期刊
JOURNAL OF INFECTIOUS DISEASES
卷 220, 期 4, 页码 666-676出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiz149
关键词
Pseudomonas aeruginosa; beta-lactams; fosfomycin; combination therapy
资金
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [U19-AI109713-SRP, R21AI114508, R01AI100560, R01AI063517, R01AI072219, R01AI090155, R01AI121430, U19AI110819]
- Louis Stokes Cleveland VA Medical Center
- Veterans Affairs Merit Review Program, Department of Veterans Affairs Biomedical Laboratory Research and Development Service [BX002872, BX001974]
- Geriatric Research Education and Clinical Center [VISN 10]
Previously, by targeting penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA with ceftazidime-avibactam-fosfomycin, antimicrobial susceptibility was restored among multidrug-resistant (MDR) Pseudomonas aeruginosa. Herein, ceftazidime-avibactam-fosfomycin combination therapy against MDR P. aeruginosa clinical isolate CL232 was further evaluated. Checkerboard susceptibility analysis revealed synergy between ceftazidime-avibactam and fosfomycin. Accordingly, the resistance elements present and expressed in P. aeruginosa were analyzed using whole-genome sequencing and transcriptome profiling. Mutations in genes that are known to contribute to beta-lactam resistance were identified. Moreover, expression of bla PDC, the mexAB-oprM efflux pump, and murA were upregulated. When fosfomycin was administered alone, the frequency of mutations conferring resistance was high; however, coadministration of fosfomycin with ceftazidime-avibactam yielded a lower frequency of resistance mutations. In a murine infection model using a high bacterial burden, ceftazidime-avibactam-fosfomycin significantly reduced the P. aeruginosa colony-forming units (CFUs), by approximately 2 and 5 logs, compared with stasis and in the vehicletreated control, respectively. Administration of ceftazidime-avibactam and fosfomycin separately significantly increased CFUs, by approximately 3 logs and 1 log, respectively, compared with the number at stasis, and only reduced CFUs by approximately 1 log and 2 logs, respectively, compared with the number in the vehicle-treated control. Thus, the combination of ceftazidime-avibactamfosfomycin was superior to either drug alone. By employing a mechanism-based approach to combination chemotherapy, we show that ceftazidime-avibactam-fosfomycin has the potential to offer infected patients with high bacterial burdens a therapeutic hope against infection with MDR P. aeruginosa that lack metallo-beta-lactamases.
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