Pharmacodynamic interactions among meropenem ciprofloxacin and gentamicin in an in-vitro model

Meropenem, gentamicin and ciprofloxacin are often used together as empiric broad-spectrum therapy in different combinations. Recent regulations regarding the use of quinolones mean that greater justification is required when using this component of the combination. An understanding of the pharmacodynamic interactions of the different components of this combination is currently lacking-this could provide insight into the necessity of using the different agents. We aimed to study two- and three-way pharmacodynamic drug-drug interaction between meropenem, gentamicin and ciprofloxacin against Escherichia coli. Static time kill curve experiments were conducted with Escherichia coli (NCTC® 12,241) at 0.25-16 × MIC for a duration of 24 h with samples being collected at 0, 2, 4, 6, 8, and 24 h. Meropenem, gentamicin and ciprofloxacin were tested alone and in two- and three-way combinations. Bacterial load time series data were enumerated on Mueller Hinton agar and colony forming unit data were modelled using nonlinear mixed-effects models in the nlmixr package. Meropenem, gentamicin and ciprofloxacin two- and three-way combinations prevented regrowth, but regrowth was seen when these agents were studied alone. Gentamicin and meropenem were synergistic in decreasing ciprofloxacin IC₅₀. The combination effects of meropenem and gentamicin and the addition of meropenem to a gentamicin/ciprofloxacin combination were indifferent. Our findings demonstrate no additional pharmacodynamic benefit of the meropenem/gentamicin/ciprofloxacin combination over gentamicin/ciprofloxacin. A quinolone free combination of meropenem/gentamicin prevented regrowth, it did not display further synergy on IC₅₀ and was indifferent in initial killing rate.