Carbapenemase 2011
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Transcript of Carbapenemase 2011
The emerging threat posed by carbapenemase producing
enterobacteria &
how to address it
Dr. Ashok Rattan
Fortis Clinical Research Ltd.
Thienamycin
Streptomyces cattleya
Imipenem cilastatin
Meropenem Ertapenem Doripenem
+In 1 : 1 ratio
Spectrum of activity
• Broad spectrum activity– GPC & GNB– Aerobic & Anaerobic bacteria– Active against MDR isolates– Active against ESBL +ve GNB– Active against DRSP– Active against Ps aeruginosa & Acinetobacter spp.
• Not active against– MRSA– Entrococcus spp. – Stenotrophomonas maltophilia
Pramod M. Shah & Robin D. Isaacs Classification– Group 1: Broad spectrum for Community acquired infections
• Ertapenem
– Group 2: Broad spectrum for hospital acquired infections• Imipenem• Meropenem• Doripenem
– Group 3: MRSA active• Nil at present
Journal of Antimicrobial Chemotherapy (2003) 52, 538–542
Clinical Uses• Imipenem
– Lower Respiratory Tract infection– Urinary Tract Infection (uncomplicated or complicated)– Intra abdominal infection– Gynaecological infection– Bacterial septicemia– Bone & joint infection– Skin & soft tissue infection– Endocarditis– Polymicrobial infections
• Meropenem– Skin & soft tissue infection– Intra abdominal infection– Bacterial meningitis
• Ertapenem– Community acquired pneumonia requiring hospitalization
Carabpenemases: a problem in waiting ?David M Livermore & Neil Woodford
Current Opinion in Microbiology 2000; 3: 489 - 495
Natural resistance
Acquired resistance
Bush 2010 : Distribution of β lactamases according to function
Most Carbapenemases can HydrolyzeALL
Beta lactam antibiotics
Carbapenemases
• The most versatile family of -lactamases
• Two major groups based on the hydrolytic mechanism at the active site– Serine at the active site: class A and D– Zinc at the active site : class B
• All carbapenemases hydrolyze penicillins, extended spectrum cephalosporins, and carbapenems
Classification
Molecular Class
A B D
Functional Group
2f 3 2d
Active site Serine Zn++ Serine
Aztreonam Hydrolysis
+ - -
EDTA Inhibition
- + -
APBA Inhibition
+ - -
Mechanism of Resistance to Carbapenem
1. Cephalosporinase : Amp C & CTX- M+ Porin mutation = low level
resistance2. Carbapenemase: β lactamases that can hydrolyze carbapenem
Amber Class A: 9 familiesKPC, SME, NMC-A, IMI, PER, GES, SFO,
SFC, IBCAmber Class B: 6 families VIM, GIM, SIM, NDM, IMP, SPM
Amber Class D: 2 families OXA, PSE
Enzyme Ambler Class
Country Spectrum of activity Organisms
GESGuiana Extended spectrum
A French Guiana
Imipenem & extended spectrum cephalosporins
Ps.
SMESerratia marcesance enzyme
A USA Carbapenem, aztreonam but not 3rd gen cephalosporins
Serratia marcescens
NMC – A, IMINon metallo carbapenamse
A Europe Carbapenem, aztreonam but not 3rd gen cephalosporins
Enterobacter spp
KPCKleb pn. carbapenamase
A USA All β lactams Kleb. pneumoniae
OXA Oxacillin hydrolysing
D Scotland Carbapenems (weak) Acinetobacter, Ps.
Serine β lactamases:
Enzyme Ambler Class
Country Spectrum of activity Organisms
IMP (18)Imipenem Japan
B Japan All β lactams Ps., Acinetobacter
VIM (12)Verona
B Italy Pan R, may be S to aztreonam
Ps. , Acinetobacter
SPMSao Paulo
B Brazil Pan R Ps
GIM German
B Germany Pan R Ps.
SIM Souel
B South Korea
Pan R Acinetobacter, Ps.
NDM New Delhi
B India, UK Pan R Kleb pneu, E. coli
Metallo β lactamases (Zn at active site)
Lancet Infect Dis 2010; 10: 597–602 Published Online August 11, 2010
1985 1986 1990 1995 2000 2008 2010
Imipenem launched
Chromosomal R in Ps
IMP in Japan
VIM in Verona
KPC in USA
March of Carbapenemases
NDM 1
Clinical Microbiology and Infection, Volume 16 Number 12, December 2010
Castanheira M et al: Anti Agents Chem 2010SENTRY Program
Out of 39 strains collected from India in 200615 strains had NDM 1
10 strains carried OXA 48 variant2 strains carried VIM 6Multiple PFGE patterns
Location of BlaKPC gene
Why is CRE a public health emergency ?
• Significantly limits treatment options for life threatening infections
• No new drug for GNB in the pipeline
• Resistant mechanism easily transferable as it in now on a transposon
• Rapid Detection & effective infection control measures essential to control spread
Why is CRE spreading ?
• Resistance mechanism of a transposon
• Suboptimal methods of laboratory detection of isolates, large reservoir
• Continued antibiotic selection pressure
• Inadequate or incomplete institution of infection control measures
Who is infected with CRE ?
• Hospitalized patients with– Increased number of co morbid conditions– Frequent & prolonged hospitalization– Invasive devises– Antimicrobial selective pressure
• Previous Carbapenem use• Previous Metronidazole use
– CRE most frequently isolated in surgical wards from surgical drainage, bile , blood or urine
Recommendations for control
• Surveillance
• Infection control
• Laboratory detection
Surveillance
• Is CRE present in your facility ?– Review microbiology data for 6 to 12 months– If no,
• Conduct a point prevalence survey– Single round of AST in high risk patients
– If yes• Conduct AST on patients with epidemiological link
to CRE case
• Goal:– Identify undetected carriers of CRE
Infection ControlCDC’s recommendations
• Goal: Institute contact precautions to prevent patient to patient transmission
• Contact isolation– Disposable gloves & gowns available at each bedside– Alcohol based hand rub available & used– Environmental surfaces cleaned daily with aerosolized foam
quaternary ammonium compound– Disposable antibacterial wipes containing isopropanol &
quaternary ammonium compound for cleaning patient related items at least once a day
• Infection control team participated in daily round• Rectal swabs on admission & weekly
Infection control: add onsKochar S et al. Infect control & Hosp Epidemiol 2009; 30: 447 - 452
• ICU extensively cleaned: environment & pt care items• For All pts. culture positive for CRE,
– a copy of antibiogram placed in bedside records– Moved & gathered at one end of ICU– Nursing personnel also grouped
• Free standing dispensers for alcohol based hand rub available at bedside
• Disposable antibacterial wipes to clean environment at beginning of 12 hour shift and SOS
Laboratory DetectionClinical and Laboratory Standards Institute breakpoints: 2009 & 2010
Revised Break Points 2010
Agent MIC breakpoint (ug/ml) DD breakpoints (mm)
S MHT I R S MHT I R
IPM < 1
< 1
2-4 8
2
>16
>4
>16
>23
NA 14-15
20-22
<13
<19
MEM < 1
< 1
2-4 8
2
>16
>4
>22 >23
16-21 14-15 20-22
<13 <19
ERT < 1
< 0.25
2 4
0.5
>8
>1
> 22 >23
19-21 16-18 20-22
<15 <19
Screening for CRE
Screening for CRE carriage
Sample Select Differentiate TSB + carbapenem disk
CHROMagarESBL & KPC
Panagea T et al : Evaluation of CHROMagarTM KPC for the detection of carbapenemase-producing Enterobacteriaceae in rectal surveillance cultures.International JournalofAntimicrobialAgents xxx (2010) xxx–xxx
Randall LP et al: Evaluation of CHROMagar CTX, a novel medium for isolating CTX-M-ESBL-positive Enterobacteriaceae while inhibiting AmpC-producing strains. Journal of Antimicrobial Chemotherapy (2009) 63, 302–308
Test for Carbapenemase DetectionAnderson KF et al. Evaluation of methods to identify KPC in
enterobacteriaceae. JCM 2007; 45: 2723 – 2725.
Modified Hodge Test (MHT)
Carbapenem Inactivation Assay
Carbapenem Disk
Susceptible E. coli
Test Isolate
Double DiskPicao RC et al: MBL detection: Double Disk Synergy vs Combined Disk.
JCM 2008; 46: 2028 - 2037
Combined DiskDoi Y et al. Single disk method for detecting KPC by use of a
Boronic acid compound. JCM 2008; 46: 4083 - 4086
E testWalsh T et al. Evaluation of a new Etest for detecting MLB in routine
clinical testing. JCM 2002; 40: 2755 - 2759
Pasteran F et al. Controlling false positive results in MHT.. JCM 2010; 48: 1323 - 1332
Pasteran F et al. Controlling false positive results in MHT.. JCM 2010; 48: 1323 - 1332
Pasteran F et al. Controlling false positive results in MHT.. JCM 2010; 48: 1323 - 1332
False Positive
MASUDA ASSAY
Phenotypic Detection
Enzyme Inhibited by Cloxacillin Boronic acid EDTA/DPA
ESBL N N N
Amp C Y Y N
KPC N Y N
MBL N N Y
OXA N N N
Sensitivity & specificity of phenotypic methods
Test β lactamase Sensitivity Specificity
APBA KPC 100 98
APBA+
CLX
Amp C 80 100
DPA MBL 100 100
EDTA MBL 100 80
Modified Hodge
Carbapenemase 100 77
Genotypic detection of CREMendes RE et al: RT PCR for MBL
JCM 2007; 45: 544 - 547
Naaz T et al: Evaluation of a DNA Microarray, the Check-Points ESBL/KPC Array, for Rapid Detection of TEM, SHV, and CTX-M Extended-Spectrum β-Lactamases and KPC Carbapenemases. Anti Agents Chemother 2010; 54: 3086 - 3092
Detecting CRE
• Clinical CRE is tip of iceberg
• Asymptomatic carriage is common (faecal)
• Active Surveillance Test would help identify carriage
• Institution of contact precautions & monitoring of pt to pt transmission within ICU
• AST: When pt is transferred in from other hospitals
• AST: ? On discharge (medical tourism)
Guideline for phenotypic screening and confirmation of carbapenemasesin Enterobacteriaceae 2010Dutch Working Party on the Detection of Highly Resistant Microorganisms
Clinical isolates
Algorithm for disk diffusion synergy tests to detectCarbapenem Non Susceptible Enterobacteriaceae
APBA = aminophenyl boronic acid (β lactamase inhibitor)DPA = dipicolinic acid (metal chelating agent)
Epidemiological scale & stage of nationwide expansion of CNSE
Areas of Improvement
1. Ad hoc care ascertainment with existing laboratory capacity2. Standardization of detection & reporting3. Need for consistent capacity building of reference diagnostics4. Need for structured surveys to determine sensitivity & specificity of break points5. Need for harmonized typing tool/initiative6. Need for control data collection on dissemination & introduction of strains of public health importance7. Need for guidelines for graded approaches to infection control8. Antibiotic policy9. Treatment and clinical research10. Political commitment
Carry Home messages
• Carbapenemases in Enterobacteriaceae compromise our ability to effectively treat life threatening infections
• Pt to pt transmission can be halted by application of strict infection control measures
• Laboratory identification of infection or carriage must be paired with rapid implementation of Infection control interventions
• Ongoing Surveillance is essential
• Laboratory can help preserve Carbapenem antibiotics as very important resource for life threatening infections
• Susceptibility to Carbapenem must be determined accurately in the laboratory:– Wild type– ESBL producers– ESBL + omp mutation– CRE
Would respond to treatment withA carbapenem
We may not be able to stop the emergence of Super bugs
but we CAN