Modifiable Risk Factors for the Emergence of Ceftolozane-tazobactam Resistance

• Published in: Clinical infectious diseases Vol. 73; no. 11; pp. e4599 - e4606
• Main Authors: Tamma, Pranita D, Beisken, Stephan, Bergman, Yehudit, Posch, Andreas E, Avdic, Edina, Sharara, Sima L, Cosgrove, Sara E, Simner, Patricia J
• Format: Journal Article
• Language: English
• Published: United States 06-12-2021
• Subjects: Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Azabicyclo Compounds - pharmacology; Ceftazidime - pharmacology; Cephalosporins - pharmacology; Cephalosporins - therapeutic use; Drug Combinations; Drug Resistance, Multiple, Bacterial - genetics; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa - genetics; Pseudomonas Infections - drug therapy; Pseudomonas Infections - epidemiology; Risk Factors; Tazobactam - pharmacology; Tazobactam - therapeutic use; AmpC; PBP3; DNA polymerase; ceftazidime-avibactam; antimicrobial resistance
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1093/cid/ciaa1306

Ceftolozane-tazobactam (TOL-TAZ) affords broad coverage against Pseudomonas aeruginosa. Regrettably, TOL-TAZ resistance has been reported. We sought to identify modifiable risk factors that may reduce the emergence of TOL-TAZ resistance.
Twenty-eight consecutive patients infected with carbapenem-resistant P. aeruginosa isolates susceptible to TOL-TAZ, treated with ≥72 hours of TOL-TAZ , and with P. aeruginosa isolates available both before and after TOL-TAZ exposure between January 2018 and December 2019 in Baltimore, Maryland, were included. Cases were defined as patients with at least a 4-fold increase in P. aeruginosa TOL-TAZ MICs after exposure to TOL-TAZ. Independent risk factors for the emergence of TOL-TAZ resistance comparing cases and controls were investigated using logistic regression. Whole genome sequencing of paired isolates was used to identify mechanisms of resistance that emerged during TOL-TAZ therapy.
Fourteen patients (50%) had P. aeruginosa isolates which developed at least a 4-fold increase in TOL-TAZ MICs(ie, cases). Cases were more likely to have inadequate source control (29% vs 0%, P = .04) and were less likely to receive TOL-TAZ as an extended 3-hour infusion (0% vs 29%; P = .04). Eighty-six percent of index isolates susceptible to ceftazidime-avibactam (CAZ-AVI) had subsequent P. aeruginosa isolates with high-level resistance to CAZ-AVI, after TOL-TAZ exposure and without any CAZ-AVI exposure. Common mutations identified in TOL-TAZ resistant isolates involved AmpC, a known binding site for both ceftolozane and ceftazidime, and DNA polymerase.
Due to our small sample size, our results remain exploratory but forewarn of the potential emergence of TOL-TAZ resistance during therapy and suggest extending TOL-TAZ infusions may be protective. Larger studies are needed to investigate this association.