Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 63, Issue 8, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00779-19
Keywords
Klebsiella pneurnoniae; Pseudomonas aeruginosa; antibiotic combinations; ceftazidime-avibactam
Categories
Funding
- Paratek, Spero
- Tetraphase
- Achaogen, Inc., Albany College of Pharmacy and Health Sciences, Allecra Therapeutics
- American Proficiency Institute
- Becton, Dickinson and Company
- bioMerieux SA, Boston Pharmaceuticals [CEM-102]
- CorMedix Inc.
- DePuy Synthes, Destiny Pharma
- Entasis Therapeutics, Eurofarma Laboratorios SA
- GlaxoSmithKline plc
- Nabriva Therapeutics plc
- Roivant Sciences, Ltd.
- T2 Biosystems, Inc.
- TenNor Therapeutics Ltd.
- University of Colorado
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Multidrug-resistant (MDR) Gram-negative organisms are a major health concern due to lack of effective therapy. Emergence of resistance to newer agents like ceftazidime-avibactam (CZA) further magnifies the problem. In this context, combination therapy of CZA with other antimicrobials may have potential in treating these pathogens. Unfortunately, there are limited data regarding these combinations. Therefore, the objective of this study was to evaluate CZA in combination with amikacin (AMK), aztreonam (AZT), colistin (COL), fosfomycin (FOS), and meropenem (MEM) against 21 carbapenem-resistant Klebsiella pneumoniae and 21 MDR Pseudomonas aeruginosa strains. The potential for synergy was evaluated via MIC combination evaluation and time-kill assays. All strains were further characterized by whole-genome sequencing, quantitative real-time PCR, and SDS-PAGE analysis to determine potential mechanisms of resistance. Compared to CZA alone, we observed a 4-fold decrease in CZA MICs for a majority of K. pneumoniae strains and at least a 2-fold decrease for most P. aeruginosa isolates in the majority of combinations tested. In both P. aeruginosa and K. pneumoniae strains, CZA in combination with AMK or AZT was synergistic (>= 2.15-logio CFU/ml decrease). CZA-MEM was effective against P. aeruginosa and CZA-FOS was effective against K. pneumoniae. Time-kill analysis also revealed that the synergy of CZA with MEM or AZT may be due to the previously reported restoration of MEM or AZT activity against these organisms. Our findings show that CZA in combination with these antibiotics has potential for therapeutic options in difficult to treat pathogens. Further evaluation of these combinations is warranted.
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