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BL+BLIs: Emerging evidences

BL+BLIs: Emerging evidences.

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BL+BLIs: Emerging evidences

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  1. BL+BLIs: Emerging evidences “Disclaimer:Presentations are intended for educational purposes only and do not replace independent professional judgment. Statements of fact and opinions expressed are those of the speakers individually and, unless expressly stated to the contrary, are not the opinion or position of AstraZeneca. AstraZeneca does not endorse or approve, and assumes no responsibility for, the content, accuracy or completeness of the information presented. “"Disclaimer: This slide set contains information on the topic based on recent published literature & international guidelines and not endorsed by AstraZeneca. Its the presenter's discretion to modify the slides suitably."

  2. A global study on prevalence of ESBL in K.pneumoniae of over 86,000 isolates from 266 centers Reinert RR, Low DE, Rossi F, et al. J AntimicrobChemother (2007) 60:1018–29.

  3. Clinical suspicion of the β-lactamases in the absence of detection methods

  4. Pip+tazo resistance in tertiary care centers in India hinting coproduction of ESBL+AmpC+OXA

  5. So on one side bugs are getting worseand on other sideNew antibiotic development is not happening

  6. BLIs: Avibactam (NXL104 - Novexel / AstraZeneca) Inhibits • Class A b-lactamases, Inc. ESBLs & KPC • AmpC types • Some class D (OXA) • Few metallo’s Being combined with: • Ceftazidime, Ceftaroline Expected in 2015 Shahid M et al.Critical Reviews in Microbiology, 2009; 35(2): 81–108

  7. The use of the three classical β -lactamase inhibitors (clavulanic acid, tazobactam and sulbactam) in combination with β-lactam antibacterials is currently the most successful strategy to combat β -lactamase-mediated resistance.

  8. BL+BLIs: April 2010 review in Drugs • Various authors have also reported ecological supporting evidence for the activity BL+BLIs against ESBL-producing bacteria, • Use of BL+BLIs as a replacement for extended-spectrum cephalosporins as part of a formulary strategy to, over a period, lower the prevalence of ESBL-producing GNB in healthcare settings. • This strongly suggests that these compounds have a useful ecological impact on the overall reduction of infections due to ESBL-producing bacteria.

  9. Antibiotic susceptibilities BL & BLI combinations from various countriesAntibiotic susceptibilities always increase by adding BLI %

  10. Adding BLI to existing BL: A practical solution to revive exisisting antibiotic • Old and recently developed cephalosporins are threatened by ever evolving new beta-lactamases. • To rescue or at least improve the activity of cephalosporins, • The well-known & established practice of using beta lactamase inhibitor combinations has been revived and applied to recent developmental activities. Current Opinion in Pharmacology 2011, 11:433–438

  11. Cefepime & international guidelines • Cefepime: excellent molecule for nosocomial infections like septicemia, VAP, severe CAP, cIAI, cUTI, cSSTI, menigitis • Recommended by most prestigious international guideline & books like • However, in India, due to high ESBLs • we need to protect cefepime from ESBLs with tazobactam

  12. Cefepime: the most active 4th Gen Ceph • Stable against AmpC & OXA • But it is inactivated by ESBLs • Therefore significant resistance is seen usually when used alone (due to high ESBL prevalence in India)

  13. Appropriate BL+BLI Livermore DM et al. ClinMicrobiol Infect. 2008 Jan;14 Suppl 1:189-93.

  14. Matching PK of Cefepime + Tazobactam

  15. Initial work on combination was done by Dr.David Livermore, HPA, UKCefepime + BLI: Activity against ESBL +ves No of ESBL+ve Klebsiella isolates with MIC (total n=226) MIC (mg/L) MICs reduced from 32-64 to <0.06 Livermore DM et al. ClinMicrobiol Infect. 2008 Jan;14 Suppl 1:189-93.

  16. Adapted from Pal RB et al. J Indian Med Assoc 2008; 106: 605-11

  17. Mouton et al. ICAAC 2010, using EUCAST breakpoints An innovative approach for ESBL... • take a 4th generation cephalosporin (cefepime [PM]) • should cover (partly AmpC) and resist to OXA • add a -lactamase inhibitor (tazobactam [TZ]) • will take care of many ESBL

  18. CLSI 2012 breakpoints S I R 2gm cefepime+250mg tazo BD/TDS can be an optimal dosage

  19. Apollo Chennai study • 50 ESBL+ve E.Coli & K.pneumonaie from variety of specimens Conclusion: Cefepime+tazobactam appears to be a promising alternative in the management of ESBL+ve E.coli & K.pneumoniae. Sureshkumar D and Thirunarayan MA. Comparison of in vitro activities of cefepime vs. cefepime+tazobactam against ESBL producers. Proceedings of the 1st annual conference of clinical infectious disease society (CIDS); 2011 Aug 13-14; Hyderabad, India: abstract book, page-19

  20. Project - EXXTEND

  21. EXXTEND - Study Objectives: • To study the molecular epidemiology of TEM, SHV, CTX-M,  OXA, Amp C & MBL betalactamase producing gram negative (Enterobacteriaceae) pathogens seen among Indian medical centers • To determine the MIC of BL+BLI combinations against Enterobacteriaceae isolates producing betalactamases • To determine the relationship of the zone of inhibition diameter of two available commercial disc preparations of cefepime-tazobactam (30:10) (HiMedia, India) with the MIC (mcg/mL) determined by agar dilution method thereby to arrive at their breakpoints.

  22. Study time line • Feb 2010 TO June 2010 : Study initiation discussions and protocol finalization • September to Dec 2010: IRB approval, procurement of supplies, staff appointments and collection of strains • Jan 2011: Study initiation • Jul 2011: Presentation of initial study results • Dec: Part-1 (breakpoints) Submitted in ECCMID • Jan 2012: Acceptance by ECCMID • June / October 2012: submission at IDSA / ICAAC / ICID

  23. Distribution of 1571 Enterobacteriaceae causing BSI (n=507), UTI (n=469) ,SSTI (n=370), RTI (n=225) at Indian medical centers during (2007-2010)

  24. Distribution of ESBL prevalence among 1571 Enterobacteriaceae obtained from BSI (n=507), UTI (n=469) ,SSTI (n=370), RTI (n=225) at Indian medical centers

  25. AMR seen against three antimicrobial classes: Amikacin, Levofloxacin, Cefotaxime, Piperacillin/Tazobactam, Cefepime/ Tazobactam among 1196 cefepime resistant isolates tested from Indian medical centers

  26. AMR seen among Amikacin, Levofloxacin, Cefotaxime, Cefepime, Cefepime/ Tazobactam, Piperacillin/Tazobactam Cefoperazone/ Sulbactam tested against Enterobacteriaceae strains collected from Indian medical centers

  27. Cefepime:Tazobactam [4µg/ml MIC(µg/ml)] susceptible and resistant among 1196 cefepime resistant Enterobacteriaceae E coli [690] ,Klebsiella spp [424], Enterobacterspp [82] isolates obtained from patients with clinically significant infection BSI [401], UTI [355], SSTI [262], RTI [178] from Indian medical centers Susceptible=957/1196 80% Resistance=239/1196 20%

  28. MIC distribution of Piperacillin:Tazobactam[4µg/ml MIC(µg/ml)] against 1196 Cefepime Resistant E coli (690) , Klebsiella spp (424), Enterobacterspp (82) isolates obtained from patients with BSI (401), UTI (355), SSTI (262), RTI (178) from Indian medical centers Susceptible=798/1196 66.7% Resistance=398/1196 33.3%

  29. MIC distribution of Cefoperazone:Sulbactam [4µg/ml MIC(µg/ml)] against 963 Cefepime Resistant E coli (560) , Klebsiella spp (334), Enterobacterspp (69) isolates obtained from patients with BSI (315), UTI (299), SSTI (221), RTI (128) from Indian medical centers Susceptibility=661/963 68.6%

  30. MIC 50 and MIC 90 of 1196 cefepime resistant gram negative isolate E. coli (n=690), Klebsiellaspp (n=424) and Enterobacterspp (n=82)from Indian medical centers during (2007-2010), when tested againstCefepime/ Tazobactam Cefepime Resistant=690 Ecoli Resistant=424 Resistant=82 Klebsiella spp Enterobacter spp Cefepime/ Tazobactam S=87.1%, R=12.9% S=73.2%, R=26.8% S=69.8%, R=30.2% Sensitive=601 Resistant=89 Sensitive=296 Resistant=128 Sensitive=60 Resistant=22

  31. ID consultant from KIMS, Trivandrum - publication in process • 84 patients • Mean age: 51 years (17) • Site of infection (% of total cases) • Urine : 50.6% • Skin: 14.17% • Lung: 13.15% • Blood: 7.8%

  32. Efficacy of CEF/TAZ by organism isolateA clinical study

  33. Duration of Treatment in CEF/TAZ Responders % of patients Days

  34. Conclusion of this study • The combination of CEF/TAZ will possibly result in superior outcomes compared to other BL+BLI. • These preliminary results suggest that this combination could be a useful alternative, particularly where cost or availability of carbapenems may be an issue. • While we demonstrated 100% susceptibility in vitro in our centre in an unselected group of patients, this may not necessarily imply 100% clinical efficacy.

  35. A study of in vitro Sensitivity of Cefepime+tazobactam & other antimicrobial agents against ENterobacteriaceae Isolated from hospitalized patients of a Tertiary care hospital in India. (ASCENT study) 30 studies

  36. Gram –ve including ESBL producers Gram +ve Minus MRSA MDR Gram -ves Suggested Antibiotics in ICU in current Indian resistance scenario Pathogens Non-Fermentors MRSA Serious to life threatening infections Indications Vancomycin in Serious NP / VAP, Severe/Serious Sepsis, Severe FN & cSSSIs Septic Shock Sepsis Group-2 carbapenems Empiric /1st line in Severe NP / VAP, Sepsis, Severe FN, Bacterial meningitis Severe NP VAP Severe FN / Severe IAI BM Moderate to severe infections • BL+BLIs • Cefepime+Tazobactam can be a potential option) • De-escalation • First line in Moderately severe infections with haemodynamically stable patient profile cIAI / cSSTI / Severe CAP NP/ CAP Non-severe FN / IAI cSSSIs / cUTI For Carbapenem non responders, consider addition of Colistin

  37. Take home messages • ESBLs are highest in India even in community infections. • Bacteria are commonly co-producing AmpC & OXA along with ESBLs • We desperately need new & effective antibiotics against GNB • A practical approach: Cefepime is stable against AmpC & OXA, Tazobactam inactivates ESBL • A combination effectively covers all 3 major resistance mechanisms • Which can be a possible carbapenem saving strategy for de-escalation as well as upfront usage in patients with moderately severe infections in ICU. • Will preserve cefepime in India, which is recommended by guidelines • Combination backed up by multiple Indian & international studies • For the first time ever, India has given breakpoint of an antibiotic to the world

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