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ARTICLE

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

OCT 08, 2017 | BRIAN HOYLE, PHD
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.


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