期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 59, 期 2, 页码 1020-1029出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.04238-14
关键词
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资金
- AstraZeneca Pharmaceuticals
- Case Western Reserve University [T32 GM07250]
- Cleveland Department of Veterans Affairs and a Veterans Affairs Career Develop-ment Award
- Department of Veterans Affairs Merit Review Program [1I01BX001974]
- Veterans Integrated Service Network 10 Geriatric Research, Education, and Clinical Center [VISN 10 GRECC]
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01 AI100560, R01 AI063517]
- AstraZeneca Pharmaceuticals, Waltham
- Merck Pharmaceuticals
- Cubist Pharmaceuticals
- Cubist Pharmaceuticals, and Steris
Pseudomonas aeruginosa is a notoriously difficult-to-treat pathogen that is a common cause of severe nosocomial infections. Investigating a collection of beta-lactam-resistant P. aeruginosa clinical isolates from a decade ago, we uncovered resistance to ceftazidime-avibactam, a novel beta-lactam/beta-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 beta-lactamase enzymes and that bla(PDC) 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 combination of antimicrobial agents (ceftazidime/avibactam/fosfomycin) 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 development of antimicrobial agents targeted for the treatment of multidrug-resistant bacteria may encounter clinically important resistance. Antibiotic therapy in the future must consider these factors.
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