Once daily aminoglycoside therapy - Is it less toxic than multiple daily doses and how should it be monitored?

After 50 years of clinical experience with the aminoglycoside agents, there is continuing debate over the most appropriate administration regimen for these drugs. In recent years, once daily administration has been used incre asingly, in the hope of both improving efficacy and reducing toxicity. At l east 30 controlled clinical trials have compared once versus conventional m ultiple daily administration. Efficacy was assessed in some, but not all, s tudies using clinical and/or bacteriological cure. Toxicity was generally d etermined using rather nonsensitive end-points such as measurement of serum creatinine for nephrotoxicity and clinically detectable hearing loss for o totoxicity. The results of individual clinical trials and subsequent meta-analyses have been variable. However, 5 of 9 meta-analyses found clinical efficacy to be significantly better with once daily administration, and in 3 of the 9 the re were significantly less nephrotoxicity with once daily administration. T he results were not significant for ototoxicity in any of the meta-analyses . There is debate about how therapeutic drug monitoring should be performed, and whether it is still required with once daily administration. Previous e xperience with the aminoglycosides, especially in patients with impaired dr ug clearance caused by renal impairment, suggests that monitoring is still prudent. Results from the once daily administration trials appear to suppor t this. Various methods of monitoring and dose adjustment have been proposed. The m ost common is to measure a 24-hour trough concentration and to adjust the d ose to maintain the trough concentration below a value of 2, 1 or 0.5 mg/L. However, this method allows for greater total aminoglycoside exposure than has been permitted with conventional dosages, increasing the likelihood of toxicity in patients with impaired aminoglycoside clearance. Other methods measure drug concentrations at a time-point or points within the dose interval (when the concentration is still measurable), and adjust the dose according to concentration-time curve nomograms or to a target are a under the concentration-time curve. This allows the use of higher doses i n those with high drug clearance. Furthermore, in patients with impaired cl earance, drug exposure is limited to the same extent as, or less than, that with conventional multiple daily administration. To date no controlled tri als have compared methods of dose-individualisation. In summary, in addition to a slight overall improvement in efficacy, once d aily administration has resulted in a small reduction in nephrotoxicity. In the studies using more sensitive measures of toxicity, the differences in toxicity were greater, strengthening the case for once daily administration . Therapeutic drug monitoring is probably required with once daily administ ration. Methods which use mid-dosage interval concentrations to gauge drug exposure would seem to be preferable over trough concentration measurement.