Unexpected Challenges in Treating Multidrug-resistant Gram-negative Rods: Resistance to Ceftazidime-Avibactam in Archived Isolates of Pseudomonas aeruginosa.
Antimicrob Agents Chemother. 2014 Dec 1;
Authors: Winkler ML, Papp-Wallace KM, Hujer AM, Domitrovic TN, Hujer KM, Hurless KN, Tuohy M, Hall G, Bonomo RA
Abstract
Pseudomonas aeruginosa is a notoriously difficult-to-treat pathogen that is a common cause of severe nosocomial infections. By investigating a collection of β-lactam resistant P. aeruginosa clinical isolates from a decade ago, we uncovered resistance to ceftazidime-avibactam, a novel β-lactam-β-lactamase inhibitor combination. The isolates were systematically analyzed through a variety of genetic, biochemical, genomic, and microbiological methods to understand how resistance manifests to a unique drug combination that is not yet clinically released. We discovered that avibactam was able to inactivate different AmpC β-lactamase enzymes and that blaPDC regulatory elements and penicillin-binding protein differences did not contribute in a major way to resistance. By using carefully selected combinations of antimicrobial agents, we deduced that the greatest barrier to ceftazidime-avibactam is membrane permeability and drug efflux. To overcome the constellation of resistance determinants, we show that a triple combination of antimicrobial agents targeting multiple cell wall synthetic pathways can restore susceptibility. In P. aeruginosa, efflux, as a general mechanism of resistance, may pose the greatest challenge to future antibiotic development. Our unexpected findings create concern that even the developing of antimicrobial agents targeted for the treatment of multidrug-resistant bacteria may encounter clinically important resistance. The development of antibiotic therapy in the future must consider these factors.
PMID: 25451057 [PubMed - as supplied by publisher]