PHARMACODYNAMIC EFFECTS OF EXTENDED DOSING INTERVALS OF IMIPENEM ALONE AND IN COMBINATION WITH AMIKACIN AGAINST PSEUDOMONAS-AERUGINOSA IN AN IN-VITRO MODEL

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 infecti on. Imipenem was administered as monotherapy (simulated 1-g bolus ever y 8 or every 12 h) and in combination with amikacin (7.5-mg/kg bolus e very 12 h or a 15-mg/kg bolus once). Monotherapy with imipenem adminis tered every 8 h was equally bactericidal at 24 h compared with regimen s combined with amikacin for ATCC 27853. Imipenem administered every 1 2 h against the sensitive strain and both imipenem monotherapy regimen s 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 i n log10 CFU/milliliter, regrowth at 24 h was observed at levels reachi ng or exceeding the initial inoculum. All combination regimens resulte d in no detectable growth by 24 h regardless of dosing interval for ei ther drug or initial susceptibility to imipenem. Results from this stu dy indicate the potential for several novel dosing regimens against P. aeruginosa. Monotherapy with imipenem, 1 g every 8 h, was effective a gainst a sensitive strain of P. aeruginosa. Combination therapy with i mipenem and once-daily or twice-daily amikacin resulted in increased k illing activity against imipenem-resistant P. aeruginosa. Once-daily o r twice-daily amikacin in combination therapy, regardless of P. aerugi nosa susceptibility, allowed for extension of imipenem dosing interval s.