Quinoline synergy and reduced use: a study of pharmacodynamic interactions

Background: Meropenem, gentamicin and ciprofloxacin have been used as empiric broad-spectrum combination therapy in different combinations. Recent restrictions on the use of quinolones jeopardises the rational of administering this combination to increase the spectrum of coverage for this particular case. A mechanistic understanding of pharmacodynamic interaction for these combinations is lacking but can provide insight in the necessity of using the different moieties. Objectives: To study pharmacodynamic drug-drug interaction between meropenem, gentamicin and ciprofloxacin against Escherichia coli. Methods: Static time kill curve experiments were conducted with Escherichia coli (NCTC 12241) at 0.25 - 16 x MIC for a duration of 24 hours with samples being collected at 0, 2, 4, 6, 8, and 24 hour. Meropenem, gentamicin and ciprofloxacin were tested alone, in two- and three-way combinations. Bacterial load time series data were enumerated on Meuller Hinton plates and Colony Forming Unit data was modelled using nonlinear mixed-effects models in nlmixr. Results: Meropenem, gentamicin and ciprofloxacin two- and three-way combinations prevented regrowth, but did not when these moieties were studied alone. Gentamicin and meropenem were synergistic by decreasing ciprofloxacin IC50 and the combination effects of meropenem and gentamicin and the addition of meropenem on top of a gentamicin and ciprofloxacin combination were indifferent. Conclusions: Our findings emphasize the added value of a quinolone in the drug combination. In light of the recent move towards reduced use of quinolones, a quinolone free combination still prevented regrowth, it just did not display further synergy on IC50 and was indifferent in initial killing.