Application of Bayes Theorem to Aminoglycoside‐Associated Nephrotoxicity: Comparison of Extended‐Interval Dosing, Individualized Pharmacokinetic Monitoring, and Multiple‐Daily Dosing

Abstract

The objective of this study was to examine the incidence of aminoglycoside-associated nephrotoxicity related to extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing by applying Bayes theorem. An electronic literature search of MEDLINE (1966-2003) and a manual search of references from published meta-analyses and review articles were performed. Studies using extended-interval dosing, individualized pharmacokinetic monitoring, or multiple-daily dosing and reported aminoglycoside-associated nephrotoxicity for patients > or = 16 years of age were included. Quality scores were assigned based on the rigor of definition of aminoglycoside-associated nephrotoxicity, duration of therapy, and length of follow-up of renal function after completion of therapy. Inclusion criteria were then based on these quality scores. Quantitative data on the incidence of aminoglycoside-associated nephrotoxicity were abstracted. Twelve extended-interval dosing studies (n = 916), 10 individualized pharmacokinetic monitoring studies (n = 2066), and 27 multiple-daily dosing studies (n = 4251) met the inclusion criteria. Prior probabilities of aminoglycoside-associated nephrotoxicity were derived from a combination of a review of published studies and expert judgment. The maximum densities for the final posterior probabilities of aminoglycoside-associated nephrotoxicity for extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing were located at 12% to 13%, 10% to 11%, and 13% to 14%, respectively. Application of Bayes theorem demonstrates that aminoglycoside dosing by individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity than extended-interval dosing or multiple-daily dosing.

Evaluation of Four Once‐Daily Aminoglycoside Dosing Nomograms

“…Recent data show that individualized pharmacokinetic monitoring results in reduced nephrotoxicity compared with both once-daily aminoglycoside and traditional multiple-daily dose therapy. 29…”

Section 3: Prevention and Treatment of AKI

“…For these reasons, therapeutic drug monitoring, in combination with or independent from, single-dose daily treatment regimens is recommended. 318, 319, 320, 321 When using therapeutic drug monitoring in single-dose or extended-dose treatment strategies, the C max should be at least 10-fold greater than the MIC of the infecting microorganism. This C min (trough level) should be undetectable by 18–24 hours to limit accumulation of aminoglycosides in renal tubular cells and to minimize the risk of AKI.…”

“…Uniform guidance, based upon carefully performed pharmacokinetic/pharmacodynamic studies on the optimal timing and method of therapeutic drug monitoring with single-daily dosing regimens, would be of great assistance. 319 It is generally recommended that patients receiving extended-dosing interval aminoglycosides should have aminoglycosides administered at even greater dosing intervals if mild or moderate degrees of underlying renal impairment exist. Optimal therapeutic monitoring in the setting of infrequent dosing intervals for patients with underlying CKD needs to be standardized and uniform recommendations need to be provided by careful pharmacokinetic/pharmacodynamic observational studies.…”

“…Uniform guidance, based upon carefully performed pharmacokinetic/pharmacodynamic studies on the optimal timing and method of therapeutic drug monitoring with single-daily dosing regimens, would be of great assistance. 319 …”

Chronopharmacology and Antimicrobial Therapeutics

“…Once-daily administration may reduce the incidence of aminoglycoside nephrotoxicity, [206,212, reviewed in 213]. However, results are not conclusive as some authors have determined that aminoglycoside dosing by individualised pharmacokinetic monitoring results in less aminoglycosideassociated nephrotoxicity than once-or multiple-daily dosing [214,215]. For a once daily dosing schedule, temporal variations either in pharmacokinetics or toxicity, or both, may have clinical implications.…”