The nephrotoxicity and ototoxicity associated with once-daily versus twice-daily administration of aminoglycosides was assessed in patients with suspected or proven gram-negative bacterial infections in a randomized, double-blind clinical trial. Patients who received therapy for ≥72 h were evaluated for toxicity. Patients also received concomitant antibiotics as deemed necessary for treatment of their infection. Plasma aminoglycoside concentrations, prospective aminoglycoside dosage adjustment, and serial audiologic and renal status evaluations were performed. The probability of occurrence of a nephrotoxic event and its relationship to doses and daily aminoglycoside exposure served as the main outcome measurement. One hundred twenty-three patients were enrolled in the study, with 83 patients receiving therapy for at least 72 h. For 74 patients plasma aminoglycoside concentrations were available for analysis, and the patients formed the group evaluable for toxicity. The primary infectious diagnosis for the patients who were enrolled in the study were bacteremia or sepsis, respiratory infections, skin and soft tissue infections, or urosepsis or pyelonephritis. Of the 74 patients evaluable for toxicity, 39 received doses twice daily and 35 received doses once daily and a placebo 12 h later. Nephrotoxicity occurred in 6 of 39 (15.4%) patients who received aminoglycosides twice daily and 0 of 35 patients who received aminoglycosides once daily. The schedule of aminoglycoside administration, concomitant use of vancomycin, and daily area under the plasma concentration-time curve (AUC) for the aminoglycosides were found to be significant predictors of nephrotoxicity by multivariate logistic regression analysis (P ≤ 0.001). The time to a nephrotoxic event was significantly influenced by vancomycin use and the schedule of administration, as assessed by Cox proportional hazards modeling (P ≤ 0.002). The results of the multivariate logistic regression analysis and the Cox proportional hazards modeling demonstrate that both the probability of occurrence and the time to occurrence of aminoglycoside nephrotoxicity are influenced by the schedule on which the aminoglycoside is administered as well as by the concomitant use of vancomycin. Furthermore, this risk of occurrence is modulated by the daily AUC for aminoglycoside exposure. These data suggest that once-daily administration of aminoglycosides has a predictably lower probability of causing nephrotoxicity than twice-daily administration.

OBJECTIVE: We compared the pharmacokinetics of two methods for dosing gentamicin for the treatment of postpartum endometritis with the goal of achieving adequate peak serum concentrations (>12 mg/L) and prolonged trough levels below 2 mg/L. METHODS: Group-I subjects (n = 5) received intravenous gentamicin, 5 mg/kg per total body weight over 60 min., with a maximum dose of 500 mg. Group-II subjects (n = 17) were dosed intravenously according to the following formula: Dose = desired peak concentration (fixed at 14 mg/L) * (volume of distribution, i.e., 0.35 L/kg) * adjusted body weight (in kilograms). Serum gentamicin levels were obtained 1 hr. and 8-12 hr. after infusion of the second dose. Pharmacokinetic parameters for the subjects in each group were calculated according to standard formulas. RESULTS: Subjects in Group I had significantly higher doses and peak drug concentrations (P < 0.01), while in Group II, 76% of patients had peak levels less than desired (<12 mg/L). Both groups maintained trough levels of <2 mg/L in excess of 12 hr. CONCLUSIONS: Changing to the adjusted body weight formula for Group I, while maintaining a dose between 4 and 5 mg/kg, would reduce excessive peak concentrations. Using a calculated volume of distribution of 0.4 L/kg in Group II would improve peak serum concentrations to the desired levels. Both dosing regimens ensure adequate aminoglycoside pharmacokinetic parameters and avoid the need for monitoring serial serum drug concentrations, provided the expected clinical response is also achieved. While the first dosing formula is simpler to calculate, the second dosing formula allows for more individualized dosing considerations.

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