new beta-lactams and beta-lactamase inhibitors
TRANSCRIPT
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