Establishment of a database of in vitro combined drug efficacy against multi-drug resistant Gram-negative bacilli

Objective To study the synergistic and additive effects of commonly used antibiotics on multi-drug resistant Gram-negative bacilli and to establish a database of combined pharmacodynamics in vitro. Methods Seven antibiotics including fosfomycin (PHOS), levofloxacin (LEV), ceftazidime (CAZ), compound sulfamethoxazole (SMZ), piperacillin/tazobactam (TZP), cefoperazone/sulbactam (SCF) and imipenem (IMP) were selected and grouped into 21 drug pairs. Based on the results of extended spectrum β-lactamases (ESBLs) test and modified carbapenem inactivation method (mCIM), a total of 172 strains of multidrug-resistant Gram-negative bacilli were divided into four groups: 20 strains of carbapenem-resistant Klebsiella pneumoniae (group A), 50 strains of pan-resistant Acinetobacter baumannii (group B), 62 strains of ESBLs-producing Enterobacter (group C) and 40 strains of carbapenem-resistant Pseudomonas aeruginosa (group D). Chessboard dilution method was used to detect the in vitro combined efficacy of 21 drug pairs on drug-resistant bacteria from the four groups. Whonet 5.6 was used for statistical analysis. Results All 172 strains were single drug resistant to the seven antibiotics. Results of the combined drug efficacy test showed that no antagonism was found in the four groups. In group A, ten drug pairs, especially the combination of PHOS+ LEV (30%, 6/20), had synergistic effects and 14 showed partial synergistic effects, but no additive effect was detected. Synergistic effects, partial synergistic effects and additive effects were respectively achieved by 12, ten and three drug pairs in group B. The LEV+ SMZ combination had synergistic effects against 56% (28/50) of the strains, which was the highest among all combinations. There were 14, 17 and 16 drug pairs showing synergistic effects, partial synergistic effects and additive effects in group C, respectively, and the strongest synergistic effects were achieved by the IMP+ LEV combination (30.6%, 19/62). There were 12, 14 and 13 drug pairs having synergistic effects, partial synergistic effects and additive effects in group D, respectively, and the strongest synergistic effects were achieved by the IMP+ LEV combination (20%, 8/40). Conclusions The combined use of quinolones, carbapenems, sulfonamides and PHOS could have good synergistic effects against multi-drug-resistant gram-negative bacilli. Monitoring the in vitro combined efficacy before treatment would improve the accuracy of antibiotic use and is of great clinical value. Key words: Multi-drug resistance; Antibiotics; Gram-negative bacilli; Combined drug efficacy; Synergistic effect; Additive effect