1 / 47

Extended-Spectrum -lactamases: Current situation, Diagnosis & Management

Extended-Spectrum -lactamases: Current situation, Diagnosis & Management. Siriluck Anunnatsiri, MD Infectious Diseases & Tropical Medicine Faculty of Medicine Khon Kaen University. Extended-spectrum -lactamases.

sirius
Download Presentation

Extended-Spectrum -lactamases: Current situation, Diagnosis & Management

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Extended-Spectrum -lactamases: Current situation, Diagnosis & Management Siriluck Anunnatsiri, MD Infectious Diseases & Tropical Medicine Faculty of Medicine Khon Kaen University

  2. Extended-spectrum -lactamases • Mutant, plasmid-mediated -lactamases enzymes derived from amino acid substitutions in native -lactamases, particularly TEM-1, TEM-2, and SHV-1 • Their ability permit hydrolyze all penicillins, cephalosporins (except cephamycins), and monobactams • Typically associated with multidrug resistance (fluoroquinolones, co-trimoxazole, aminoglycosides)

  3. Extended-spectrum -lactamases • Most commonly produced by Klebsiella spp., Escherichia coli but can occur in other GNB, including Enterobacter, Salmonella, Proteus, and Citrobacter spp., Morganella morganii, Serratia marcescens, Shigella dysenteriae, Pseudomonas aeruginosa, and Burkholderia cepacia

  4. Major groups of -lactamases Shah AA, et al. Research in Microbiology 2004; 155: 409-421.

  5. Major groups of -lactamases Shah AA, et al. Research in Microbiology 2004; 155: 409-421.

  6. Selected -lactamases of gram-negative bacteria Peterson DL. Am J Med 2006; 119 (6 Suppl 1):S20-8.

  7. Selected -lactamases of gram-negative bacteria Peterson DL. Am J Med 2006; 119 (6 Suppl 1):S20-8.

  8. Major sources of extended-spectrum -lactamases

  9. Prevalenceof ESBL-producing isolates in Europe (1997-2004) and USA (1999-2004) Europe USA Goossens H, GrabeinB. Diagn Microbiol Infect Dis 2005; 53: 257-64.

  10. Distribution of ESBL in E. coli SMART, 2003, IAI, Asia-Pacific Countries % <48 hours 48 hours Paterson DL et al. J Antimicrob Chemother 2005;55:965-73.

  11. Distribution of ESBL in Klebsiella spp. SMART, 2003, IAI, Asia-Pacific Countries % <48 hours 48 hours Paterson DL et al. J Antimicrob Chemother2005;55:965-73.

  12. Prevalence of ESBL producing organisms 346 isolates of GNB, Siriraj Hospital, 2003 Chayakulkeeree M, et al. Southeast Asian J Trop Med Public Health 2005; 36: 1503-9.

  13. Prevalence of ESBL-producing organisms2974 isolates of GNB, Srinagarind Hospital, 2005 %

  14. Risk factors associated with infection or colonization with ESBL-producing pathogens • Critically ill patients / Severely debilitated residents • Prolonged hospital or ICU unit stay • Invasive procedures: indwelling catheter, central venous catheter, gastrostomy, tracheostomy, endotracheal or nasogastric tube • Residency in long-term care facility • Decubitus ulcer • Total dependence on health care workers • Prior antibiotic use in last 3 months • Exposure to 2nd-3rd cephalosporins, aztreonam, penicillins, and quinolones • Delayed appropriate therapy

  15. CLSI screening criteria for ESBLs in K. pneumoniae, K. oxytoca, and E.coli Stürenburg E, Mark D. J Infect 2003; 47: 273-95.

  16. Laboratory tests for ESBLs detection

  17. Laboratory tests for ESBLs detection

  18. Confirmatory tests for ESBL detection Stürenburg E, Mark D. J Infect 2003; 47: 273-95.

  19. Multi-drug resistance in ESBL-producing organisms Chayakulkeeree M, et al. Southeast Asian J Trop Med Public Health 2005; 36: 1503-9.

  20. Resistance of ESBL-Producing E. coli and K. pneumoniae 1,182 Isolates, Srinagarind Hospital, Khon Kaen2005 %

  21. Resistance of ESBL-Producing E. coli and K. pneumoniae 1,182 Isolates, Srinagarind Hospital, Khon Kaen2005 %

  22. Inadequate antimicrobial treatment of infections: arisk factor for hospital mortality among critically ill patients Independent risk factors for hospital mortality Kollef MH et al. Chest 1999; 115: 462-74.

  23. Retrospective study, 32/187 (17%) patients died Inadequate initial antimicrobial therapy(IIAT) was a risk factor for mortality OR 10.04, 95% CI (1.90-52.96) Risk factors for IIAT Infection with multidrug-resistant ESBLs (14.58 [1.91-111.36]) Health care-acquired ESBLs infection (4.32 [1.49-12.54]) Arch Intern Med 2005;165:1375-80.

  24. Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing ESBL Peterson et al. J Clin Microbiol 2001; 39: 2206-12.

  25. Clinical implications of ESBL-producing Klebsiella species and Escherichia coli on cefepime effectiveness • A retrospective, case–controlled study • None-urine source (~80% from lung) of 10 ESBL-cases & 20 controls (non-ESBL) treated with cefepime (2 grams/day, adjusted for GFR) Kotapati S, et al. J Infect 2005; 51: 211-7.

  26. High-dose cefepime as an alternative treatment for infections caused by TEM-24 ESBL-producing Enterobacter aerogenes in severely-ill patients • Retrospective study • Seriously-ill patients infected with ESBL-producing Enterobacter aerogenes, mostly TEM-24 • 21 treated with cefepime (6 grams/day) / 23 treated with carbapenems (in combination with ciprofloxacin or amikacin) Cefepime Carbapenems P-value Clinical improvement 62% 70% 0.59 Bacteriological eradication 14% 22% 0.76 30-day mortality rate 33% 26% 0.44 • Nevertheless, a statistically significant increase in failure to eradicate ESBL-producing E. aerogenes was observed as the MICs of cefepime rose (p=0.017). K. Goethaert et al. Clin Microbiol Infect 2006; 12: 56-62.

  27. Cefepime versus Imipenem-Cilastatin for Treatment of Nosocomial Pneumonia in Intensive Care Unit Patients: a Multicenter, Evaluator-Blind, Prospective, Randomized Study • A randomized, evaluator-blind, multicenter tria • Compared cefepime (6 g/day) vs. imipenem-cilastatin (2 g/day) for the treatment of nosocomial pneumonia in 281 intensive care unit patients. • In subgroup analysis, therapy of pneumonia caused by an organism producing an extended spectrum-lactamase failed in 4 of 13 patients (31%) in the cefepime group but in none of 10 patients in the imipenem group. Zanetti G, et al. Antimicrobe Agents Chemother 2003; 47: 3442-7.

  28. Bacteremia due to Klebsiella pneumoniaeisolates producing the TEM-52 extended-spectrum -lactamase: treatment outcome of patients receiving imipenem or ciprofloxacin • Retrospective study • ESBL (TEM-52) – K. pneumoniae bacteremia, non-fatal disease • 10 treated with imipenem / 7 treated with ciprofloxacin Ciprofloxacin*Imipenem P-value • Treatment failure 5/7 2/10 0.03 * 2/7 = partial response • Because the isolates had MICs of ciprofloxacin close to the susceptibility breakpoint, treatment failure could be ascribed to the inability of the drug to reach therapeutic concentrations at infected sites. Endimiani et al. Clin Infect Dis 2004; 38: 243-51.

  29. A prospective, observational study • 12 centers, 455 episodes • 18.7% with ESBL-K. pneumoniae

  30. Pharmacodynamics of intermittent infusion piperacillin/tazobactam and cefepime against ESBL-producing organisms  Cefepime 1 gram q 12 hrs Pip/tazo 4.5 grams q 8 hrs Cefepime 1 gram q 8 hrs Pip/tazo 3.375 grams q 6 hrs  Cefepime 2 gram q 12 hrsPip/tazo 3.375 grams q 4 hrs Reese AM, et al. Int J Antimicrobe Agents 2005; 26: 114-9.

  31. Pharmacodynamics of continuous infusion piperacillin/tazobactam and cefepime against ESBL-producing organisms  Cefepime 3 grams  Pip/tazo 6.75 grams Cefepime 4 grams  Pip/tazo 13.5 grams Reese AM, et al. Int J Antimicrobe Agents 2005; 26: 114-9.

  32. Pharmacodynamics of levofloxacin, gatifloxacin, and ciprofloxacin against ESBL-, and non-ESBL producing organisms Moczygemba LR, et al. Clin Ther 2004; 26: 1800-7.

  33. Summary of 3rd-generation cephalosporins on treatment of ESBL-producing organisms • Clinical significance of inoculum effect • Poor clinical outcomes are observed when 3rd-generation cephalosporins are used for treatment • Higher fatal outcome • Higher rate of clinical failure • 3rd-generation cephalosporins should not be used to treat serious infections with ESBL-producing organisms, even in the presence of apparent susceptibility. Peterson et al. J Clin Microbiol 2001; 39: 2206-12. Ariffin H et al. Int J Infect Dis 2000; 4: 21-5. Wong-Beringer et al. Clin Infect Dis 2002; 34: 135-46.

  34. Summary of 4th-generation cephalosporins on treatment of ESBL-producing organisms • More stable than 3rd-generation cephalosporins againt some ESBLs and very stable against AmpC-type -lactamases • Inoculum effect, susceptible to SHV-type • Need high dosage (> 4 grams/day) of cefepime for achieving the T>MIC target, preferably in combination with aminoglycoside for synergistic effect • Cefepime should not be used to treat serious infections with ESBL-producing organisms.

  35. Summary of -lactam/-lactamase inhibitor on treatment of ESBL-producing organisms • Limited clinical information • Class A ESBLs are susceptible to clavulanate and tazobactam in vitro, nevertheless many producers are resistant to -lactamase inhibitor due to • Hyperproduction of the ESBLs → overwhelm inhibitor • Co-production of inhibitor-resistant penicillinases (e.g. OXA-1) or AmpC enzyme • Relative impermeability of the host strain • -lactam/-lactamase inhibitor should not be used to treat serious infections with ESBL-producing organisms.

  36. Summary of cephamycins on treatment of ESBL-producing organisms • Limited clinical data • Generally effective against Enterobacteriaceae producing TEM-, SHV-, and CTX-M-derived ESBLs • Cefotetan > cefoxitin : lower MICs • Reports of cephamycins resistance development during prolonged therapy • Loss of outer membrane porin (porin deficient mutant) • Acquisition of plasmid-mediated AmpC -lactamase (ACT-1)

  37. Summary of treatment recommendations for infections with ESBL producers Livermore DM, Peterson DL. ESBLs in resistance 2006.

  38. Carbapenem classification

  39. Dosage and Cost of Treatment in Patients with ESBL-producing bacteria Infections Choice of Ertapenem can save cost of treatment about 1,265-2,435 Baht in patients with ESBL-producing bacteria infections. * ราคายาโรงพยาบาลศรีนครินทร์ ณ วันที่ 21 มิถุนายน พ.ศ. 2549

  40. Control of a Prolonged Outbreak of ESBL-Producing Enterobacteriaceae in a University Hospital ■ Imported ESBL-cases  Acquired ESBL-cases Lucet JC, et al. Clin Infect Dis 1999; 29: 1411-8.

  41. Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella * P < 0.01 Rahal JJ, et al. JAMA 1998; 280: 1233-7.

  42. OASIS I-II : Bowel Colonization with resistant GNB after antimicrobial therapy of IAI ESBL-producing Enterobacteriaceae DiNubile MJ et al. Eur J Clin Microbiol Infect Dis 2005; 24: 443-9.

  43. OASIS I-II : Bowel Colonization with resistant GNB after antimicrobial therapy of IAI P. aeruginosaresistance DiNubile MJ et al. Eur J Clin Microbiol Infect Dis 2005; 24: 443-9.

  44. Summary of interventions that could be used to prevent problem with ESBL-producing bacteria in hospitalized patients Livermore DM, Peterson DL. ESBLs in resistance 2006.

  45. Take Home Messages • ESBL-producing bacterial infection is an emerging problem worldwide. • These organisms are associated with multi-drug resistance causing high rate of mortality and treatment failure. • The significant risk factors for ESBL-producing bacterial infection are prior use of antibiotics, especially 3rd generation cephalosporins, and critically ill or debilitated patients. • Need the ESBL-laboratory testing for establish the problem. • Carbapenems is the drug of choice for serious ESBL-producing bacterial infection. • Avoiding overuse or misuse of 3rd generation cephalosporins and implementing isolation and contact precaution to prevent and control the ESBL outbreak.

  46. Thank You for your attention

More Related