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
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.