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PROFESSOR PETER M. HAWKEY
Health Protection Agency West Midlands Public Health Laboratory, Heart of England
NHS Foundation Trust, B5 9SS
The University of BirminghamEdgbaston, B15 2TT
[email protected] ;[email protected]
Treatment Options for Multiple Resistant Gram Negative
Infections
BSAC Spring MeetingTuesday 7th April 2009
International Convention Centre, Birmingham
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Some antibiotic resistance genes that threaten treatment of Gram -ve infections
“Mobile” ampC
Carbapenemases blaOXA blaKPC blaIMP / blaVIM
ESBL’s blaCTX-M blaSHV / blaTEM / blaPER
“Intrinisically resistance bacteria”
Acinetobacter / Pseudomonas / Stenotrophomonas
Topoisomerase mutants (gyrA / parC)
Plasmid borne quinolone resistance (qnr/aac6’-cr)
Efflux genesAminoglycoside inactivating enzymes
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Effect of genetic location of resistance genes
• CHROMOSOMAL – All isolates carry resistance most will express depending on expression controle.g.
• L1/L2 β-lactamase Stenotrophomonas maltophilia • AmpC β-lactamase in Enterobacter spp.
• ACQUIRED – variable rates of carriage, commonly gives multiple resistancee.g.
• CTX-M, KPC, TEM plasmid mediated β-lactamases• AAC – 6’ – cr, APH3’ aminoglyside inactivating
enzymes
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Meta-analysis of mortality in ESBL-producing versus non-ESBL-producing Enterobacteriaceae bacteraemia
Schwaber & Carmelli, 2007, J Antimicrob Chemother, 60: 913-20
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Meta-analysis of delay in effective therapy in in ESBL-producing versus non-ESBL-producing Enterobacteriaceae bacteraemia
Schwaber & Carmelli, 2007, J Antimicrob Chemother, 60: 913-20
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Mortality rates (21 day) in 97 ESBL-BSI patients treated with antimicrobial agents to which the infecting organism displayed in vitro susceptibility
Tumbarello, M., 2007, Antimicrob Agents Chemother 51: 1987-94
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Use of cephalosporins to treat ESBL in China - but all CTX-M 14/3 no OXA-1 so....
22 cases of bacteremia Survival %
ceftazidime (7) 86imipenem/cilastatin (8) 86cefoperazone/sulbactam (7) 72
Cao, et al, Diag. Micro. & ID (2006) 56:351-7
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Things are bad quite close to home....
A. baumannii bacteremiaGreece 83%, Spain 48% (ImiR)
Klebsiella sppGreece 46% (ImiR) 58% (Quin) 63% (3GC)
Pseudomonas aeruginosa Greece 51% (ImiR)
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CARBAPENEM ANTIBIOTICS...
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Resistance mechanisms to carbapenems
• Intrinsic carbapenemases L1 • Loss of porin D2• Efflux pumps MexEF-OprN,MexXY • Class A&D KPC-2, OXA-23,OXA-46• Class B carbapenemase IMP,VIM
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C.youngae(01) IMP-4 P.aeruginosa (01) IMP-9
K.pneumoniae(00) IMP-5, 8 P.aeruginosa(00) VIM-2,3
P.aeruginosa(01) IMP-7
K.pneumoniae (00) IMP-1 P.aeruginosa (01) OXA-27 P.pudita (02) VIM-6
Acinetobacter(00) IMP-4
>12 species (91-) IMP-1,3,6,10,11
Pseudomonas(01) VIM-1
P.aeruginosa(02) OXA-23
Pseudomonas (01) S.marcesence(01) VIM-2
P.aeruginosa(02) GES-2
P.aeruginosa (02) IMP-7
S.marcesence(82) SME-1
E.cloacae(84) IMI-1
S.marcesence(00) SME-2,3
P.aeruginosa (00-01) IMP-2 VIM-1,2, 5
Acinetobacter(01) IMP-1, OXA-27
K.pneumoniae(01) KPC-1/2
Acinetobacter(00) IMP-5
P.aeruginosa (01-02) VIM-2, VIM-4
Acinetobacter (00-02) OXA-24, 25,40
Acinetobacter (01) OXA-26
Global spread of carbapenem resistance
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Endemic KPC Sporadic cases of KPC
Distribution of KPC in 2009
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Temocillin
Matagne, et al, Biochem 1993, 293, 607-11
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Temocillin• Developed and marketed by Beechams in
1980’s• 6 x methoxy derivative of ticarcillin → +++ β-
lactamase stability• Stable to serine activated β-lactamase e.g.
CTX-M, TEM, SHV, ESBLs• No selection for depressed AmpC production• Probably little C. difficile selection• Burkholderia cepacia susceptible (mode MIC
32 mg/L)
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But....
• Withdrawn because of low sales• Temocillin has no activity against
Pseudomonas anaerobes or Gram positive bacteria
• Better with continuous infusion – serum levels ≥ 16 mg/L
• Most experience in UTI, but also BelgiumVAP (non Pseudomonas spp)
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Effect of temocillin against KPC producing bacteria from 2 states in USA
MIC Temocillin mg/L
8 16 32 64 1281 x 104 K. pneumoniae (30) 12 15 3
E. coli (3) 1 21 x 106 K. pneumoniae (30) 1 3 15 10 1
E. coli (3) 1 1 1
Adams-Haduch, et al, AAC (2009) epub 30th March
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Tetracyclines
•Discovered by Benjamin Duggar in 1945 (aureomycin)
•Produced by Streptomyces aureofaciens
•Inhibitors of protein synthesis
•Bacteriostatic antibacterial activity
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Tigecycline: Glycylcycline Class
NH2
O
OH
OO OHOH
N
N(CH3)2
OH
N
O
H
N(CH3)2
H3C
H3C
CH3
H9
87
Tigecycline
•Developed to evade the classic mechanisms of resistance
•Inhibitor of protein synthesis
•Generally bacteriostatic
•Binds with 5x greater avidity
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Tygacil binding to 30S subunitComparison of Tetracycline and Tigecycline docking
tetracyclinetetracycline
tigecyclinetigecycline
Side chain results in 5x increase in binding strength
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Tetracycline blocked from binding
Tetracycline pumped out of cell
Tigecycline is still able to bind to ribosome
Tigecycline cannot be pumped out of cell
Ribosomal protection
Efflux Pump Protection
Efflux pump
Efflux pump
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Tigecycline is Active Against a Broad Spectrum of Clinically Relevant Pathogens
• Escherichia coli• Klebsiella pneumoniae• Klebsiella oxytoca• Citrobacter freundii• Citrobacter diversus• Enterobacter cloacae• Enterobacter aerogenes• Salmonella spp.
• Shigella spp.• Stenotrophomonas
maltophilia• Acinetobacter baumannii• Haemophilus influenzae• Moraxella catarrhalis• Neisseria gonorrhoeae• Eikenella corrodens• Pasteurella multocida
Gram-Negative
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Comparative in vitro activity of tigecycline andβ-lactam antimicrobials against A.baumanii (USA)
0.004
0.015
0.06
0.25 1 4
16 6425
6
020406080
100
Tigecycline
Ampicillin
Amox/ClavPip/Taz
Ceftazidime Ceftriaxone
Cefepime
MIC (mg/L)
% ofisolates
n=762
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Comparative in vitro activity of tigecycline andβ-lactam antimicrobials against Multidrug-Resistant Acinetobacter spp. (USA)
0.004
0.015
0.06
0.25 1 4
16 6425
6
020406080
100
TigecyclineAmpicillin
Amox/ClavPip/Taz
Ceftazidime
Ceftriaxone
Cefepime
MIC (mg/L)
% ofisolates
n=42
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Tigecycline for Acinetobacterspp infections review
• 22 microbiological studies of 2,384 isolates (1906 Acb)
• 90% susceptibility (MIC ≤ 2mg/L)• Efficacy 42 severely ill patients (31 resp.
Infections, 8 bacteremia)• Tigecycline used in combination in 28/42
patients – effective in 32/42
Karageorgopoulos, et al, JAC (2008); 62:45-55
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Resistance to tigecycline
• No resistance reported for MRSA• Acinetobacter baumannii upregulation of
RND pump AdeABC important1
• Pseudomonas aeruginosa MexXY-OprM• Enterobacteriacae AcrAB2
1AAC (2007)51:2065-92CMI(2006)13:354-62
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Polymyxins (A-E) – Colistin (A-B)• Mixtures of cyclic peptides –
colistimethate for i.v. use.• Variation in potency of different
preparations, hydrolysed to colistin variably in patient.
• Colomycin (Forest Labs) 240-480 mg colistimethate/day (Usually 2 doses)
• Renal toxicity seen particularly if prior damage,neurotox as well.
Landman, et al, Clin Micro Revs (2008) 21: 449-65
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Colistin mode of action
• Cationic agent that binds to anionic components of outer membrane e.g. peptidoglycan- displaces Mg++/Ca++
leading to membrane leakage• Moct GNB sensitive except
Proteus/Providencia Burkholderia cepacia & Chromobacterium
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Resistance to colistin• Resistance in Proteus due to linkage of 4’-
PO4++ with 4-amino-4deoxy-L-
arabinopyranosea in Lipid A leads to reduced binding(also seen in other species with acquired resistance)
• Genetically stable resistance in Pseudomonas due to extra OMP H1, ? Replaces divalent cations in outer membrane
aSidorczyk et al.Eur.J. Microbiol.137:15-22
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Colistin resistant K. pneumoniae in Greek ICUs
• Heavy empirical use of colistin• 18 isolates from 13 patients over 16/12• Long stay (median: 69 days),
Old (mean: 70 yrs)Long course colistin (median: 27 days)
• 2 bacteraemia, 1 VAP, 2 cSSTI
Antoniadou, et al, JAC (2007) 59: 786-90
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Sulbactam
• Has intrinsic activity against A. baumannii
• Early studies showed high rates of susceptibility a- declined recently b
• Has been used in pneumonia with moderate effect
a CID (1996) 22:1026b JAC (2007) 59:583
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Odds & Sods
Nitrofuratonin FosfomycinAmikacinMecillinam (± clavulanic acid)
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Future Approaches• Trinem (Tricyclic carbapenem) – most
discontinued but LK-157 structureal analogue.• Inhibits Class A & C β-lactamase but not
stable to carbapenemases.
LK-157
Paukner, et al, AAC (2009) 505-11
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NXL 104 - Novexel
• Non – β‐lactamase inhibitor of serine activated Ambler class A enzymes e.g. CTX‐M, KPC, OXA‐48
• Could be combined with ceftazidime for specific GNB cover or ceftaroline for broad spectrum activity (including MRSA) or a monobactam for cabapenemase producers
Livermore, et al, JAC 2008, 62, 1053-56
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Beta-lactamase bingo cardAmp Pip/
TazCRD CXN CTX CPM AZT IMI
A TEM1/SHV1 R S R S S S S STEM3/CTX-M R S R R R R R S
A CMY/FOXKPC
RR
RS
RR
RR
RR
RR
RR
SR
B(Zn++)
VIM/IMP R R R R R R S R
C Chromosomal (hyperproducer)
R R R R R S R S
D OXAOXA (carbapenemase)
RR
RR
RR
RR
SS
SS
SS
SR
e.g. AcinetobacterOXA-23, OXA-51