In vitro activity of daptomycin combined with other antimicrobial agents against Gram-negative bacteria

Daptomycin (DAP), a cyclic lipopeptide, exerts rapid bactericidal activity against clinically important Gram-positive bacteria. Combination therapy might be beneficial to cover also Gram-negative pathogens in mixed infections. We evaluated the in vitro activities of DAP in combination with 11 other relevant drugs against clinical isolates of Escherichia coli (ECO), Klebsiella pneumoniae (KPN), Klebsiella oxytoca (KOX), Enterobacter cloacae (ECL), Pseudomonas aeruginosa (PAE) and Acinetobacter baumannii (ABA). Methods A total of 50 organisms including strains with various resistance phenotypes were studied. Synergy testing was performed by using the checkerboard broth microdilution method. DAP in combination with amikacin (AMK), tobramycin (TOB), ceftazidime (CAZ), ceftriaxone (CRO), piperacillin-tazobactam (P/T), meropenem (MEM), imipenem (IMP), ciprofloxacin (CIP), moxifloxacin (MOX) or fosfomycin (FOS) were tested against strains of ECO (n=10), ECL (n=10), KPN (n=6) and KOX (n=4) (in total 300 drug combination tests), while DAP in combination with AMK, TOB, CAZ, P/T, MEM, IMP, CIP, MOX or colistin (COL) was tested against 10 strains each of PAE and ABA (in total 180 drug combination tests). The fractional inhibitory concentration indices (∑FICIs) were calculated to interpret the results. Synergism was defined as ∑FICI 0.5 to 4. Results Antagonism was not detected with any combination. Of the 300 drug tests performed with the enterobacterial strains, 284 revealed an indifferent effect, while synergism of DAP plus CIP, CRO, MEM or MOX was observed for 10, 3, 2 and 1 strain, respectively. For non-fermenting bacteria indifference was observed for nearly all drug combinations, while synergism was seen for 2 ABA with COL and 1 ABA with TOB. Conclusions