Evaluation of the Synergy of Ceftazidime-Avibactam in Combination with Meropenem, Amikacin, Aztreonam, Colistin, or Fosfomycin against Well-Characterized Multidrug-Resistant Klebsiella pneumoniae and Pseudomonas aeruginosa

Abstract

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-log10 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.

Parenteral Fosfomycin for the Treatment of Multidrug Resistant Bacterial Infections: The Rise of the Epoxide

“…Colistin and tigecycline were largely indifferent in combination . Ceftazidime‐avibactam was not synergistic with fosfomycin against two isolates in one study but demonstrated synergy against three ceftazidime‐avibactam–resistant isolates in another study …”

“…Several fosfomycin combinations have also been evaluated against K. pneumoniae . Colistin combinations have produced mixed results, demonstrating synergy against some isolates but showing indifference or antagonism against several others .…”

“…80 Several fosfomycin combinations have also been evaluated against K. pneumoniae. 76,79,80,[82][83][84][85][86][87][88] Colistin combinations have produced mixed results, demonstrating synergy against some isolates but showing indifference or antagonism against several others. 79,[82][83][84][85][86][87] Fosfomycin synergy with colistin may depend on fosfomycin resistance because the combination routinely failed to provide any additive effect against fosfomycin-resistant isolates.…”

“…79,87 Fosfomycin has been evaluated in combination with carbapenems, colistin, tigecycline, and ceftazidime-avibactam against P. aeruginosa. 76,79,88,89 Doripenem demonstrated the greatest synergistic activity with fosfomycin among the carbapenems. 76 Colistin and tigecycline were largely indifferent in combination.…”

“…79 Ceftazidimeavibactam was not synergistic with fosfomycin against two isolates in one study but demonstrated synergy against three ceftazidime-avibactam-resistant isolates in another study. 88,89 1088 PHARMACOTHERAPY Volume 39, Number 11, 2019 Fosfomycin was evaluated against A. baumannii in combination with colistin, minocycline, sulbactam, aminoglycosides, b-lactams, and fluoroquinolones. [90][91][92] Sulbactam combinations were synergistic against 75% of isolates tested.…”