New beta-lactams and beta-lactamase inhibitors

David Paterson

Overview

• Ceftolozane/tazobactam

• Ceftazidime/avibactam

• Ceftaroline/avibactam

• Aztreonam/avibactam

• Imipenem/MK7655

Ceftolozane/tazobactam

• Superior antipseduomonal activity compared to ceftazidime

• Active against most ESBL and AmpC producing organisms

• Not active against KPC or MBLs • In Phase 3 trials • Approval expected 2015 (Cubist)

Efficacy against P. aeruginosa

• Ceftolozane has greater binding to penicillin-binding proteins (PBPs) compared to ceftazidime

• Ceftolozane appears to be stable to many Pseudomonas aeruginosa resistance mechanisms. – Ceftolozane enters P. aeruginosa independently of the

OprD channel and therefore, is active against organisms with porin deficiencies or mutations.

– Unregulated efflux has little effect on ceftolozane as ceftolozane is not a substrate for the efflux pumps commonly found in P. aeruginosa

– Low affinity for AmpC – therefore, maintains activity in AmpC-hyperproducing P. aeruginosa.

Activity vs. P. aeruginosa

• MIC 50 1 mg/L • MIC90 4 mg/L

Activity vs ESBLs, KPC, MBLs

• Covers most ESBL-producing Escherichia coli, Klebsiella pneumoniae, and other Enterobacteriaceae

• Covers most AmpC producers

• Does not have activity against KPC or MBLs

Other organisms

Anaerobes: Ceftolozane/tazobactam has activity against Bacteroides fragilis; however, the activity is limited against other anaerobes. Staphylococcus aureus and enterococci: limited activity

PK/PD • Ceftolozane/tazobactam demonstrates linear

pharmacokinetics and there is no accumulation when dosed every 8 to 12 hours.

• Volume of distribution at steady state is 11.0 to 14.1 liters • Low protein binding • Ceftolozane is renally eliminated (almost entirely by

glomerular filtration), and its clearance is not affected by the addition of tazobactam (active renal tubular secretion).

• Ceftolozane penetrates well into the epithelial lining fluid (ELF) after IV administration.

• Mean maximum ELF concentration was 21.8 mg/L

Phase 2 study: UTI

• Ceftolozane vs. ceftazidime

• Microbiologic cure rates – 83% for ceftolozone – 76% for ceftazidime

Phase 2 Studies – Intra-abdominal infections

• Ceftolozane/tazobactam (1.5 g IV q8h) in combination with metronidazole (500 mg IV q8h) versus meropenem (1 g IV q8hrs)

C/tazo Mero Cure (CE) 91% 94% Cure (ME) 89% 96% E. coli 87% 95%

Phase III Studies • Two Phase 3 studies are currently enrolling

– ceftolozane/tazobactam (1.5 g IV q8h) versus levofloxacin (750 mg IV daily) for the treatment of adults with cUTI, including pyelonephritis.

– ceftolozane/tazobactam (1.5g IVq8h) and metronidazole (500 mg IV q8h) versus meropenem (1 g IV q8h) for the treatment of adults with complicated intra-abdominal infections

• A phase 3 RCT for ventilator-associated pneumonia (VAP) comparing ceftolozane/tazobactam 3 g IV every 8 hours with piperacillin/tazobactam 4.5 g IV every 6 hours is expected to begin later this year.

• A phase 3 RCT for VAP comparing ceftolozane/tazobactam 3 g IV every 8 hours with imipenem 1 g every 8 hours is planned. The primary objective of the study is to determine non-inferiority of 28-day mortality rates in adults with VAP using a non-inferiority margin of 10%.

Avibactam

• Novel beta-lactamase inhibitor

• Being developed by AstraZeneca plus Forrest Pharmaceuticals

• Expected to be available in Europe in 12-18 months

Ceftazidime plus Avibactam

Activity against ESBLs and some carbapenem resistant Enterobacteriaceae

• Most KPC producers (not if large amounts of AmpC as well)

• Strains with OXA-48 • Strains which are carbapenem resistant due to porin

loss plus production of an ESBL or AmpC [Livermore AAC 2011;55:390-394]

Ceftazidime plus Avibactam

• No activity against MBL producers

(Will use of avibactam and other similar inhibitors drive proliferation of MBLs?)

Ceftazidime + Avibactam for non-fermenters

• Avibactam reverses ceftazidime resistance mediated by AmpC production by P. aeruginosa

• It does not reverse resistance caused by efflux pumps or OXA beta-lactamases

[S. Mushtaq JAC 2010;65:2376-2381]

Ceftazidime-Avibactam: Phase 2

– Complicated intra-abdominal infections • Ceftazidime-avibactam-metronidazole v. meropenem • Cure rates 91% vs 93%

– Complicated UTI • Ceftazidime-avibactam v. imipenem • Microbiologic eradication rates 70% vs 71%

Ceftazidime-Avibactam

• Phase 3 studies have commenced for intra-abdominal infections and complicated UTI

Ceftaroline-avibactam

• Ceftaroline = antiMRSA cephalosporin

• Phase 2 study: Ceftaroline-avibactam vs. doripenem for complicated UTI

Aztreonam plus avibactam

Active against: • ESBL producers • KPC producers • MBL producers At concentrations of 4 and 4 µg/mL [Livermore AAC 2011;55:390-394]

Imipenem/MK7655

• MK7655 is a novel beta-lactamase inhibitor active against AmpC, ESBLs and KPC

• Active against Pseudomonas aeruginosa isolates with OprD mutations leading to imipenem resistance

• No activity against MBLs • In Phase 2 development

Conclusions

• Ceftolozane plus tazobactam will have enhanced antipseudomonal activity and be useful against some ESBL and AmpC producers

• Ceftazidime plus avibactam will have activity against most ESBL, AmpC and KPC producers

• Imipenem plus MK7655 will have activity against ESBL, AmpC and KPC producers as well as having activity against some carbapenem resistant Pseudomonas

• None of these will be useful for NDM, IMP, VIM etc