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The Promise and Peril of Second-Generation Beta-Lactam Inhibitor Combinations

There are still a lot of unknowns concerning the mechanics of C/T resistance. It is known that resistance can involve a “hypermutable state” resulting from multiple mutations that often led to the overexpression of AmpC beta-lactamases. AmpC hotspots include the omega (Ω) loop and D-loop regions.  Alterations in OXA beta-lactamases can also generate resistance.

“The take-home messages are that the main niche of C/T is multidrug-resistant P. aeruginosa. Most Enterobacteriaceae will be susceptible but it’s probably wise to reserve treatment. Clinical experience is accumulating and the results are encouraging. But, resistance (both basal and during/post C/T therapy) should worry us. Finally, the mechanisms are not fully understood although enzymatic changes are likely very important,” said Dr. Munita.

In looking at other treatments, resistance to the combination of ceftazidime and avibactam (CAZ-AVI) was explored by Yohei Doi, MD, PhD, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Avibactam was originally developed as an inhibitor of ESBLs and AmpC. It has proven to be a good inhibitor of KPC-type beta-lactamases. The CAZ-AVI combo is effective against Enterobacteriaceae that produce KPC, ESBL, AmpC, or OXA-48 beta-lactamases. It is not active against Metallo-beta-lactamase (MBL) producing Enterobacteriaceae or Acinetobacter baumannii.

The picture, so far, for CAZ-AVI is good. For example, a nationwide survey from 2012-2015 revealed 99.3% susceptibility of over 500 KPC-producing Enterobacteriaceae clinical isolates. But, resistance isolates were evident in the study. This resistance has been described by others, as has resistance to MBL. Alterations in the Ω-loop may drive acquisition of resistance.

Whether the oft-repeated pattern of initial drug success followed by increasing resistance plays out in the future for CAZ-AVI remains to be seen.
Other unknowns include the frequency of resistance development while on CAZ-AVI therapy, patient risk factors for resistance, and the persistence of resistant strains.
“CAZ-AVI resistance in Enterobacteriaceae remains rare but can occur, especially while on therapy. The mechanisms of resistance include MBL production, KPC or CTX-M mutations, and the combination of KPC production, reduced permeability, and augmented efflux. Special vigilance is required for patients at risk of MBL and for CAZ-AVI experienced patients,” concluded Dr. Doi.
Jose Munita: none
Yohei Doi: Allergan: Scientific Advisor, Consulting fee; The Medicines Company: Scientific Advisor, Consulting fee; Roche: Scientific Advisor, Consulting fee

  • Solomkin J et al. 2015 Clin Inf Dis 60:1462-1471
  • Humphries RM et al. 2015 Antimicrob Agents Chemother 59:6605-6607.
Meet-the-Professor Session
Second Generation β-Lacatamse Inhibitor Combinations: Promise and Peril
Resistance to Ceftolozane/Tazobactam: Mechanisms, Epidemiology, and Management
Jose M. Munita, MD; Instituto De Ciencias e Innovacion En Medicina (ICIM), Clinica Alemana Universidad del Desarrollo, Santiago, Chile
Resistance to Ceftazidime/Avibactam: Mechanisms, Epidemiology, and Management
Yohei Doi, MD, PhD; University of Pittsburgh Medical Center, Pittsburgh, PA
Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at
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