In vitro activity of flomoxef, fosfomycin and amikacin versus a global panel of third-generation cephalosporin-resistant Enterobacterales and prediction of their ability in pairwise combinations to work as carbapenem-sparing regimens.

OBJECTIVE: Third generation cephalosporins (3GC) -resistant Gram-negative bacteria are the major cause of neonatal sepsis. Here we predicted the ability of flomoxef, fosfomycin and amikacin pairwise combinations to work as carbapenem-sparing regimens for the empirical treatment of neonatal sepsis. METHODS: A large challenge set panel, enriched for phenotypically characterized multidrug-resistant 3GC non-susceptible Enterobacterales, was used for testing of the three drugs and other antibiotics that are used routinely to treat sepsis in neonates as monotherapy. Predicted susceptibility to the combinations was assessed based on novel combination breakpoint thresholds previously determined by hollow fibre model and checkerboard assays. RESULTS: The rates of susceptibility to the proposed new regimens were superior to other antibiotics that are used to treat neonatal sepsis. The flomoxef-fosfomycin combination was predicted to be effective against 91.8% of isolates. A similar rate of predicted susceptibility was observed for fosfomycin-amikacin (89.8), whereas 83.4% of isolates were predicted to be susceptible to flomoxef-amikacin. CONCLUSION: The results confirm the potential of these combinations as carbapenem-sparing treatments and provide additional evidence to support the evaluation of these combinations in the neonatal sepsis trial that is sponsored by GARDP (ISRCTN48721236).