Emerging Antimicrobial Resistance in Texas

Emerging Antimicrobial Emerging Antimicrobial Resistance in TexasResistance in Texas

The The newnew ESBLs ESBLs

Most Important Most Important Emerging ResistanceEmerging Resistance

MRSA in the communityMRSA in the community Resistance to alternative drugs Resistance to alternative drugs for MRSA, including vancomycinfor MRSA, including vancomycin

Re-emergence of DRSPRe-emergence of DRSP ESBL in various gram-negative ESBL in various gram-negative speciesspecies

Carbapenemases in various GNsCarbapenemases in various GNs Multi-drug resistance in Multi-drug resistance in PseudomonasPseudomonas, enterics, , enterics, AcinetobacterAcinetobacter, , S. maltophiliaS. maltophilia

To Review ESBL To Review ESBL background……background……

Extended Spectrum Beta-Extended Spectrum Beta-LactamasesLactamases

MostMost ESBL - mutations of TEM or SHV ESBL - mutations of TEM or SHV plasmid-mediated enzymes normally plasmid-mediated enzymes normally found in found in E. coli E. coli and and KlebsiellaKlebsiella

Now TEM-1 to 161, SHV-1 to 105 Now TEM-1 to 161, SHV-1 to 105 (as (as of 3-20-08) - of 3-20-08) - Source: Source: www.lahey.org/studies/webt.aspwww.lahey.org/studies/webt.asp

Differences in substrate specificity Differences in substrate specificity -especially ceftaz vs. cefotax-especially ceftaz vs. cefotax

Hydrolyze 3rd and 4th gen cephs and Hydrolyze 3rd and 4th gen cephs and aztreonam at high bacterial inoculumaztreonam at high bacterial inoculum

EnzymeEnzyme Ceftaz Ceftaz Amino Acid Amino Acid PositionPosition

MICMIC 104104 164164240240

TEM-1TEM-1 0.12 0.12 GluGlu ArgArgGluGlu

TEM-10TEM-10 > 256 > 256 GluGlu SerSerLysLys

TEM-12TEM-12 16 16 GluGlu SerSerGluGlu

TEM-26TEM-26 256 256 LysLys SerSerGluGlu

from: Jacoby, IDCNA 11:875, 1997from: Jacoby, IDCNA 11:875, 1997

Molecular Basis of Molecular Basis of ESBLsESBLs

Different Substrate Different Substrate Affinities of ESBLAffinities of ESBL

EnzymeEnzyme MICs MICs

CeftazCeftaz Cefotax Cefotax AztreoAztreo

TEM-1TEM-1 0.12 0.12 0.060.06 0.120.12

TEM-10TEM-10 > 256> 256 1 1 128128

TEM-12TEM-12 16 16 0.120.12 11

TEM-26TEM-26 256 256 0.50.5 64 64 from: Jacoby, IDCNA 11:875, 1997from: Jacoby, IDCNA 11:875, 1997

Inoculum Effect with ESBLs Inoculum Effect with ESBLs - MICs with SHV-3 producing - MICs with SHV-3 producing

C. freundiiC. freundii InoculumInoculum

101055 101077

CefotaximeCefotaxime 22 256256

CeftazidimeCeftazidime 11 32 32

CefepimeCefepime 0.50.5 >128>128

MeropenemMeropenem 0.060.06 0.060.06Thomson, AAC45:3548, 2001Thomson, AAC45:3548, 2001

Clinical Significance Clinical Significance of ESBLsof ESBLs

Global bacteremia studyGlobal bacteremia study in ‘96 and in ‘96 and ‘97‘97- 455 455 K. pneumoniaeK. pneumoniae- 18.7% (85) produced ESBLs18.7% (85) produced ESBLs- 9 treated with a cephalosporin that 9 treated with a cephalosporin that was CLSI Susceptible or Intermediatewas CLSI Susceptible or Intermediate

- 3 died, 5 required Rx change3 died, 5 required Rx change Overall, 32 pts. Rx with a ceph Overall, 32 pts. Rx with a ceph (S or I)(S or I)- 4/4 I’s failed; 15/28 S’s failed4/4 I’s failed; 15/28 S’s failed- 4/5 treated with cefepime failed4/5 treated with cefepime failed

D. D. Paterson, JCM 2001Paterson, JCM 2001

Two Step Process of Two Step Process of Detection and Detection and

Confirmation of ESBLsConfirmation of ESBLs Test “indicator” drugs with Test “indicator” drugs with special “screening” breakpointsspecial “screening” breakpoints- cefpodoxime or look for elevated cefpodoxime or look for elevated MICs of ceph 3sMICs of ceph 3s

Must confirm with clavulanate Must confirm with clavulanate combos of cefotaxime and combos of cefotaxime and ceftazidime by MIC or diskceftazidime by MIC or disk

Report as ESBL if either Report as ESBL if either clavulanate combo is positiveclavulanate combo is positive

Laboratory Reporting Laboratory Reporting of ESBL-Producing of ESBL-Producing

IsolatesIsolates ““Expertize” results to Expertize” results to resistant for all penicillins, resistant for all penicillins, aztreonam, and “true aztreonam, and “true cephalosporins” irrespective cephalosporins” irrespective of individual test results of individual test results and/orand/or

Provide a warning comment that Provide a warning comment that ESBL-producers should be ESBL-producers should be considered clinically considered clinically resistant to all penicillins, resistant to all penicillins, cephalosporins, and aztreonamcephalosporins, and aztreonam

Gram-Negative Species Gram-Negative Species Known to Harbor ESBLKnown to Harbor ESBL

Klebsiella pneumoniaeKlebsiella pneumoniae Klebsiella oxytocaKlebsiella oxytoca E. coliE. coli Proteus mirabilisProteus mirabilis SalmonellaSalmonella spp. spp. Also in Also in CitrobacterCitrobacter, , EnterobacterEnterobacter, , SerratiaSerratia, , MorganellaMorganella, , P. aeruginosa, P. aeruginosa, AcinetobacterAcinetobacter

AmpC Beta-LactamaseAmpC Beta-Lactamase

ampC gene is present in all ampC gene is present in all Enterobacter, Citrobacter freundii, Enterobacter, Citrobacter freundii, Morganella morganii, P. aeruginosaMorganella morganii, P. aeruginosa

Selection of resistant mutants Selection of resistant mutants with “up-regulated” production of with “up-regulated” production of ampC during therapyampC during therapy- Resistance to all cephs except cefepimeResistance to all cephs except cefepime

ampC can be plasmid-mediated in ampC can be plasmid-mediated in some some E. coliE. coli and and K. pneumoniaeK. pneumoniae

– Jacoby and Munoz-Price, NEJM 352:380, 2005Jacoby and Munoz-Price, NEJM 352:380, 2005

ESBL vs. AmpCESBL vs. AmpC

ESBLESBL Spectrum “extended” Spectrum “extended” from parent enzymefrom parent enzyme

Susceptible to Susceptible to cefotetancefotetan

Inhibited by Inhibited by clavulanateclavulanate

Can hydrolyze Can hydrolyze cefepime at high cefepime at high inoculuminoculum

Carbapenem Carbapenem susceptiblesusceptible

ampCampC Spectrum not Spectrum not “extended,” although “extended,” although may be basal or may be basal or hyperproducing levelhyperproducing level

Resistant to Resistant to cefotetancefotetan

Not inhibited by Not inhibited by clavclav

Hydrolyzes cefepime Hydrolyzes cefepime poorlypoorly

Carbapenem susceptCarbapenem suscept

ESBL That Are ESBL That Are NotNot Derived From TEM or Derived From TEM or

SHVSHV CTX-MCTX-M-1 thru 69 - hydrolyze -1 thru 69 - hydrolyze cefotaxime better than cefotaxime better than ceftazidimeceftazidime- Derived from Derived from Kluyvera ascorbataKluyvera ascorbata- Most common ESBL in Latin America, Most common ESBL in Latin America, Japan, Eastern Europe, Japan, Eastern Europe, and U.S.?and U.S.?

OXA-1 thru 119 (~11 ESBL) OXA-1 thru 119 (~11 ESBL) - Mostly in Eastern EuropeMostly in Eastern Europe- Usually in Usually in P. aeruginosa P. aeruginosa oror AcinetobacterAcinetobacter

E. coliE. coli with with “Cefotaximase”“Cefotaximase”

P. mirabilisP. mirabilis with CTX- with CTX-M15M15

E. cloacaeE. cloacae with CTX-M15: with CTX-M15: Use of cefepime + Use of cefepime +

clavulanateclavulanate

Increasing Numbers of Increasing Numbers of ESBLsESBLs

Lewis, et al. AAC 51:4015, 2007

“First Report of the Emergence of CTX-M Type ESBLs as the Predominant ESBL Isolated in a U.S. Healthcare

System” Retrieved all frozen ESBL Retrieved all frozen ESBL isolates from 2000 - mid 2006isolates from 2000 - mid 2006- Standard CLSI ESBL screening and Standard CLSI ESBL screening and confirmatory tests used throughout confirmatory tests used throughout periodperiod

- Screening by cefpodoxime disk and Screening by cefpodoxime disk and Vitek 2Vitek 2

PCR and sequencing for TEM, PCR and sequencing for TEM, SHV, CTX-M (and OXA in some)SHV, CTX-M (and OXA in some)

Lewis, et al, AAC, November, Lewis, et al, AAC, November, 20072007

Emergence of CTX-M Emergence of CTX-M ESBLs in San AntonioESBLs in San Antonio

Have emerged as predominant ESBL over Have emerged as predominant ESBL over last 3 yearslast 3 years- %CTX-M in 2000-2002: 0-25%%CTX-M in 2000-2002: 0-25%- %CTX-M in 2003-2006: 60-89%%CTX-M in 2003-2006: 60-89%

CTX-M in CTX-M in E. coli, K. pneumoniae, K. E. coli, K. pneumoniae, K. oxytocaoxytoca, , P. mirabilisP. mirabilis, , EnterobacterEnterobacter spp., spp., M. morganiiM. morganii

Now predominantly CTX-M15 in Now predominantly CTX-M15 in E. coliE. coli, , often outpatient urines - 8% with 2nd ESBLoften outpatient urines - 8% with 2nd ESBL

86% fluoroquinolone resistant; 66% to SXT86% fluoroquinolone resistant; 66% to SXT• Lewis, et al, AAC 2007Lewis, et al, AAC 2007

Evolution of CTX-M Evolution of CTX-M ESBLsESBLs

From Lewis, et al, AAC 51:4015, 2007

ESBL Producers in 2007ESBL Producers in 2007

64% (48) of ESBL in 64% (48) of ESBL in E. coliE. coli; 15% (11) ; 15% (11) in in K. pneumoniaeK. pneumoniae, 9.3% (7) , 9.3% (7) K. oxytocaK. oxytoca, , 6.7% (5) 6.7% (5) Enterobacter, Enterobacter, 22 Serratia Serratia, 1 , 1 P. P. mirabilismirabilis, 1, 1C. koseriC. koseri

53% from urine; 22% from blood or BF53% from urine; 22% from blood or BF What are risk factors for OP What are risk factors for OP E coliE coli CTX-M UTI?CTX-M UTI?

When is a urine culture needed?When is a urine culture needed? What agents are available for therapy What agents are available for therapy of OP E. coli ESBL?of OP E. coli ESBL?

ESBL Producers in 2007ESBL Producers in 2007

64% (48) of ESBL in 64% (48) of ESBL in E. coliE. coli; 15% (11) ; 15% (11) in in K. pneumoniaeK. pneumoniae, 9.3% (7) , 9.3% (7) K. oxytocaK. oxytoca, , 6.7% (5) 6.7% (5) Enterobacter, Enterobacter, 22 Serratia Serratia, 1 , 1 P. P. mirabilismirabilis, 1, 1C. koseriC. koseri

53% from urine; 22% from blood or BF53% from urine; 22% from blood or BF What are risk factors for OP What are risk factors for OP E coliE coli CTX-M UTI?CTX-M UTI?

When is a urine culture needed?When is a urine culture needed? What agents are available for therapy What agents are available for therapy of OP E. coli ESBL?of OP E. coli ESBL?

Cefotaxime and Ceftazidime Cefotaxime and Ceftazidime Zones with Different Zones with Different

Species Producing CTX-M Species Producing CTX-M ESBLsESBLs

The Newest Mechanisms The Newest Mechanisms of Concern - of Concern -

CarbapenemasesCarbapenemases The alphabet soup of The alphabet soup of rapidly emerging rapidly emerging carbapenemases carbapenemases - KPCs 1-4KPCs 1-4- IMP 1-23IMP 1-23- VIM 1-18VIM 1-18- PER, SME, VEBPER, SME, VEB- Some OXA enzymesSome OXA enzymes

Source: Source: www.lahey.org/studies/webt.aspwww.lahey.org/studies/webt.asp

KPC CarbapenemasesKPC Carbapenemases

Plasmid-mediated - KPCs 1-4Plasmid-mediated - KPCs 1-4- KKlebsiella lebsiella ppneumoniaeneumoniae ccarbapenemasearbapenemase- Can hydrolyze all beta-lactams, including Can hydrolyze all beta-lactams, including carbapenemscarbapenems

- Often also resistant to FQs, SXT, Often also resistant to FQs, SXT, aminoglycosides - Suscept to colistin, aminoglycosides - Suscept to colistin, tigecyclinetigecycline

- Have rapidly spread in the Eastern U.S.Have rapidly spread in the Eastern U.S.- Difficult to detect by commercial or ref. Difficult to detect by commercial or ref. methodsmethods

- Are they in Texas??Are they in Texas??

How Do Labs Perform in How Do Labs Perform in Detection of KPCs?Detection of KPCs?

CAP sample DA-05, 2007 CAP sample DA-05, 2007 illustrated problems of detectionillustrated problems of detection- Partial or inconsistent clavulanate Partial or inconsistent clavulanate effect - like ESBLeffect - like ESBL

- Some commercial systems (and disks) Some commercial systems (and disks) had a high false susceptible rate had a high false susceptible rate with imipenemwith imipenem

- Meropenem also problematicMeropenem also problematic- Best detection by testing ertapenemBest detection by testing ertapenem- Ertapenem > meropenem > imipenemErtapenem > meropenem > imipenem

Detection of KPCsDetection of KPCs

Look for resistance to all Look for resistance to all penicillins and penicillins and cephalosporinscephalosporins

Look for carbapenem MICs > 1Look for carbapenem MICs > 1 Perform “modified Hodge Perform “modified Hodge test”test”

PCR using primers for all PCR using primers for all KPC, and sequence productKPC, and sequence product

Modified Hodge TestModified Hodge Test

Other Carbapenemases - Other Carbapenemases - Metallo-Beta-Metallo-Beta-LactamasesLactamases

Mostly found in Mostly found in P. aeruginosaP. aeruginosa - IMP, VIM, SIM, GIM, and SPMIMP, VIM, SIM, GIM, and SPM- Europe, Asia, S. America, N. America Europe, Asia, S. America, N. America (IMP, VIM)(IMP, VIM)

- Plasmid, chromosomal, or integronsPlasmid, chromosomal, or integrons P. aeruginosaP. aeruginosa with VIM-2 in CAP DA- with VIM-2 in CAP DA-01, 200701, 2007- Resistant to all carbapenems, cephs, pensResistant to all carbapenems, cephs, pens- Suscept. to aztreonam, pip-tazoSuscept. to aztreonam, pip-tazo- Colistin suceptibleColistin suceptible

Newer Beta-Lactamases Newer Beta-Lactamases are emerging in Texasare emerging in Texas

• • Labs must look for themLabs must look for them

• • Physicians must be Physicians must be aware of their existenceaware of their existence