Emergence of ESBL worldwide has become a threat to successful treatment of noocomial infections. This deals with detection and treatment of ESBL infetions.

1. Extended Spectrum Beta Lactamases (ESBL): From Petri Dish to Patient Dr. Ashok Rattan, Super Religare Laboratories, India

2. Sir Alexander Fleming Ernest Boris Chain Sir Howard Florey

3. Beta lactams & β lactamases Oxyimino aminothiazolyl caphalosporin Cefuroxime, cefotaxime, ceftriaxone, Ceftazidime, cefepime, cefpirome

4. TEM & SHV β lactamases

9. Plasmid-mediated TEM and SHV  -lactamases Ampicillin 1965 TEM-1 E.coli S.paratyphi 1970s TEM-1 Reported in 28 Gm(-) sp 1983 ESBL in Europe 1988 ESBL in USA 2000 > 130 ESBLs Worldwide Extended-spectrum Cephalosporins 1963 Evolution of  -Lactamases Look and you will find ESBL

15. Double disk synergy test Jarlier V et al: Rev Infect Dis 1988;10: 867 - 878

16. E test Ceftaz/CA Ceftaz > 8 fold reduction in MIC in presence of CA= ESBL Cefotaxime/CA Cefepime/CA Cefotaxime Cefepime

17. Combination disk method Carter MW et al: J Clin Microbiol 2000; 38: 4228 - 4232 Difference > 5 mm

22. Vitek ESBL confirmatory test Vitek 2 Advanced Expert Simultaneous assessment of antibacterial activity of cefepime, cefotaxime & ceftazidime either alone or + CA  interpretation through advanced expert system

23. Phoenix ESBL test (BD) Uses growth response in 5 wells containing to cefpodoxime, ceftazidime, Ceftazidime + CA, cefotaxime + CA ceftriaxone + CA Results are interpreted through a computer system

24. Microscan ESBL Panel Panels contain ceftazidime alone and in combination with CA And cefotaxime alone and in combination with CA

25. Routine “research” laboratory in a teaching hospital ?

26. Amp C

35. Labor intensive, can be technically challenging, can be difficult to interpret manual methods The gold standard, can detect all variants Nucleotide sequencing Requires a large number of oligonucleotide primers Can distinguish between a number of SHV variants LCR Requires special electrophoresis conditions Can distinguish between a number of SHV variants PCR-SSCP Nucleotide changes must result in altered restriction site for detection Easy to perform, can detect specific nucleotide changes PCR-RFLP Requires specific oligonucleotide probes, labor intensive, cannot detect new variants Detects specific TEM variants Oligotyping Cannot distinguish between ESBLs and non-ESBLs, cannot distinguish between variants of TEM or SHV Easy to perform, specific for gene family (e.g., TEM or SHV) PCR Labor intensive, cannot distinguish between ESBLs and non-ESBLs, cannot distinguish between variants of TEM or SHV Specific for gene family (e.g., TEM or SHV) DNA probes Disadvantages Advantages Test

41. A. TEM, B. SHV

45. Outcome of Serious ESBL Infections When Treated with 3 rd gen Cephalosporin Paterson et.al. 2001. JCM.39:2206-12 54% (15/28) Total 18% (2/11) 27% (3/11) ≤ 1 S 0 (0/3) 67% (2/3) 4 S 0 (0/3) 33% (1/3) 2 S 33% (2/6) 100% (6/6) 8 S Died within 14 d of bacteremia Failure MIC ( µ g/ml) 3 rd gen cef

47. Fatality rates for episodes of bloodstream infections Kim et. al. 2002. AAC.46:1481 – 91. 4 / 78 1 / 9 7 / 39 5 / 6 Subtotal 4 / 36 0 / 25 1 / 1 1 / 8 2 / 2 Competent 13 / 96 4 / 53 0 / 8 6 / 31 3 / 4 Compromised - + - + Shock -> Total Non ESBL ESBL group No. of fatal episodes (%) Immune status

52. MIC (  g/ml) of Ceftazidime alone and in combination (4 +1) with Pot. Clavulonic Acid MIC E.coli 16 E.coli 435 E.coli 387 E.coli 324 kleb. pneum.700603 Kleb. pneum.WHO1 K.aeruginosa KL 139 Klebseilla spp. 53 Proteus spp. Proteus spp. P23 Proteus spp. P18 Proteus spp. P10 Pseudomonas 210 Pseudomonas 204 Pseudomonas 35 Serratia 196 Serratia 63 H S.aureus 240 S.aureus 29213 Ceftazidime Cefta.+ Pot. Clav 32 8 16 0 64 128 256

53. In vivo Escherichia coli lethal mouse model 0 6

55. Association of ampicillin resistance & ESBL production with resistance to non  lactam antibiotics in invasive E. coli Oteo et. al. 2002. AAC.50:945 - 52 16.7 6.3 9.9 2.5 Gentamicin 77.3 32.9 44 9 Cotrimoxazole 63.3 17.2 24 7.3 Ciprofloxacin + - R (%) S (%) ESBL Ampicillin

62. Carbapenem

66. Pharmacokinetics 95 2 30% Protein binding 155 49 41 – 83 ug/ml Cmax 4 1 1 hour T ½ IV / IM IV / IM IV Route 24 8 6 – 8 hours Frequency 1 G 500 mg – 1 G 250 mg – 1 G Dose Ertapenem Meropenem Imipenem

70. Thank you for your attention