Efficacy of intermittent versus continuous administration of netilmicin in a two-compartment in vitro model

Abstract

Several aminoglycoside dosage regimens were studied in a kinetic in vitro model. Pseudomonas aeruginosa, Escherichia coli, Klebsieila pneumoniae, and Staphylococcus aureus were exposed in serially placed artificial capillary units to netilmicin concentrations that changed based on human two-compartment pharmacokinetics. The same total dose per 24 h was administered as a continuous infusion (3.7 ,ug/ml) or in 1-h infusions given every 24 (24 ,.g/ml) or 8 h (8 ,Lg/ml). The once daily administration showed the best response in terms of either faster killing of E. coli, K. pneumoniae, and S. aureus or greater reduction of the inocula ofP. aeruginosa. After 28 h of treatment, however, all regimens reduced the nonpseudomonads by more than 99.99%, whereas all three P. aeruginosa strains regrew to >108 CFU/ml due to selection of resistant subpopulations. In contrast to the bactericidal effect of the first dose, no killing occurred after subsequent doses if the ratio of peak drug concentration to MIC was low (c6). These results support the concept of administering high doses of aminoglycosides once every 24 h.

Impact of netilmicin regimens on the activities of ceftazidime-netilmicin combinations against Pseudomonas aeruginosa in an in vitro pharmacokinetic model

“…Eventually all strains regrew to 109 CFU/ml. When multiple doses were administered every 8 h, there was no bactericidal effect of the second and third doses due to the selection of resistant subpopulations (4). In fact, the re- sponses to the Nl x 16 and N3 x 8 regimens were so similar that at any given time between 0 and 28 h the CFU counts differed by less than 1.5 log for each strain.…”

“…A two-compartment pharmacokinetic model which provides exposure of bacteria to changing concentrations of ceftazidime and netilmicin was used in this investigation. A detailed description of this model has been published previously (3,4). In brief, a sterile central compartment consisting of a central reservoir, tubing, and the lumina of capillary bundles represented the systemic circulation.…”

Efficacy of once- and thrice-daily dosing of aminoglycosides in in-vitro models of infection

“…During treatment of either Gram-negative or Gram-positive bacteria resistant subpopulations emerge unless the peak to MIC ratio is high enough to drastically reduce the bacterial inoculum within a few hours (Blaser et al, 1985a). Similarly, rapid emergence of resistant subpopulations has been reported during aminoglycoside treatment in neutropenic animals.…”

“…However, data from in-vitro and experimental in-vivo studies suggest that once-daily dosing of aminoglycoside might be at least as efficacious and potentially less toxic (Frame et al, 1977;Blaser, Stone & Zinner, 1985a;Gerber et al, 1989;Mattie, Craig & Pechere, 1989). Single-daily dosing of aminoglycosides has also been studied clinically (Powell et al, 1983;Hollender et al, 1989).…”

Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Kill Curves versus MIC

“…An additional "absorption" compartment may be added between the diluent reservoir and the central compartment to simulate first-order absorption (10). The model can be used for simulation of both continuous and intermittent drug administration (13). Simultaneous first order elimination kinetics of two drugs with different half-lives were simulated to study antibacterial effects of drug combinations (120,119,14).…”