Prospective Evaluation of the Effect of an Aminoglycoside Dosing Regimen on Rates of Observed Nephrotoxicity and Ototoxicity

Abstract

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.

Experience with a once-daily dosing program of aminoglycosides in critically ill patients

“…Reported nephrotoxicity of aminoglycosides dosed once daily varies between 0-5% [26,27], while this occurs in up to 17% in multiple dosing [27]. Assessment of nephrotoxicity of aminoglycosides in ICU patients is hampered by the presence of numerous other risk-factors, such as hypotension and the concomitant use of other nephrotoxic drugs.…”

Massive gentamicin overdose in a 14-month-old

“…Risk factors may include duration of therapy and magnitude of peak drug concentrations in the context of divided daily therapy [5]. In contrast, single-dose daily aminoglycoside therapy may reduce the incidence of renal dysfunction [6]. The mechanism for aminoglycoside uptake into proximal tubular cells is saturable, and thus, giving the total daily dose at one time may reduce cellular accumulation [7].…”

“…The mechanism for aminoglycoside uptake into proximal tubular cells is saturable, and thus, giving the total daily dose at one time may reduce cellular accumulation [7]. However, once-daily dosing does not change aminoglycoside-associated ototoxicity [6]. In addition, peak levels greater than 40 mg/L have rarely been reported [8].…”

Pharmacokinetic/pharmacodynamic antimicrobial individualization and optimization strategies

“…In view of its concentration-dependent killing, the peak drug concentration in relation to the minimum inhibitory concentration (MIC) ratio for aminoglycosides has been repeatedly shown to be the PK/PD parameter most closely linked to bacterial killing against gram-negative bacteria. Some clinical trials demonstrated a small but significant benefit in clinical outcomes with once-daily dosing [3], whereas other studies demonstrated that the once-daily regimens significantly delayed the onset of nephrotoxicity compared to twice-daily and thrice-daily administration [4,5]. As a result, almost 75% of US hospitals have adopted the extended-interval aminoglycoside dosing, and usage among all age groups has increased [6].…”