Acientobacter resistance to antibiotics
Journal of thoracic disease
Staphylococcus auresus sensitivity to Vancomycin
100 100
90
100 100 100
100 100
100
84
86
88
90
92
94
96
98
100
102
2008 2009 2010 2011 2012 2013 2014 2015 2016
Vancomycin
Alexandria Critical Care Department
Klebsiella pneumonia sensitivity to carbapenem
100 100 100
846
718
52163 615
59 58
45
50
974895
621
736 73711 73
50
86
0
20
40
60
80
100
120
0
20
40
60
80
100
120
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Pseudomonas aeruginosasensitivity to carbapenems
42
325
413 476
306
45
5153
35
49
388408
481
249
285
41
57
31
0
10
20
30
40
50
60
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Acinetobacter baumaniisensitivity to carbanems
221
176141
38
84
65
29
9 83
396
345
167
118 136
2229
96
0
5
10
15
20
25
30
35
40
45
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Solutions
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Staphylococcus auresus sensitivity to Vancomycin
100 100
90
100 100 100
100 100
100
84
86
88
90
92
94
96
98
100
102
2008 2009 2010 2011 2012 2013 2014 2015 2016
Vancomycin
Alexandria Critical Care Department
Klebsiella pneumonia sensitivity to carbapenem
100 100 100
846
718
52163 615
59 58
45
50
974895
621
736 73711 73
50
86
0
20
40
60
80
100
120
0
20
40
60
80
100
120
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Pseudomonas aeruginosasensitivity to carbapenems
42
325
413 476
306
45
5153
35
49
388408
481
249
285
41
57
31
0
10
20
30
40
50
60
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Acinetobacter baumaniisensitivity to carbanems
221
176141
38
84
65
29
9 83
396
345
167
118 136
2229
96
0
5
10
15
20
25
30
35
40
45
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Solutions
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Klebsiella pneumonia sensitivity to carbapenem
100 100 100
846
718
52163 615
59 58
45
50
974895
621
736 73711 73
50
86
0
20
40
60
80
100
120
0
20
40
60
80
100
120
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Pseudomonas aeruginosasensitivity to carbapenems
42
325
413 476
306
45
5153
35
49
388408
481
249
285
41
57
31
0
10
20
30
40
50
60
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Acinetobacter baumaniisensitivity to carbanems
221
176141
38
84
65
29
9 83
396
345
167
118 136
2229
96
0
5
10
15
20
25
30
35
40
45
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Solutions
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Pseudomonas aeruginosasensitivity to carbapenems
42
325
413 476
306
45
5153
35
49
388408
481
249
285
41
57
31
0
10
20
30
40
50
60
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Acinetobacter baumaniisensitivity to carbanems
221
176141
38
84
65
29
9 83
396
345
167
118 136
2229
96
0
5
10
15
20
25
30
35
40
45
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Solutions
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Acinetobacter baumaniisensitivity to carbanems
221
176141
38
84
65
29
9 83
396
345
167
118 136
2229
96
0
5
10
15
20
25
30
35
40
45
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department
Solutions
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Solutions
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
bullCeftobiprole
bullCeftarolineCephalsporin
bullCeftozolanetazobactambullCeftazidimAvibactam
B-lactamase inhibitors
bulldoripenem biapenem Tomopenem
bull razupenem Panipenem TebipenemCarbapenem
bulltelavancin oritavancin
DalbavancinGlycopeptides
bullTedizolid
bullRadezolidOxazolidinones
bullGatifloxacin Delafloxacin Nemonoxacin
bullZabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones
bullEravacycline
bullOmadacyclineTetracyclines
bullPlazomicinAminoglycosides
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
5th Cephalosporins
1 Ceftobiprole medocaril
2 Ceftaroline fosamil
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Ceftobiprole medocaril
bull Better than other cephalosporins aganist
1 MRSA VISA VRSA macrolide-resistant S pyogenes
bull bind to PBP2a protein conferring ORSA resistance to b-lactam
2 Penicillin-resistant S pneumoniae
bull bind PBP2x in
3 Enterococci (fecalis not feacium)
4 Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5 Pseudomonas species superior to cefepime
bull Trials (phase 3)
1 Complicated skin and soft tissue infection ldquocSSSIldquo (MRSA)
2 CAP and HAP (not VAP) Bassetti M Springer 2015
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Ceftaroline fosamil
bull Similar to Ceftobiprole
1 MRSA heteroresistant VISA VRSA (PBP2a inhibition )
2 No Enterococci
3 less activity against gram-ve (as ceftriaxone)bull Not ESBL-producing Enterobacteriaceae
bull Not Pseudomonas aeruginosa
bull Not Acinetobacter baumanii
bull Not Bacteroides fragilis
bull FDA (2010) and European Medical Agency (EMA) (2012) for
1 SSSIs including MRSA
2 CAP including MDR S pneumoniaBassetti M Springer 2015
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
B-lactam ampB-lactamase inhibitor
1 Tazobactam Ceftozolanetazobactam
2 Avibactam Ceftazidimeavibactam
3 MK-7655
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins
Class A -bull penicillinasesbull ESBLbull Carbapenemases
Class C ndash Amp C enzymes ndash not inhibited by clavulanic acid
Class D ndash Oxacillinases some are carbapenemases
Class B ndash Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by clavulanic acid
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Ceftozolanetazobactam
bull Superior to ceftazidime in
1 Greater gram ndashve coverage bull Most ESBL producing enterobactracae
bull Bacteroides spp
2 Unique anti-Psuedomonalbull superior to ceftazidime carbapenem piperacillintazobactam
bull ability to escape various resistance mechanisms (eg PBP mutations efflux pumps)
bull Not to carbapemenases or metallo-B-lactamases (MBL)
bull Trial (Phase 3)
1 Complicated intrabdominal infections (as meropenem) cIAI
2 Complicated UTI (superior to levofloxacin) ldquocUTIrdquo
3 Ongoing for HAPVAPZhanelGG Springer 2013
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
New B-lactamases inhibitors
bull Avibactambull beta-lactamase inhibitor characterized by
bull high affinity with class A and C and some D B-lactamasesbull potential to inhibit ESBLs KPCs OXA and AmpC
bull Combinations
1 with ceftazidime (Phase 3)
2 with ceftaroline (Phase 1)
3 With aztreonam (phase 1)
bull MK-7655 another novel beta-lactamase inhibitor under investigation
bull activity against class A and class C carbapenemasesbull Ongoing phase 2 trials for cIAIs and cUTIs (with imipenemcilastatin)
bull BLI-489 inhibit Class ACD lactamases (with piperacillin)
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Ceftazidimeavibactam
bull Active against
1 ESBL
2 AmpC strains
3 OXA-48 and Klebsiella carbamases (KPC)
4 MDR psuedomonas
bull not metallo-beta-lactamase not likely Acinetobacter
bull Trials
1 Phase 3 in cIAIs cUTIs HAP and VAP
2 cIAIs (as to meropenem) in combination with metronidazole
Sharma R Clin Ther 2016
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe PseudAcinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti M Springer 2015
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Clinical indications
Carbapenem Clinical indications
Meropenemimpinem HAP cUTIs cIAIs and BSI FDA
Doripenem
05 G8 hr
pyelonephritis cUTI and cIAI
HAPVAP
FDA
EMA
doripenem + colisitin colistin-resistant carbapenemase
producing K pneumoniae (KPC)
RCT
Tebipenempivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenembetamipron
05g12 hr
UTIs lower RTI
obstetricalgynaecological and
surgical infections
FDA China Korea
Japan
Biapenem 03g12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP RCT
Razupenem cSSSI RCT
Bassetti M Springer 2015
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
AB
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G Expert Opin Investig Drugs 2010
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Clinical indications
bull Telavancin has good penetration in the alveolar macrophages and unlike daptomycin its activity is not affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP EMA
S aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA MRSA Strep amp E faecalis FDA
dalbavancin SSSI including those caused by MRSA
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G Expert Opin Investig Drugs 2010
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Oxazolidinones
Tedizolidbull oral and IV
bull superior than linezolid
1 Staphylococcus spp
2 Streptococcus spp
3 Enterococcus spp
4 Anaerobes
bull once daily
bull Better safety profile bull No hematological Side effects
bull does not inhibit the monoamine oxidase pathway
bull FDA approved for SSSI
Radezolid
bull higher efficacy than linezolid
1 S pneumoniae S pyogenes
2 Staphylococci
3 Enterococci
4 GNR H influenzae amp Moraxellacatarrhalis (commonly in CAP)
bull Phase 2 trial uncomplicated SSSI CAP
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
QuinolonesGram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
Delafloxacin ++++ ++++ +++ + -
Nemonoxacin ++++ ++++ +++ + ++
Zabofloxacin ++++ ++++ +++ +
Finafloxacin +++ ++++ +
JNJ-Q2 ++++ ++++ +++ - - _
WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
Low potential for development of resistance due to multiple mechanisms of action
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Clinical indications
Quinolones RTIs UTIs SSSI and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA
EMA
Delafloxacin CAP (oraliv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oraliv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Plazomicin
bull new aminoglycoside against both gram-positive and gram negative pathogens
1 In combination bull against MRSA and VISA with daptomycin ceftobiprole
bull against P aeruginosa with doripenem imipenem piperacillintazobactam cefepime
2 cUTI and acute pielonephritisbull Phase 2 study (As to levofloxacin)
3 BSI or HAI due to carbapenem-resistant Enterobacteriaceaebull Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Glycylcyclines (new Tetracyclines)
Eravacyclinebull Broad-spectrum gram-
positive and gram-negative against
1 MRSA VRE
2 Enterobacteriaceae(ESBL or carbapenemases) more than tigecycline
3 Not P aeruginosa
bull Phase 3 clinical trials for cIAIs and cUTIs
Omadacycline
bull Active against both gram positive and gram-negative bacteria
1 MRSA VRE S pneumonia
2 Enterobacteriaceae amp Bacteroides fragilis
bull Phase 2 study in SSSI
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Other classes
bull Macrolides
1 Telithromycin bull FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2 Cethromycinbull very potent against macrolide-resistant strep and enterococci
bull More potent against S aureusepidermidis H pylori M avium Corynebacterium spp M pneumoniae C trachomatis and pneumoniae Borrelia burgdorferi H influenzae M catarrhalis and Toxoplasma gondii
bull Phase 2 trial for mild to moderate CAP
bull Trimethoprim Iclaprim bull MRSA VISA MDR S pneumonia
bull GNB Enterobacter Salmonella L pneumophila H influenzae C pneumoniae
bull Phase 3 trial for cSSSI
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Other classes
bull NXL103 bull mixture of modified quinupristindalfopristin
ampstreptogramin
bull More effective against gram positive than other antibiotics (MRSA VRSA VRE S pnuemonia H influenza
bull Oral formulation
bull Nitazoxanide (Nidazodereg)bull broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
bull FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children
bull off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Conclusions
Only 7 new antibiotics has been approved by US FDA
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Bassetti M Springer 2015
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Bassetti M Springer 2015
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Take home message
bull Still limited therapeutic options forbull Carbapenemase producing Enterobacteriaceae
bull XDR A baumannii and P aeruginosa
bull No good evidence but may bebull ceftozolanetazobactam
bull new carbapenems
bull combination of avibactam with B-lactam
bull New tetracylines
bull plazomicin in combination
bull Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Proper usage of antibiotics
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Phases of antibiotic development
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Antibiotic Abuse in Our units 2013
570
430
Antibiotic Abuse in ICU1
No
Yes 607
393
Antibiotic Abuse in ICU3
No
Yes
Alexandria Critical Care Department
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Types of antibiotic abuse 2013
275
45
114
06
39
22
51
70
1140
30
140
10
570
1290
00 100 200 300 400 500 600 700 800
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage hellip
ICU1
ICU3
Alexandria Critical Care Department
Thank you
Thank you
Related Documents
