Single, large, daily aminoglycoside doses in animals are less toxic than conventional dosing, and higher drug concentrations in vitro produce more-rapid bacterial killing. Thus, we compared various aminoglycoside dosing schedules in neutropenic (n = 153) and nonneutropenic (n = 192) guinea pigs with Pseudomonas aeruginosa pneumonia. Equivalent tobramycin dosages were given: 5 mg/kg every 4 h or 30 mg/kg every 24 h. Animals were serially killed during therapy, and quantitative lung cultures were performed. Bacterial titers in lungs dropped rapidly in all tobramycin-treated animals, both neutropenic and nonneutropenic, during the initial 16 h of therapy. In nonneutropenic guinea pigs, lung titers remained constant despite continued 4-h dosing. With subsequent 24-h dosing, titers continued to drop, and by 72 h there were a significant number of animals with sterile lungs (P less than .01). In neutropenic guinea pigs given tobramycin every 24 h, bacterial regrowth occurred; thus, therapy was ineffective. Adding mezlocillin, however, suppressed regrowth; thus, combination therapy was superior (P less than .05).

We have applied a new method of assessment of bactericidal activity in vivo. Calculation of area under the bactericidal activity curve (AUBC) provides a value which involves both the in-vitro bactericidal activity of the drug and its pharmacokinetics. With this method, the activity of combinations of antimicrobials can be assessed in vivo by comparing the AUBC obtained from the combination vs the sum of AUBC from each drug alone. This method may allow a more rational selection of dosage regimens and drug combinations for the treatment of infections.

No abstract

Although newer antimicrobials look promising for the treatment of serious Gram-negative infections, the aminoglycosides still remain part of the mainstay of their therapy. Traditional intermittent therapy is based upon the premise that high serum aminoglycoside concentrations are toxic. However, the rate of bacterial killing for aminoglycosides is also a concentration-dependent phenomenon. An animal model of pseudomonas pneumonia and staphylococcal endocarditis has been used to examine the efficacy of non-traditional aminoglycoside dosing regimens, i.e. single, large daily doses or constant infusions, versus the conventional, intermittent low doses of aminoglycosides. Results demonstrate that high peak concentrations are more efficacious. Other recent data suggest that toxicity might also be less with the large, single daily-dose regimen. The way in which we have been dosing aminoglycosides may not be maximizing their therapeutic potential, nor minimizing their toxicities.

The pharmacokinetics of teicoplanin in serum and dialysate were examined in a crossover study after intravenous and intraperitoneal administration of a 3 mg/kg dose to five anuric patients who were undergoing continuous ambulatory peritoneal dialysis (CAPD). Blood and dialysate samples were obtained for 30 and 15 days, respectively, and were assayed microbiologically. The principal pharmacokinetic parameters after intravenous administration were as follows: total body clearance, 2.76 +/- 1.08 ml/min; elimination half-life, 377 +/- 109 hours; volume of distribution at steady state, 1.04 +/- 0.18 L/kg. Only 9% +/- 6% of the intravenous dose was recovered in the dialysate and the net peritoneal clearance was 0.25 +/- 0.21 ml/min. Bioavailability values, which were assessed by use of three methods after intraperitoneal administration and while dialysate was retained in the peritoneal cavity for 5 hours (dwell time), were 0.77 +/- 0.21, 0.78 +/- 0.05, and 0.76 +/- 0.08. Changes in bioavailability with dwell time were also examined. A dosing guide, which accounts for changes in bioavailability with dwell time, is presented.