Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity

The nephrotoxicity and ototoxicity associated with once-daily versus twice- daily administration of aminoglycosides was assessed in patients with suspe cted or proven gram-negative bacterial infections in a randomized, double-b lind clinical trial, Patients who received therapy for greater than or equa l to 72 h were evaluated for toxicity. Patients also received concomitant a ntibiotics as deemed necessary for treatment of their infection. Plasma ami noglycoside concentrations, prospective aminoglycoside dosage adjustment, a nd serial audiologic and renal status evaluations were performed. The proba bility of occurrence of a nephrotoxic event and its relationship to doses a nd daily aminoglycoside exposure served as the main outcome measurement. On e hundred twenty-three patients were enrolled in the study, with 83 patient s receiving therapy for at least 72 h, For 74 patients plasma aminoglycosid e concentrations were available for analysis, and the patients formed the g roup evaluable for toxicity. The primary infectious diagnosis for the patie nts who were enrolled in the study were bacteremia or sepsis, respiratory i nfections, skin and soft tissue infections, or urosepsis or pyelonephritis. Of the 74 patients evaluable for toxicity, 39 received doses twice daily a nd 35 received doses once daily and a placebo 12 h later. Nephrotoxicity oc curred 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 aminoglycosid es were found to be significant predictors of nephrotoxicity by multivariat e logistic regression analysis (P less than or equal to 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 modeli ng (P less than or equal to 0.002). The results of the multivariate logisti c regression analysis and the Cox proportional hazards modeling demonstrate that both the probability of occurrence and the time to occurrence of amin oglycoside nephrotoxicity are influenced by the schedule on which the amino glycoside is administered as well as by the concomitant use of vancomycin, Furthermore, this risk of occurrence is modulated by the daily AUC for amin oglycoside exposure. These data suggest that once-daily administration of a minoglycosides has a predictably lower probability of causing nephrotoxicit y than twice-daily administration.