A Dimer, but not Monomer, of Tobramycin Potentiates Ceftolozane against MDR/XDR Pseudomonas aeruginosa and Delays Resistance Development.
Antimicrob Agents Chemother. 2020 Jan 06;:
Authors: Idowu T, Zhanel GG, Schweizer F
Ceftolozane/Tazobactam is a potent β-lactam/β-lactamase inhibitor combination approved for the treatment of complicated intra-abdominal and complicated urinary tract infections and, more recently, the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. Although the activities of ceftolozane are not enhanced by tazobactam against Pseudomonas aeruginosa, it remains the most potent antipseudomonal agent approved to date. Emerging data worldwide has however reported case reports of microbiological failure in patients with serious bacterial infections caused by multi-drug resistant (MDR) P. aeruginosa as a result of ceftolozane resistance development on therapy. The objective of this study is therefore to compare the efficacy of a tobramycin homodimer + ceftolozane versus ceftolozane/tazobactam alone against MDR and extensively-drug resistant (XDR) P. aeruginosa Tobramycin homodimer, a synthetic dimer of two monomeric units of tobramycin, was developed to abrogate the ribosomal properties of tobramycin with a view to mitigating aminoglycoside-related toxicity and resistance. Herein, we report that tobramycin homodimer, a non-ribosomal aminoglycoside derivative, potentiates the activities of ceftolozane versus MDR/XDR P. aeruginosa in vitro and delays the emergence of resistance to ceftolozane/tazobactam in wild-type PAO1. This combination is also more potent than a standard ceftazidime/avibactam combination against these isolates. Conversely, a tobramycin monomer with intrinsic ribosomal properties does not potentiate ceftolozane under similar conditions. Susceptibility and checkerboard studies were assessed using serial 2-fold dilution assays, following CLSI guidelines. This strategy provides an avenue to further preserve the clinical utility of ceftolozane and enhances its spectrum of activity against one of the most difficult-to-treat pathogens in hospitals.
PMID: 31907191 [PubMed - as supplied by publisher]