Evaluation of In vitro Efficacy of Meropenem/Colistin and Meropenem/Fosfomycin Combinations on Multidrug Resistant Gram-Negative Bacilli

The rate of extensively drug-resistant and pan-resistant gram-negative rods isolated as infectious agents is increasing around the world and in Türkiye. One of the important options in the treatment of these infections is the combined use of antibiotics. Therefore, the aim of this study was to investigate the in vitro effect of meropenem/colistin and meropenem/fosfomycin combinations on carbapenem-resistant gram-negative bacilli isolated as infectious agents. Escherichia coli (n= 6), Klebsiella pneumoniae (n= 10), Pseudomonas aeruginosa (n= 5), and Acinetobacter baumannii (n= 6) isolates were recovered from blood and tracheal aspirate samples of patients hospitalized in our hospital's intensive care unit were included in the study. In the first stage of the combination study, minimal inhibitory concentrations (MIC) were investigated by broth microdilution for meropenem and colistin, and agar dilution methods for fosfomycin. In the second stage of the study, synergy, partial synergy, indifference, and antagonistic effects were investigated with the checkerboard method for the meropenem/colistin combination and the agar dilution method for the meropenem/fosfomycin combination. The checkerboard results were interpreted as follows: fractional inhibitory concentration index (FICI) values ≤ 0.5 synergy, < 0.5-≤ 1 partial synergy, > 1-≤ 4 indifference and FIC values of > 4 antagonism. MIC values obtained in the study were interpreted according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. Of the 27 isolates studied with the broth microdilution method, 63% were found to be colistin-resistant and 37% susceptible. The MIC values of fosfomycin against Enterobacterales group bacteria were found to be in the range of 2-2048 mg/L. Two of the six E.coli isolates and nine of the 10 K.pneumoniae isolates were found to be resistant to fosfomycin (IV). The MIC values of ≥ 128 mg/L were found in all 11 non-fermentative gram-negative rods with intrinsic resistance to fosfomycin. In the combination of meropenem/ colistin, synergy and partial synergy were observed in 11 (40.7%) of 27 isolates, an indifference effect was observed in 13 (48.2%), and antagonistic effects were observed in three (11.1%) of the isolates. The synergy and partial synergy effects of this combination were 37.5% for Enterobacterales group bacteria, 50% for E.coli, and 30% for K.pneumoniae. Regarding the 11 non-fermentative gram-negative rods included in the study, 83.3% synergy and partial synergy was found in A.baumannii for the meropenem/colistin combination, while no synergy and partial synergistic effect was found in P.aeruginosa. Meropenem/fosfomycin synergy and partial synergy effects were 83.3% (5/6) for E.coli, 100% (8/8) for K.pneumoniae, 100% (6/6) for A.baumannii, and 25% (1/4) for P.aeruginosa. In all of the isolates studied, meropenem/fosfomycin combination was found to be more effective than the meropenem/colistin combination. It would be meaningful to support these data obtained in vitro with clinical efficacy results to be obtained as a result of the application of antibiotics in vivo, taking into account the pharmacokinetic and pharmacodynamic properties of the antibiotics used in this study.