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

OBJECTIVES: The objectives of this study were 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 reporting randomized controlled trials, controlled clinical trials, interrupted time series trials, and controlled before and after studies involving amikacin therapeutic drug monitoring (TDM) and dose adjustment were considered for inclusion. RESULTS: Seventeen studies for inclusion were identified, comprising 1677 participants. Amikacin doses ranged from 11 to 15 mg/kg/day with 13 studies using 15 mg/kg/day. Studies were generally designed to compare different aminoglycosides rather than to assess concentration-effect relationships. Only 11 papers presented data on target concentrations, rate of clinical cure and toxicity. Target peak concentrations ranged from 15 to 40 mg/L and target troughs were typically <10 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 and 1-2 mg/L, respectively. Fifteen of the included studies reported rates of nephrotoxicity; auditory and vestibular toxicities were reported in 12 and 8 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 maximize therapeutic outcomes and minimize toxicity with amikacin.

Pain leads the way: the development of evidence-based medicine for pain relief.

This paper describes the development of evidence based methods in pain medicine since the 1980s at the Pain Research Department of the Nuffield Department of Clinical Neurosciences, Oxford University. Pain medicine can be said to have led the way in terms of developing registers of randomized controlled trials (RCTs) and in developing appropriate methodology for assessing clinical trials and developing metanalytical techniques. This paper tells the story of that development which occurred in conjunction with the development of the Cochrane Collaboration. Pain has a larger body of evidence than many medical specialties with more than 30,000 RCTs and over 2,500 published systematic reviews. Our work continues to raise methodological challenges and a number of key ones are described: Size: We have added to the existing literature to show that small studies overestimate treatment effects. We consider studies with less than 50 participants per treatment group to be at high risk of bias. Mean pain scores: We have shown these to be unhelpful and misleading. We illustrate that response to analgesics is a U-shaped curve with a larger proportion of participants having either a poor response or a good response. Imputation: We discuss the problems of current methods. Tiers of evidence: We propose a way to assess evidence for pain studies. Duplicate publication of data can lead to inflated benefits in systematic reviews. In addition we touch on fraud, pharmaceutical company funding. The final sections cover developments in several areas of pain medicine, and suggest some developments going forward.