Pharmacodynamic effects of extended dosing intervals of imipenem alone and in combination with amikacin against Pseudomonas aeruginosa in an in vitro model

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Abstract
The pharmacodynamic effects of extended imipenem dosing intervals were studied against two strains of Pseudomonas aeruginosa (ATCC 27853 and an imipenem-resistant mutant, 27853R) in an in vitro model of infection. Imipenem was administered as monotherapy (simulated 1-g bolus every 8 or every 12 h) and in combination with amikacin (7.5-mg/kg bolus every 12 h or a 15-mg/kg bolus once). Monotherapy with imipenem administered every 8 h was equally bactericidal at 24 h compared with regimens combined with amikacin for ATCC 27853. Imipenem administered every 12 h against the sensitive strain and both imipenem monotherapy regimens against the resistant strain demonstrated regrowth at 24 h. Although both amikacin regimens administered as monotherapy resulted in rapid bacterial killing activity with respect to time to a 99.9% reduction in log10 CFU/milliliter, regrowth at 24 h was observed at levels reaching or exceeding the initial inoculum. All combination regimens resulted in no detectable growth by 24 h regardless of dosing interval for either drug or initial susceptibility to imipenem. Results from this study indicate the potential for several novel dosing regimens against P. aeruginosa. Monotherapy with imipenem, 1 g every 8 h, was effective against a sensitive strain of P. aeruginosa. Combination therapy with imipenem and once-daily or twice-daily amikacin resulted in increased killing activity against imipenem-resistant P. aeruginosa. Once-daily or twice-daily amikacin in combination therapy, regardless of P. aeruginosa susceptibility, allowed for extension of imipenem dosing intervals.