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Recent Changes in Gram negative Resistance - Dr Steve Jenkins - November 2010 Symposium


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Presented by Dr. Jenkins at the 40th Annual Symposium "Diagnostic and Clinical Challenges of 20th Century Microbes", held on Nov 18, 2010 in Philadelphia.

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Recent Changes in Gram negative Resistance - Dr Steve Jenkins - November 2010 Symposium

  1. 1. Recent Changes in Gram-negative Resistance: Algorithms for Detection and Reporting of ESBL, AmpC, and KPC – producing Organisms Stephen G. Jenkins, Ph.D. Director, Clinical Microbiology Laboratories New York/Presbyterian Hospital Weill Cornell Medical Center Professor of Pathology and Laboratory Medicine Professor of Medicine in Infectious Diseases Weill Cornell Medical College New York, NY
  2. 2. Case 1 <ul><li>88 yo female presented to the ED with fever, dysuria, and changes in mentation </li></ul><ul><li>The patient resides in a nursing home and has a history of recurrent UTIs treated most recently with a fluoroquinolone </li></ul><ul><li>Blood and urine cultures were performed and the patient was admitted with a tentative diagnosis of urosepsis </li></ul>
  3. 3. Case 1 <ul><li>Blood and urine cultures both yielded a strain of E. coli with the following susceptibility (Vitek II) </li></ul><ul><ul><li>Antibiotic MIC (µg/mL) Interpretation </li></ul></ul><ul><ul><li>Levofloxacin 8 R </li></ul></ul><ul><ul><li>Ampicillin >32 R </li></ul></ul><ul><ul><li>TMP-SXT >4/76 R </li></ul></ul><ul><ul><li>Gentamicin 16 R </li></ul></ul><ul><ul><li>Amp-Sulbactam 8/4 S </li></ul></ul><ul><ul><li>Pip-Tazobactam 16/4 S </li></ul></ul><ul><ul><li>Cefazolin 32 R </li></ul></ul><ul><ul><li>Cefoxitin 8 S </li></ul></ul><ul><ul><li>Ceftriaxone 8 S </li></ul></ul><ul><ul><li>Cefepime 8 S </li></ul></ul><ul><ul><li>Aztreonam 8 S </li></ul></ul><ul><ul><li>Imipenem 0.5 S </li></ul></ul>
  4. 4.  -Lactamases and Location of the Genes Encoding the Enzymes among Gram-negatives <ul><li>Molecular class A (TEM, SHV, ESBLs, CTX-M, KPC) </li></ul><ul><li>Molecular class B (metallo-  -lactamases (IMP, VIM, SPM) </li></ul><ul><li>Molecular class C (AMP C: SPICE/SPACE bacteria) </li></ul><ul><li>Molecular class D (OXA) </li></ul><ul><li>Bradford PA. (2001) Clin Micro Rev; 14:933-951and Jacoby GA, Minoz-Price LS. (2005) NEJM; 352:380-391 for excellent reviews </li></ul>
  5. 5. Class A, Chromosomal/Plasmid Encoded  -Lactam Hydrolyzing Enzymes  Class A, 2be (TEM-1  TEM-178+, SHV-1  SHV-117+), CTX-M-1  94+), 2f zinc-independent carbapenemases (KPC-1  11), ESBLs, etc.  Many inhibited by clavulanic acid and tazobactam (IRTs)  TEM, SHV, CTX-M: located on plasmids.  First group 2f enzymes were identified on the chromosome and reported in Enterobacter cloacae and Serratia marcescens ( Sme-1,-2, IMI-1, NMC-A)  More recently, KPC  -lactamases were identified and are plasmid associated
  6. 6. Extended-Spectrum β -lactamases among Enterobacteriaceae <ul><li>Derivatives of TEM-1, TEM-2 and SHV-1  - lactamases (1 - 4 amino acid substitutions) </li></ul><ul><ul><li>> 650 now described </li></ul></ul><ul><li>Most commonly observed with: </li></ul><ul><ul><li>Escherichia coli </li></ul></ul><ul><ul><li>Klebsiella pneumoniae </li></ul></ul><ul><li>Characterized by substrate profile, isoelectric point and gene/amino acid sequence </li></ul><ul><li>[http// ] </li></ul>
  7. 7. Extended-Spectrum β -lactamase Production among Enterobacteriaceae <ul><li>Carried on large plasmids often combined with multiple resistance determinants: </li></ul><ul><ul><li>gentamicin </li></ul></ul><ul><ul><li>TMP-SMX </li></ul></ul><ul><ul><li>tetracycline </li></ul></ul><ul><ul><li>chloramphenicol </li></ul></ul><ul><li>Common source hospital out-breaks occur frequently </li></ul>
  8. 8. Phenotype of ESBL-producing Enterobacteriaceae <ul><li>Elevated MICs to penicillins, cephalosporins (including advanced generation agents) and aztreonam </li></ul><ul><li>  MIC increases can be extremely modest </li></ul><ul><li>Part of rationale for changes in breakpoints </li></ul><ul><li>Susceptible to cephamycins and carbapenems </li></ul><ul><li>Usually inhibited by clavulanate </li></ul>
  9. 9. ESBL Testing <ul><li>With publication of revised breakpoints by SAST in 1/10, ESBL testing is no longer necessary except for epidemiologic purposes </li></ul><ul><li>New breakpoints capture organisms for which interpretations would otherwise have needed to have been changed using prior breakpoints (when ESBL production was confirmed) </li></ul>
  10. 10. CLSI Enterobacteriaceae Interpretive Criteria MIC Breakpoints Published by CLSI SAST (  g/mL) Drug Susceptible Intermediate Resistant Cefazolin ≤ 1 (≤ 8)** 2 (16) ≥4 (≥32) Cefotaxime ≤ 1 (≤ 8) 2 (16-32) ≥4 (≥64) Ceftizoxime ≤ 1 (≤ 8) 2 (16-32) ≥4 (≥64) Ceftriaxone ≤ 1 (≤ 8) 2 (16-32) ≥4 (≥64) Ceftazidime ≤ 4 (≤ 8) 8 (16) ≥16 (≥32) Aztreonam ≤ 4 (≤ 8) 8 (16) ≥16 (≥32) Disc Breakpoints Published by CLSI (mm) Drug Susceptible Intermediate Resistant Cefazolin * Not available; unacceptable correlation with MICs Cefotaxime ≥26 23-25 ≤22 Ceftizoxime ≥25 22-24 ≤21 Ceftriaxone ≥23 20-22 ≤19 Ceftazidime ≥21 18-20 ≤17 Aztreonam ≥21 18-20 ≤17 *Problematic for UTI isolates. Consider testing and reporting cephalothin with applicable disclaimer. ** Previous breakpoints are in parentheses
  11. 11. ESBLS – Original Rationale for Testing <ul><li>MICs of many β -lactams for ESBL producing organisms fell within susceptible range </li></ul><ul><li>Limited numbers of reports of clinical failures among patients with infections caused by ESBL-producing organisms when treated with β -lactams to which the organisms tested “S” in vitro 1 </li></ul>Paterson DL, Ko WC, Von Gottberg A, Mohapatra S, Casellas JM, Goossens H, Mulazimoglu L, Trenholme G, Klugman KP, Bonomo RA, Rice LB, Wagener MM, McCormack JG, Yu VL. Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended-spectrum beta-lactamases. Clin Infect Dis. 2004 Jul 1;39(1):31-7.
  12. 12. ESBLS – Original Rationale for Testing <ul><li>In vitro hydrolysis of β-lactams by ESBLs varies significantly based on inoculum size </li></ul><ul><li>General lack of validated PK/PD data on older β-lactam antimicrobial agents </li></ul><ul><li>As carbapenems were uniformly active at the time versus the Enterobacteriaceae, “overcalling” resistance to the cephalosporins and aztreonam still left effective antibiotic options </li></ul><ul><li>Original recommendation to report all ESBL-producing organisms as resistant to all cephalosporins and penicillins was intended to be a short term solution to address a newly recognized resistance mechanism </li></ul>
  13. 13. Basis for Changes in Interpretive Criteria <ul><li>Numerous additional mechanisms of resistance have now been identified (e.g., new ESBLs including CTX-M types, plasmid-mediated ampC-like enzymes, KPCs, etc.) </li></ul><ul><li>Increasing prevalence of organisms harboring multiple resistance mechanisms that render confirmatory (clavulanate effect) testing non-interpretable (i.e., ampC and ESBL) </li></ul>
  14. 14. ESBLs Basis for Changes in Interpretive Criteria <ul><li>Carbapenems are no longer routinely active against all isolates of Enterobacteriaceae (KPCs, metallo-β-lactamases (i.e., NDM-1) </li></ul><ul><li>May be driving carbapenem resistance by reporting ESBL-producing organisms as resistant to all other β -lactams </li></ul><ul><li>CLSI revised cephalosporin and aztreonam breakpoints better represent the clinical effects these compounds have with currently recommended antibiotic dosage regimens when treating infections caused by contemporary bacterial isolates </li></ul>
  15. 15. ESBLs Basis for Changes in Interpretive Criteria <ul><li>Supported by improved understanding of the pharmacokinetic and pharmacodynamic (PK/PD) determinants of efficacy with β -lactam agents (Monte Carlo simulations) </li></ul><ul><li>Supported by animal model studies </li></ul><ul><li>Communication!! </li></ul><ul><ul><li>CMIDCC </li></ul></ul><ul><ul><li>Bulletins </li></ul></ul>
  16. 16. EXPOSURE & RESPONSE IN MICE ESBL Versus Non-ESBL Producing Strains Ambrose PG, Bhavnani SM, Jones RN, Craig WA, Dudley MN. Use of PK-PD and Monte Carlo Simulation as Decision Support for the Re-Evaluation of NCCLS Cephem Susceptibility Breakpoints for Enterobacteriaceae [abstract A-138]. 44th ICAAC; Washington; 2004 Oct 30-Nov 2. Washington. Key message: When adequate concentrations of drug are provided, ESBL and non-ESBL producing strains look the same. There is no hidden, “mystery” behind ESBL-producing strains (i.e., “it’s all about the MIC”)
  17. 17. Clinical outcome with cephalosporin mono-therapy in 35 patients with bacteremia due to cephalosporin-susceptible, ESBL-producing Klebsiella spp . or E. coli “susceptible” by current breakpoints Craig WA, Bhavnani SM, Ambrose PG, Dudley MN, Jones RN. Evaluation of clinical outcome among patients with ESBL-producing Enterobacteriaceae treated with cephalosporin mono-therapy. ICAAC 2005, Abstract K-1291 CLINICAL DATA in Bacteremia Outcome in Cephalosporin Treatment Correlates with MICs and NOT ESBL Production MIC (mg/L) Cures/Total Percentage ≤ 1 8/11 73 2 6/8 75 4 3/9 33 8 1/7 14
  18. 18. Proposed Alternative Approach to ESBL Testing to Address Infection Control Concerns <ul><li>Use cefotaxime (CTAX) or ceftriaxone (CTRX) as a surrogate marker for ESBL production </li></ul><ul><li>99% of 679 confirmed ESBL producers in 2009 at NY Presbyterian Hospital/Weill Cornell Medical Center were ceftriaxone resistant based on new breakpoints </li></ul><ul><li>If an enteric isolate is resistant to CTRX or CTAX (other than a SPICE/SPACE organism), enter a comment in the report such as the following: “This multi-drug resistant organism may not respond optimally to β -lactams (other than the carbapenems) or the β -lactam/ β -lactamase inhibitor combinations </li></ul><ul><li>Also serves as a flag for Infection Control purposes </li></ul>
  19. 19. Case 2 <ul><li>A 22 yo female presented to the ED with low grade fever, pain on urination, pyuria, and bacteriuria </li></ul><ul><li>It was the patient’s first presentation with such symptoms </li></ul><ul><li>The patient was diagnosed with simple cystitis </li></ul><ul><li>A urine culture was performed and the patient was empirically started on Keflex® (cephalexin), and sent home with instructions to phone back for the culture results </li></ul>
  20. 20. Case 2 <ul><li>Upon receiving the culture results, the ED phones you because the cefazolin result has not been reported on the E. coli recovered in culture </li></ul><ul><li>Historically, the ED used cefazolin to predict the activity of cephalexin for urinary tract isolates (because of concentration in the urine) </li></ul><ul><li>What do you do? </li></ul>
  21. 21. Issues with Revised Cefazolin Breakpoints <ul><li>Cephalexin is frequently used for UTIs </li></ul><ul><li>In such cases, the new cefazolin breakpoints are probably too low </li></ul><ul><li>Automated systems do not contain dilutions low enough to detect resistance with the new interpretive criteria </li></ul><ul><li>Cefazolin Etest strips are not commercially available </li></ul><ul><li>Disk test does not work </li></ul>
  22. 22. Potential Solutions <ul><li>Use cephalothin as a surrogate test by disk or Etest </li></ul><ul><ul><li>Requires an additional procedure on the part of the clinical microbiology laboratory </li></ul></ul><ul><ul><li>May under-call susceptibility for cefazolin as it is somewhat more active than cephalothin against gram-negatives, potentially taking away a useful drug for therapy </li></ul></ul><ul><li>Fine tune the breakpoints a bit more </li></ul>
  23. 23. Proposed Revised CLSI Cefazolin Breakpoints Effective January 1, 2011 <ul><li>MIC </li></ul><ul><li>Susceptible ≤ 2 µg/mL </li></ul><ul><li>Intermediate = 4 µg/mL </li></ul><ul><li>Resistant ≥ 8 µg/mL </li></ul><ul><li>DISK </li></ul><ul><li>Susceptible ≥ 23 mm </li></ul><ul><li>Intermediate: 20 – 22 mm </li></ul><ul><li>Resistant ≤ 19 mm </li></ul>
  24. 24. Case 3 <ul><li>A 72 yo lady broke her arm in a fall 3 months earlier </li></ul><ul><li>She presented with infected hardware following a humerus repair (the hardware was eroding through the skin over the acetabulum) </li></ul><ul><li>In the OR all hardware and 6 inches of her necrotic humerus were removed </li></ul><ul><li>Intraoperative findings described a “soup of pus and dead bone” in the arm </li></ul>
  25. 25. Case 3 <ul><li>Cultures yielded MSSA and an Enterobacter cloacae resistant to ampicillin, cefazolin and cefoxitin, but susceptible to ceftazidime, ceftriaxone, piperacillin-tazobactam, aztreonam, trimethoprim-sulfamethoxazole and levofloxacin </li></ul><ul><li>The ID physician phoned asking whether ceftriaxone might be an option as the patient will be on long term IV therapy </li></ul><ul><li>How do you respond? </li></ul>
  26. 26. amp (C)  -lactamases Among Gram-negative Bacilli <ul><li>Once thought to be exclusively chromosomal and generally “non-transferable” </li></ul><ul><li>Inducible by cephamycins and imipenem </li></ul><ul><li>Low-level expression </li></ul><ul><li>Stable derepression and hyper-production  </li></ul><ul><li>high-level resistance (MICs  8 μ g/mL) to: </li></ul><ul><ul><ul><li>penicillins and  -lactamase inhibitor combos </li></ul></ul></ul><ul><ul><ul><li>ALL cephalosporins (except cefepime and cefpirome) </li></ul></ul></ul>
  27. 27. Class C, Chromosomally or Plasmid Encoded AMP-C Enzymes  Bush et. al. class 1, (molecular class C) AMP-C type β -lactamases  Chromosomally or plasmid mediated  Hydrolyze oxyiminocephalosporins (ceftriaxone, ceftazidime, cefotaxime, cefpodoxime) and 7-  - methoxy-cephalosporins (cefoxitin, cefotetan, moxalactam).  Also hydrolyze carbapenems at very low rates. They are not significantly inhibited by β -lactamase inhibitors.
  28. 28. Remember SP I CE / SP A CE for Organisms with Chromosomally-Encoded Type-1 / Amp-C  -lactamases <ul><li>S = Serratia </li></ul><ul><li>P = Pseudomonas </li></ul><ul><li>I = Indole positive Proteus spp & Providencia spp </li></ul><ul><li>A = Acinetobacter spp & Aeromonas spp </li></ul><ul><li>C = Citrobacter </li></ul><ul><li>E = Enterobacter </li></ul>
  29. 29. Methods for Laboratory Detection of amp (C) β -lactamases <ul><li>Most susceptibility testing methods are likely to detect constitutive amp (C)-positive Enterobacteriaceae </li></ul><ul><li>Full-range broth microdilution screen: </li></ul><ul><ul><li>MICs ≥ 8 μ g/mL to all penicillins,  -lactamase inhibitor combinations, cephalosporins (except cefepime), cephamycins, and aztreonam, </li></ul></ul><ul><ul><li>MICs ≤ 4 μ g/mL: cefepime and imipenem/meropenem/doripenem </li></ul></ul><ul><li>Disk diffusion </li></ul><ul><li>Detection of plasmid-mediated ampC </li></ul><ul><li>resistance more problematic </li></ul>
  30. 30. Phenotypic Detection of Inducible ampC Enzymes in Enterobacteriaceae <ul><li>If cefoxitin resistant, but susceptible to 3 rd generation cephalosporins, may assume that the isolate contains an inducible ampC </li></ul><ul><li>Livermore et al recommend that 3 rd generation cephalosporins never be used as monotherapy for these organisms outside of the urinary tract </li></ul><ul><li>Double disk tests: </li></ul><ul><ul><li>Place cefoxitin and ceftazidime, cefoxitin and cefotaxime, and cefoxitin and aztreonam 15 - 25 mm apart on a 0.5 McFarland lawn of the test organism on a MH plate </li></ul></ul><ul><ul><li>Incubate overnight </li></ul></ul><ul><ul><li>Blunting of the zones of inhibition indicates a cefoxitin-induced ampC enzyme (similar to D-test) </li></ul></ul><ul><li>Also set up a ceftazidime clavulanic acid disk or strip and look for small colonies within the zone of inhibition resulting from clavulanic acid induction of the ampC enzyme </li></ul>
  31. 31. Case 3 <ul><li>The isolate exhibited an inducible ampC with cefoxitin and aztreonam </li></ul><ul><li>Patient was treated with ertapenem as an outpatient for 8 weeks without recurrence of infection </li></ul>
  32. 32. Case 4 <ul><li>A 48 year old obese female was admitted for elective knee replacement surgery following an automobile accident </li></ul><ul><li>Post-surgery she idiopathic heparin-induced thrombocytopenia </li></ul><ul><li>Loss of perfusion to her intestines resulted in small bowel transplant </li></ul><ul><li>Post-surgery # 2 she developed ARDS and was placed on a ventilator </li></ul><ul><li>The patient’s condition continued to deteriorate and she developed a nosocomial pneumonia </li></ul>
  33. 33. Case 4 <ul><li>The antimicrobial susceptibility pattern of the isolate was as follows: </li></ul><ul><li>Resistant to: ampicillin, piperacillin, amoxicillin-clavulanate, ampicillin-sulbactam, ticarcillin-clavulanate piperacillin-tazobactam, aztreonam, cefazolin, cefuroxime, cefotetan, ceftriaxone, cefotaxime, ceftazidime, cefepime, imipenem,, ertapenem, gentamicin, tobramycin, levofloxacin, ciprofloxacin, chloramphenicol, and trimethoprim-sulfamethoxazole </li></ul><ul><li>Intermediate susceptibility to: meropenem, amikacin, and tetracycline </li></ul><ul><li>Susceptible to: tigecycline and polymyxin B </li></ul>
  34. 34. What gram-negative was recovered from BAL, an empyema collection, urine, and blood?
  35. 35. Klebsiella pneumo niae
  36. 36. Klebsiella pneumoniae  Polymyxin B MIC = 2  g/mL (Susceptible?)  Patient treated with tigecycline and polymyxin B - responded  Reports in the literature of successful treatment of this organism with polymyxin B plus rifampin and combinations of agents that include imipenem and/or an aminoglycoside
  37. 37. The Patient Developed a Second Pneumonia Related to:      
  38. 38. Follow-up Hyperinfestation with Strongyloides stercoralis
  39. 39. Follow-up Treated with ivermectin and recovered, only to develop a new pneumonia with:
  40. 40.                  
  41. 41.                
  42. 42. Follow-up  Aspergillus fumigatus  Again responded to therapy (voriconazole), but developed bilateral CMV pneumonia
  43. 43. Follow-up Controlled with high-dose gancyclovir, but became septic with:
  44. 44.                
  45. 45. Multi-drug Resistant Strain of Acinetobacter baumannii   -lactam (including imipenem), aminoglycoside, and fluoroquinolone resistant  Expired 13 months after initial surgery
  46. 46. Carbapenemases <ul><li>Class A: KPC , SME, IMI, NMC  </li></ul><ul><li> serine residue at the active site </li></ul><ul><li>Class B: IMP, VIM, GIM, SPM, SIM, NDM </li></ul><ul><ul><li> Zn 2+ -dependent metallo-enzyme </li></ul></ul><ul><li>Class C: N/A </li></ul><ul><li>Class D: OXA family (1  178) </li></ul>
  47. 47. Class B Plasmid-Mediated Metallo-  -Lactamases <ul><li> Zinc containing β -lactamases: not inhibited by clavulanic acid, tazobactam, or sulbactam </li></ul><ul><li>Low rates of aztreonam hydrolysis </li></ul><ul><li>Most common in Pseudomonas aeruginosa, Acinetobacter baumannii , and Enterobacteriaceae (outside of US) </li></ul><ul><li> Carbapenemase of Stenotrophomonas maltophilia </li></ul>
  48. 48. Class B Plasmid-Mediated Metallo-  -Lactamases  IMP-1-first identified and reported in Pseudomonas aeruginosa in 1991 and later in Serratia marcescens  Variants (IMP-2  26) identified predominantly in Pseudomonas aeruginosa , Klebsiella pneumoniae, and Acinetobacter baumannii
  49. 49. Class B Plasmid-Mediated Metallo-  -Lactamases <ul><li> NDM-1: New Delhi metallo- β -lactamase </li></ul><ul><li>Recently bla NDM-1 detected in 3 isolates in US ( E. coli, Enterobacter cloacae, Klebsiella pneumoniae ) </li></ul><ul><li>Confers resistance to all β -lactams except aztreonam (3 isolates also aztreonam-R due to other mechanism) </li></ul><ul><li>All 3 isolates recovered from patients who received recent medical care in India </li></ul>
  50. 50. NDM-1-  -Lactamases <ul><li>Resistance reliably detected by standard susceptibility testing methods and by MHT </li></ul><ul><li>“ Laboratory ID of carbapenem-resistance mechanisms is not necessary to guide treatment or infection control practices but should be used for surveillance and epidemiologic purposes” - MMWR </li></ul><ul><li>“ Clinicians should be aware of the possibility of NDM-1 producing Enterobacteriaceae in patients who have received medical care in India and Pakistan and should specifically inquire about this risk factor when carbapenem-resistant enterics are reported” </li></ul><ul><li>Isolates should be forwarded to CDC for confirmation </li></ul>
  51. 51. New CLSI Carbapenem Breakpoints MIC Breakpoints Recently Approved by CLSI SAST (  g/mL) Drug Susceptible Intermediate Resistant Imipenem ≤ 1 (4) 2 (8) ≥4 (16) Meropenem ≤ 1 (4) 2 (8) ≥4 (16) Doripenem ≤ 1 (NA) 2 (NA) ≥4 (NA) Ertapenem ≤ 0.25 (2) 0.5 (4) ≥1 (8) Disc Breakpoints Recently Approved by CLSI SAST (mm) Drug Susceptible Intermediate Resistant Imipenem ≥23 20-22 ≤19 Meropenem ≥23 20-22 ≤19 Doripenem ≥22 20-21 ≤19 Ertapenem ≥23 20-22 ≤19
  52. 52. CARBAPENEMS - CLSI <ul><li>New (revised) interpretive criteria for carbapenems were established following evaluation of: </li></ul><ul><ul><li>The pharmacokinetic-pharmacodynamic properties </li></ul></ul><ul><ul><li>Monte Carlo simulations </li></ul></ul><ul><ul><li>Limited clinical data, and </li></ul></ul><ul><ul><li>MIC distributions </li></ul></ul>
  53. 53. CARBAPENEMS - CLSI <ul><li>These include isolates with MICs of 2 - 4 µg/mL for doripenem, imipenem and meropenem; MICs of 0.5 – 1 µg/mL for ertapenem; and zone diameters of 19 - 22 mm for doripenem, ertapenem, imipenem, and meropenem </li></ul><ul><li>Due to lack of data from controlled clinical trials there remains some uncertainty whether or not the carbapenems might be effective in the treatment of infections due to Enterobacteriaceae with carbapenem MICs or zone diameters that fall within the intermediate range or at the breakpoint for resistance </li></ul>
  54. 54. CARBAPENEMS - CLSI <ul><li>In the setting of limited treatment options, clinicians managing infections due to these isolates may wish to consider maximum approved dosage regimens and/or prolonged intravenous infusions of carbapenems as described in the medical literature </li></ul><ul><li>Each laboratory should develop a mechanism for informing clinicians about such circumstances in a timely manner. This might include a telephone call and/or a comment appended to the laboratory report. Consultation with an Infectious Disease specialist is recommended. </li></ul>
  55. 55. CARBAPENEMS <ul><li>NOTE: Imipenem MICs for Proteus spp., Providencia spp., and Morganella morganii tend to be higher (e.g., MICs in the intermediate and at the breakpoint of resistance) than those with meropenem or doripenem MICs.  These isolates can be imipenem resistant by mechanisms other than production of carbapenemases. </li></ul><ul><li>Until laboratories implement the new interpretive criteria, the modified Hodge test (MHT) should be performed as described in the updated Supplemental Table 2A-S2. After implementation of the new interpretive criteria, the MHT need not be performed other than for epidemiologic or infection control purposes. </li></ul>
  56. 56. Modified Hodge Test (Carbapenem Inactivation Test) 1 2 3 The MHT performed on a small MHA plate. (1) K. pneumoniae D-05 , positive result; (2) K. pneumoniae 6179, negative result; and (3) a clinical isolate, positive result E. coli ATCC  25922 Inhibition of E. coli ATCC  25922 by ertapenem Enhanced growth of E. coli ATCC  25922. Carbapenemase produced by K. pneumoniae D-05 destroyed ertapenem that diffused into the media. Thus, there is no longer sufficient ertapenem to inhibit E. coli ATCC  25922 and an indentation of the zone is noted.
  57. 57. Detection of KPC-mediated Resistance
  58. 58.                                                                                                  
  59. 59. Susceptibility Testing Frequency of Very Major, Major, and Minor Errors Testing Method Number (%) of Isolates with Indicated Result Very Major Major Minor 2010 CLSI Meropenem Interpretive Criteria Etest 1 (2.2) 0 (0) 1 (2.2) Vitek 2 11 (23.9) 0 (0) 18 (39.1) Sensititre 3 (6.5) 0 (0) 12 (26.1) Microscan 0 (0) 0 (0) 1 (2.2) FDA Meropenem Interpretive Criteria__ Etest 1 (2.2) 0 (0) 7 (15.2) Vitek 2 27 (58.7) 0 (0) 8 (17.4) Sensititre 27 (58.7) 0 (0) 12 (26.1) Microscan 0 (0) 0 (0) 2 (4.3) Bulik CC, Fauntleroy KA, Jenkins SG, Abuali M, LaBombardi VJ, Nicolau DP, Kuti JL. 2010. J Clin Microbiol. 48: 2402–2406.
  60. 60. imipenem Surgical ICU