Improved efficacy with nonsimultaneous administration of first doses of gentamicin and ceftazidime in vitro

First doses of aminoglycoside and beta-lactam antibiotics, when used in combination, are usually given simultaneously; however, nonsimultaneous administration may be more efficacious. We used a dynamic in vitro model, which simulates in vivo serum kinetics, to assess the effect of spacing the first doses of gentamicin and ceftazidime used against Pseudomonas aeruginosa ATCC 27853 and two clinical isolates of P. aeruginosa, PA1 and PA2. The following dose regimens against P. aeruginosa ATCC 27853 were compared: (i) gentamicin given alone, (ii) ceftazidime given alone, (iii) gentamicin and ceftazidime given simultaneously, (iv) gentamicin followed by ceftazidime at 15 or 50 min or at 2, 4, or 8 h, and (v) ceftazidime which was followed by gentamicin at 4 h. The effects of regimen iii and the 4-h interval in regimen iv against PA1 and PA2 were also compared. Initial peak concentrations used were 8 mg/liter for gentamicin and 80 mg/liter for ceftazidime, with drug half-lives of 2.5 and 1.8 h, respectively. Compared with simultaneous administration, nonsimultaneous administration (regimens iv and v) produced greater overall bacterial killing and was associated with a delay in bacterial regrowth (p < 0.005) of up to 6.6 to 8.3 h, regardless of the order in which the drugs were given. The optimal interval between gentamicin and ceftazidime doses, which maximized initial bactericidal effect and the time before regrowth, appeared to be 2 to 4 h.