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."

A global study on prevalence of ESBL in K 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 Antimicrob Chemother (2007) 60:1018–29.

Clinical suspicion of the β-lactamases in the absence of detection methods Known as % prevalence in large scale Indian studies Antibiotics usually found to be resistant A ESBLs 60-80% 3rd, 4th Gen ceph C AmpC 40% Conventional BL+BLIs D OXA 40-60% B Metallo 5% Carbapenems

Pip-Tazo resistance (%) Pip+tazo resistance in tertiary care centers in India hinting coproduction of ESBL+AmpC+OXA Author ESBL (%) Pip-Tazo resistance (%) Anandan et al, 2009 (CMC Vellore) 70-80 63.1 Taneja, et al, 2008 (PGI) 36.5-51.2 31 Prabhash, et al, 2009 (TMH) 20 52 Shahid, et al, 2007 (JNMC) - 81.9-90.6 Rawat et al, 2009 (Safdarjung) 62.4 30.2 Agarwal, et al, 2008 (AFMC) 16-30 18-30 Mohanty, et al, 2003 (AIIMS) 70 60-78 Parveen, et al, 2010 (JIPMER) 100 (K. pneumoniae)

ESBL KPC NDM-1 MRSA MDR/XDR TB International Journal of Antimicrobial Agents 37 (2011) 291–295

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

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) Chronic disease medications are in; antiinfectives are out Projan, S. Current Opinion in Microbiology2003, 6, 427-430

Steady decline in the No. of FDA approvals

Zinforo / Teflaro: AstraZeneca Ceftaroline: 1st cephalosporin active against MRSA Active against VRSA, DRSA, LRSA, TRSA Gram negative activity: similar to 3rd & 4th 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

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 MIC (mg/L) KPC+ve Kleb E.Coli Pip+Tzo >2048 Pip+NXL 104 8 Ceftriaxone Ceftriaxone+ NXL 104 0.06 Imipenem 32 128 Imipenem+ NXL 104 0.25 0.5 Expected in 2015 Shahid M et al.Critical Reviews in Microbiology, 2009; 35(2): 81–108

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

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.

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.

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

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

Difference between western world & India Parameters Western world India Common Isolates prevalent in ICUs Gram+ves Gram-ves ESBL prevalence in gram –ves Much less Very high Prevalence of ESBLs in last few years Slow increase Rapidly increasing ICU type Mostly closed ICUs Mostly open ICUs Generics Very few Hundreds of generic Restriction of antibiotic prescription Strict Relaxed 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.

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

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)

Appropriate BL+BLI ESBL AmpC OXA Ampicillin + Sul /X X Piperacillin + Tazo  Cefixime + Clav / X Cefotaxime + Sul Ceftazidime + Tazo Cefoperazone+Sul Cefepime + Tazo So, a combination of Cefepime (active agaisnt AmpC & OXA), and Tazobactam (active agaisnt ESBL) should offer a complete solution to a resistant infections, and it can be a potential carbapenem saving strategy. (unlike other BL+BLIs which are not covering AmpC & OXA). Livermore DM et al. Clin Microbiol Infect. 2008 Jan;14 Suppl 1:189-93.

Matching PK of Cefepime + Tazobactam Half life 2 hrs 1 hr Plasma protein binding 20% 20-23% excretion 85% excreted unchanged in urine 80% excreted unchanged in urine Pharmacokinetically also, there is no such concern with this combination.

Initial work on combination was done by Dr Initial work on combination was done by Dr.David Livermore, HPA, UK Cefepime + 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 Similarly, by adding a BLI to cefepime, MICs of all the strains of ESBL+ve Klebsiella isolates were also drastically decreased. (from 0.5-64 to <0.06-0.5). Livermore DM et al. Clin Microbiol Infect. 2008 Jan;14 Suppl 1:189-93.

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

76 ESBL producing Enterobacteriaceae were selected from a variety of clinical specimens. Mouton et al. ICAAC 2010

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 Mouton et al. ICAAC 2010, using EUCAST breakpoints

2gm cefepime+250mg tazo BD/TDS can be an optimal dosage CLSI 2012 breakpoints S I R 2gm cefepime+250mg tazo BD/TDS can be an optimal dosage Tazo dose Tazo conc in blood % sensitivity according to this study based on CLSI breakpoint as per this study 250mg ~16mg/ml 100% 125mg ~8mg/ml 62.5mg ~4mg/ml ~95% 32.125mg ~2mg/ml ~85%

Sensitive to cefepime+tazobactam Apollo Chennai study 50 ESBL+ve E.Coli & K.pneumonaie from variety of specimens Sensitive to cefepime Sensitive to cefepime+tazobactam 50% 82% 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

Project - EXXTEND

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.

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

Laboratory protocols Identification and confirmation of organisms by manual and automated method. DD screen by Kirby Bauer Method Minimum Inhibitory Concentration determination by Agar dilution and ETest

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

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

AMR seen among three antimicrobial classes: Amikacin, Levofloxacin, Cefotaxime, Cefepime, Piperacillin/Tazobactam tested against 1571 Enterobacteriaceae collected from Indian medical centers

AMR seen among three antimicrobial classes: Amikacin, Levofloxacin, Cefotaxime, Cefepime, Piperacillin/Tazobactam from patients at Indian medical centers during (2007-2010) when tested against 1571 Enterobacteriaceae isolate obtained from BSI (n=507), UTI (n=469) ,SSTI (n=370), RTI (n=225)

AMR seen among 1571 Enterobacteriaceae E AMR seen among 1571 Enterobacteriaceae E. coli (n=915), Klebsiella spp (n=541) and Enterobacter spp (n=115) from Indian medical centers When tested against three classes: Amikacin, Levofloxacin, Cefotaxime, Cefepime, Piperacillin/Tazobactam  

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

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

Cefepime:Tazobactam [4µg/ml MIC(µg/ml)] susceptible and resistant among 1196 cefepime resistant Enterobacteriaceae E coli [690] ,Klebsiella spp [424], Enterobacter spp [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%

MIC distribution of Piperacillin:Tazobactam [4µg/ml MIC(µg/ml)] against 1196 Cefepime Resistant E coli (690) , Klebsiella spp (424), Enterobacter spp (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%

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

MIC 50 and MIC 90 of 1196 cefepime resistant gram negative isolate E MIC 50 and MIC 90 of 1196 cefepime resistant gram negative isolate E. coli (n=690), Klebsiella spp (n=424) and Enterobacter spp (n=82) from Indian medical centers during (2007-2010), when tested against Cefepime/ 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

MIC 50 and MIC 90 of 1194 Cefepime Resistant E MIC 50 and MIC 90 of 1194 Cefepime Resistant E. coli (n=689), Klebsiella spp (n=423) and Enterobacter spp (n=82) from Indian medical centers during (2007-2010) when tested against Piperacillin/ Tazobactam   Piperacillin/ Tazobactam S=71.3%, R=28.7% S=63.4%, R=26.% S=60.3%, R=39.7% Sensitive=491 Resistant=198 Sensitive=255 Resistant=168 Sensitive=52 Resistant=30 Klebsiella spp (n=423) E coli (n=689) Enterobacter spp (n=82)

MIC 50 and MIC 90 of 963 Cefepime resistant E MIC 50 and MIC 90 of 963 Cefepime resistant E. coli (n=560), Klebsiella spp (n=334) and Enterobacter spp (n=69) from Indian medical centers during (2007-2010) when tested against Cefoperazone/ Sulbactam   Cefoperazone/ Sulbactam S=76.6%, R=23.4% S=63.8%, R=36.2% S=56.3%, R=43.7% Sensitive=429 Resistant=131 Sensitive=188 Resistant=146 Sensitive=44 Resistant=25 Klebsiella spp (n=334) E coli (n=560) Enterobacter spp (n=69)

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%

Efficacy of CEF/TAZ by organism isolate A clinical study

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

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.

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

Suggested Antibiotics in ICU in current Indian resistance scenario Gram –ve including ESBL producers Gram +ve Minus MRSA Pathogens MDR Gram -ves 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

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