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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."

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Reinert RR, Low DE, Rossi F, et al. J Antimicrob Chemother (2007) 60:101829. A global study on prevalence of ESBL in K.pneumoniae of over 86,000 isolates from 266 centers

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Clinical suspicion of the -lactamases in the absence of detection methods - lactamases Known as % prevalence in large scale Indian studies Antibiotics usually found to be resistant AESBLs60-80%3 rd, 4 th Gen ceph CAmpC40%Conventional BL+BLIs DOXA40-60%Conventional BL+BLIs BMetallo5%Carbapenems

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

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ESBL KPC MDR/XDR TB MRSA NDM-1 International Journal of Antimicrobial Agents 37 (2011) 291295

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So on one side bugs are getting worse and on other side New antibiotic development is not happening

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Big Pharma No Longer Has a Large Footprint in the Area. Why? Drug development is costly, risky, and lengthy Multiple indications multiple clinical trials Need a clear advantage/differentiation over marketed and generic agents Downward pressure on pricing due to generics Pressure on physicians not to treat Segmented market hospital and community Period of market exclusivity has shrunk for first-in-class drugs High cost of bulk drug (API) Projan, S. Current Opinion in Microbiology2003, 6, 427-430 Chronic disease medications are in; antiinfectives are out

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Steady decline in the No. of FDA approvals

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Zinforo / Teflaro: AstraZeneca Ceftaroline: 1 st cephalosporin active against MRSA Active against VRSA, DRSA, LRSA, TRSA Gram negative activity: similar to 3 rd & 4 th gen ceph Multicentre, randomised, double-blind, phase III trials For cSSTI: CANVAS-1 and CANVAS-2 Non-inferiority of ceftaroline fosamil versus vancomycin + aztreonam For CAP: FOCUS 1 and FOCUS-2 Non-inferiority of ceftaroline vs ceftriaxone + clarithromycin USFDA approval in 2011 Evaluation in sepsis going on

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BLIs: Avibactam (NXL104 - Novexel / AstraZeneca) Inhibits Class A b-lactamases, Inc. ESBLs & KPC AmpC types Some class D (OXA) Few metallos Being combined with: Ceftazidime, Ceftaroline Shahid M et al.Critical Reviews in Microbiology, 2009; 35(2): 81108 MIC (mg/L) KPC+ve Kleb KPC+ve E.Coli Pip+Tzo>2048 Pip+NXL 10488 Ceftriaxone>2048 Ceftriaxone+ NXL 104 0.06 Imipenem32128 Imipenem+ NXL 104 0.250.5 Expected in 2015

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Strategies to preserve utility of -lactam antibiotics Discover or design new -lactam antibiotics that evade enzymatic inactivation Difficult, will take too long - non viable Inhibit -lactamase production for partner -lactam to reach PBP the site of drug action Easy, practical & immediate option Restores efficacy of existing -lactam antibiotic

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

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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. BL+BLIs: April 2010 review in Drugs

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Antibiotic susceptibilities BL & BLI combinations from various countries Antibiotic susceptibilities always increase by adding BLI %

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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, 11:433438

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Difference between western world & India Guidelines made by western world keeping their issues in mind may not suitable for India. 1 1. Soong JH et al. Am J Infect Control 2008;36:S83-92.

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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

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Cefepime: the most active 4 th 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)

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

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Matching PK of Cefepime + Tazobactam CefepimeTazobactam Half life2 hrs1 hr Plasma protein binding 20%20-23% excretion85% excreted unchanged in urine 80% excreted unchanged in urine

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