Optimal diagnosis & treatment of ESBL strains infection

1. Optimal diagnosis & treatment of ESBL strains infection 中國醫藥大學 附設醫院 感染科主任 王任賢

2. The beta-lactams

3. Bush group 1 b-lactamase • Representive enzymes: AmpC • Cephalosporinase • Resistant to b-lactamase inhibitor • Chromosomally encoded inducible: Enterobacter,Citrobacter freundii, Serratia, P. aeruginosa, -------constitutive: E. coli • Plasmid mediated: E. coli, K. pneumoniae • Only susceptible to cefepime and imipenem

4. Bush group 2 b-lactamase • Inhibited by b-lactamase inhibitor • 2a: penicillinase (PC1 of S. aureus) 2b: broad-spectrum enzymes (TEM-1,2, SHV-1) 2be: ESBLs (TEM-3 to 28, SHV-2 to 6) 2br: broad-spectrum enzymes with reduced binding to clavulanic acid (TEM-30-36, TRC-1) 2c: carbenicillinase (PSE-1, CARB-3) 2d: cloxacillinase (OXA-1, PSE-2) 2e: cephalosporinase (P. vulgaris) 2f: nonmetallo-carbapenemase (IMI-1, NMC-A, Sme-1)

5. Bush group 3 b-lactamase • Metallo-b-lactamase • Hydrolyze carbapenem • Found in Stenotrophomonas maltophiliaAeromonas species some strains of Bacteroides some strains of P. aeruginosa

6. Bush group 4 b-lactamase • Penicillinase not inhibited by clavulanic acid • Found in P. cepacia

7. Extended-spectrum b-lactamase (ESBLs): I • First reported in 1983 • Mutant, plasmid-mediated b-lactamase derived from older, broad-spectrum b-lactamase (eg TEM-1, TEM-2, SHV-1) • Hydrolyze all cephalosporins, penicillins, and aztreonam EID 2001;7:333-6

8. Extended-spectrum b-lactamase (ESBLs): II • Commonly produced by Klebsiella spp. and E. coli, but may also occur in other GNBs, including Enterobacter Salmonella Proteus Citrobacter spp. Morganella morganii Serratia marcescens Shigella dysenteriae Pseudomonas aeruginosa Burkholderia cepacia Capnocytophaga ochracea EID 2001;7:333-6

9. Why detect ESBL producers? ESBL producers may: • Appear sensitive to some cephalosporins in vitro • Show major inoculum effects • Fail in therapy, despite appearing susceptible

10. Outcomes: infections with cephalosporins sensitive ESBL producers • Prospective study of K. pneumoniae bacteraemia & literature review • 32 evaluable patients with ceph ‘S/I’ ESBL producers • 19/32 failed with cephalosporin Tx • Don’t use cephs vs. ESBL producers, even if they appear susceptible Paterson et al. JCM 2001 39, 2206

11. NCCLS two-step approach to ESBL detection • Screening testing: reduced susceptibility to any of the recommended agents (cefotaxime, ceftriaxone, ceftazidime, cefpodoxime, aztreonam) • Confirmatory testing:potentiation of screening agent in the presence of b-lactamase inhibitor

12. Detection of ESBL production Resistant to penicillins & cephalosporins + Sensitive to beta-lactamase inhibitors (e.g. clavulanic acid)

13. Suspect ESBL if • E coli, K oxytoca, K pneumoniae • VITEK: R to ceftazidime, cefotaxime, aztreonam • Kirby-Bauer: • S to Cefotetan • R/I to • Ceftazidime, Cefotaxime • Ceftriaxone, Cefpodoxime • Aztrenonam

14. NCCLS screening criteria for ESBLs in K. pneumoniae, K. oxytoca, and E. coli

15. Confirmation of ESBLs • Seek ceph/clav synergy in ceph R isolates • Double disc • Combination disc • Etest See http://www.hpa.org.uk

18. Confirm ESBLs: Combination discs 5mm Ceftazidime Cefotaxime Ceftazidime/Clauvulanic acid Cefotaxime /Clauvulanic acid

19. Zone differences (mm), Klebs & E. coli C’pod/clav 10+1 mg - C’pod 10 mg

20. Sensitive organism

21. Organism with ESBL

22. ESBL detection : Combination discs M’Zali et al. 2000, JAC, 45, 881

23. Etest for ESBLs Cefotaxime Cefotaxime + clavulanate

24. Etest for ESBLs Cefotaxime Cefotaxime + clavulanate

25. Sensitivity of confirmatory tests, alone or in combination, for detecting ESBL-producing organisms IPDDT: inhibitor-potentiated disc diffusion test Eur J Clin Microb Infect Dis 2004;23:813-7

26. Pitfalls in ESBL detection • Methods optimised for E. coli & Klebsiella • More difficult with Enterobacter • clavulanate induces AmpC; hides ESBL • Best advice is to do synergy test (NOT SCREEN) with 4th gen ceph

27. Cephalosporins resistant but synergy negative

28. Bacteria not to test for ESBLs • Acinetobacters • Often sensitive to clavulanate alone • S. maltophilia • positive result by inhibition of L-2 chromosomal b-lactamase, ubiquitous in the species

29. Plasmid-mediated AmpC b-lactamase • Transfer of chromosomal genes for the inducible AmpC b-lactamase onto plasmid • Found in isolates of E.coli, K. pneumoniae, Salmonella spp., Citrobacter freundii, E. aerogenes, P. mirabilis • All plasmid-mediated AmpC b-lactamases have similar substrate profiles EID 2001;7:333-6

30. K1 hyperproducer K. oxytoca • Chromosomal enzyme from K. aerogenes NCTC 418 • Hydrolyze many monobactams more rapidly than cephalosporins & penicillins • 1st ESBL designed by Bush 1989, not inhibit by clavulanic acid • Hyperproduction by point mutation of promotor • Resistant to cefuroxime, piperacillin–tazobactam and aztreonam, having borderline resistance to cefotaxime and cefepime, but remaining fully susceptible to ceftazidime

31. Limitation of NCCLS recommendations for new pathogens • Usual lag of 12 or more years before new types of resistant organisms are detected • Responsibilities of NCCLS are regulation, standardization, and safety, but not research • Bacteria can produce multiple b-lactamases EID 2001;7:333-6

32. Unresolved issues of ESBL testing: I • Need two-step approach ? • Which screening agent is the most reliable? Cefpodoxime: most sensitive for K. pn & E. coli poor for K. oxytoca poor specificity to ESBL(-) strains • Is clavulanate unreliable for AmpC coproducer ? include cefepime as an ESBL screening agent • Report all cephalosporins & penicillins resistance in ESBL strains ? EID 2001;7:333-6

33. Type of plasmid-Mediated Extended-Spectrum β-Lactamase Enzymes Pharmacotherapy Volume 21, Number 8, 2001

34. Example of false-negative, clavulanate-based test for detecting ESBL with an isolate producing an inducible AmpC b-lactamase EID 2001;7:333-6

35. Unresolved issues of ESBL testing: II • Inoculum effect ? • Detecting and reporting isolates producing plasmid-mediated AmpC b-lactamse decreased susceptibility to cephamycin negative ESBL confirmatory tests (AmpC or reduced OM permeability) EID 2001;7:333-6

36. Standard and high-inoculum microdilution MICs in tests with SHV-3-producing Citrobacter freundii (MICs in μg/mL) EID 2001;7:333-6

37. Risk Factors Associated with ESBL Colonization and Infection Pharmacotherapy Volume 21, Number 8, 2001

38. Multivariate analysis for the development of ESBL bacteria in community patients Eur J Clin Microbiol Infect Dis (2004) 23:163-167

39. Features of 49 patients infected with community-acquired ESBLEC JCM 2004: 1089-97

40. Crude analysis of potential risk factors for community-acquired ESBLEC infection a OR, odds ratio; CI, confidence interval. JCM 2004: 1089-97

41. Treatment of multi-resistant GNBs • ESBL strains carbapenem, cefamycin, b-lactam/b- lactamase inhibitor combination • Plasmid-mediated AmpC b-lactamase carbapenem, cefepime

42. Mono- & combination therapy for ESBL-producing K. pneumoniae(log10 viable colony counts at 24 h from time-kill curves) Int J Antimicrob Agents 2004;24:48-52

43. Burgess D et al 2004 Diag Microb Infect Dis 49: 41

44. Patients receiving 3GC for ≥5 days to which isolate sensitive in vitro Kim et al (2002) AAC 46: 1481

45. Antibiotic choice and mortality associated with bacteremia due to ESBL-producing K. pneumoniae CID 2004;39:31

46. Thank you for your attention