Amikacin use and therapeutic drug monitoring in adults: do dose regimens and drug exposures affect either outcome or adverse events? A systematic review

Objectives To identify the amikacin dosage regimens and drug concentrations consistent with good outcomes and to determine the drug exposures related to nephrotoxicity and ototoxicity. Methods A literature review was conducted in Medline, EMBASE and the Cochrane Central Register of Controlled Trials. Full journal articles of randomised controlled trials, controlled clinical trials, interrupted time series trials and controlled before and after studies involving amikacin TDM and dose adjustment were considered for inclusion. Results Seventeen included studies were identified, comprising 1677 participants. Amikacin doses ranged from 11-15 mg/kg/day with thirteen studies using 15 mg/kg/day. Studies were generally designed to compare different aminoglycosides rather than to assess concentration-effect relationships. Only eleven papers presented data on target concentrations, rate of clinical cure and toxicity. Target peak concentrations ranged from 15 – 40 mg/L and target troughs were typically <10 mg/L or <5 mg/L. It was not clear whether these targets were achieved. Measured peaks averaged 28 mg/L for twice daily dosing and 40-45 mg/L for once daily dosing; troughs averaged 5 mg/L and 1-2 mg/L, respectively. Fifteen of the included studies reported rates of nephrotoxicity; auditory and vestibular toxicities were reported in twelve and eight studies. Conclusions This systematic review found little published evidence to support an optimal dosage regimen or TDM targets for amikacin therapy. The use of alternative approaches, such as consensus opinion and a review of current practice, will be required to develop guidelines to maximise therapeutic outcomes and minimise toxicity with amikacin.