In Vitro Activity of Fosfomycin in Double and Triple Combinations with Imipenem, Ciprofloxacin and Tobramycin Against Multidrug-Resistant Escherichia coli

Abstract

The rates of urinary tract infection with multidrug-resistant (MDR) Escherichia coli have dramatically increased and the treatment of these infections with single and double antibiotic combinations became limited or ineffective. The present study aimed at finding effective antibiotic combinations against MDR uropathogenic E. coli. Antibiotic susceptibility testing of uropathogenic E. coli isolates (n = 29) showed that all the examined isolates were found to be MDR. The interaction of double and triple combinations of fosfomycin (FOS) with imipenem (IPM), ciprofloxacin (CIP) and tobramycin (TOB) against selected isolates (n = 8) by checkerboard method showed that all the examined combinations exhibited synergistic effects (FIC index < 1) against tested isolate. However, 1/8, 5/8 and 6/8 of the isolates remained resistant to the constituent antibiotics in FOS/IPM, FOS/CIP and FOS/TOB combinations, respectively. Notably, the triple combinations (FOS/IPM/CIP, FOS/IPM/TOB and FOS/CIP/TOB) increased the synergism against all selected isolates at MIC levels lower than the susceptible breakpoints. Furthermore, time-kill analysis demonstrated that FOS/IPM combination exhibited synergistic and bactericidal effects with UTI-9. However, the combination had no effect on UTI-13. The highest synergistic and bactericidal effects against both representative isolates were achieved by FOS/IPM/CIP, FOS/IPM/TOB and FOS/CIP/TOB combinations after 2 h of post-treatment and lasted up to 24 h. Therefore, we report here that the combinations of FOS with IPM, CIP and TOB could be beneficial against MDR uropathogenic E. coli at least in vitro. The effectiveness of these antibiotics increased in combination with FOS compared to individual antibiotics acting alone.