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

Drug development for pathogenic bacteria is often a race to achieve tangible clinical benefits with the knowledge that the norm for bacteria is to develop resistance, which often subsequently becomes widely disseminated. With that reality in mind, a Meet-the-Professor session at ID Week 2017 being held in San Diego, California considered the promise and peril of second-generation beta-lactam inhibitors.

To this end, Jose M. Munita, MD, Instituto De Ciencias e Innovacion En Medicina, Clinica Alemana Universidad del Desarrollo, Santiago, Chile, discussed the emerging resistance to the ceftolozane/tazobactam (C/T) combination.

C/T combines ceftolozane—a novel oxymino-aminothiaozyl cephalosporin with a chemical structure very similar to ceftazidine—with the tried-and-true tazobactam beta-lactamase inhibitor. Ceftolozane is active against common gram-negative pathogens, similar to ceftazidime and ceftriaxone. Also, like these latter 2 drugs, ceftolozane is inactivated by extended-spectrum beta-lactamases (ESBLs). This hurdle has been overcome by the addition of tazobactam. The C/T combination is active against most ESBL producers and anaerobic bacteria and was approved in 2014 by the Food and Drug Administration for complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs). The standard dose is 1.5 g Q8 hours delivered intravenously.

“The main projected niche for CT is drug-resistant Pseudomonas aeruginosa,” said Dr. Munita. The drug’s most valuable characteristic, according to him, is its’ “remarkable stability against mechanisms of resistance employed by P. aeruginosa.” The drug targets penicillin-binding proteins (PBP) 1 and 3, with limited action against PBP4. It is also inactive against carbapenemases.

“In vitro, for Enterobacteriaceae, C/T has excellent overall activity against ESBL-positive Escherichia coli and Klebsiella pneumonia, ampicillin-positive E. coli and Enterobacter spp., K. pneumonia carbapenemase producers, and OXA-48 carbapenemase. For P. aeruginosa, C/T is consistently the most active beta-lactam, including for multidrug-resistant species. It is not active for carbapenemase-positive P. aeruginosa,” said Dr. Munita. Inhibitory activity against meropenem non-susceptible P. aeruginosa blood, respiratory tract, and wound isolates have been described. C/T has limited activity against staphylococci and enterococci.

The efficacy and safety of C/T have been reported in a number of randomized controlled trials involving cIAIs (ASPECT-cIAI; NCT01445665 and NCT01445678), cUTI (ASPECT-cUTI; NCT01345929), and ventilated nosocomial pneumonia (ASPECT-NP; NCT02070757).

Trials are one thing. Real-life experience is another. The latter experience from case reports has also revealed good news for C/T, with high rates (67%-74%) of clinical success. However, the picture is not completely rosy. “Resistance is a problem that is looming,” said Dr. Munita. C/T resistance at baseline and both during and following treatment have been documented.

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.

DISCLOSURES

Jose Munita: none

Yohei Doi: Allergan: Scientific Advisor, Consulting fee; The Medicines Company: Scientific Advisor, Consulting fee; Roche: Scientific Advisor, Consulting fee

SOURCES

• Solomkin J et al. 2015 Clin Inf Dis 60:1462-1471
• Humphries RM et al. 2015 Antimicrob Agents Chemother 59:6605-6607.

PRESENTATIONS

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 hoyle@square-rainbow.com.