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Therapeutics

Meta-analysis: A single daily dose of aminoglycosides is as effective as multiple daily dosing with less nephrotoxicity

ACP J Club. 1996 July-Aug;125:10. doi:10.7326/ACPJC-1996-125-1-010


Source Citation

Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ. 1996 Feb 10;312:338-45. [PubMed ID: 8611830]


Abstract

Objective

To determine the efficacy and toxicity of aminoglycosides when given as a single daily dose compared with multiple daily doses.

Data sources

Studies were identified by searching MEDLARS databases (January 1966 to January 1995) with the keywords aminoglycoside and the names of individual drugs and by scanning the bibliographies of identified articles.

Study selection

Studies were selected if they were randomized controlled trials comparing a single daily dose of an aminoglycoside with the same total daily dose given multiple times each day. Studies were excluded if the aminoglycosides were used for surgical prophylaxis, there were no identifiable outcomes for efficacy and toxicity, or aminoglycosides were included in combinations differing between treatment groups.

Data extraction

Data were extracted on the clinical setting and anatomic sites of infection; number of randomized and evaluable patients; specific aminoglycoside used; route, dose, and dosing frequency; duration of treatment; bacteriologic data; use of concurrent antibiotics; definitions and number of failures of antibiotic treatment; and definitions and number of events of nephrotoxicity and ototoxicity. Clinical response took priority over bacteriologic results. For the main analysis, a 50% increase in serum creatinine level was used to define nephrotoxicity.

Main results

21 trials, involving 3091 patients with bacterial infection, met the selection criteria. Data pooled from 19 trials showed that a single daily dose produced a nonsignificant increase in clinical successes {90% vs 87%, risk ratio 1.03, 95% CI 0.99 to 1.07, P = 0.11}*. Single-dose compared with multiple-dose regimens reduced nephrotoxicity (overall rate weighted by study size 5.5% vs 7.7%, P = 0.05). {This absolute risk reduction of 2.2% means that 56 patients (weighted calculation) would need to be treated with a single daily dose (rather than multiple doses) to prevent 1 additional nephrotoxic event, CI 29 to 626; the relative risk reduction was 26%, CI 0% to 46%.}* Ototoxicity did not differ between the 2 dosing regimens, but the statistical power to detect a difference with the pooled results was low. There was also no difference in mortality. The same findings applied to trials with high rates of Pseudomonas infections and to trials in febrile neutropenic patients.

Conclusion

A single daily dose of aminoglycosides in patients without pre-existing renal impairment is as effective as multiple daily dosing, has a lower risk for nephrotoxicity, and has no greater risk for ototoxicity or death.

Source of funding: Agency for Health Care Policy and Research.

For article reprint: Dr. M. Barza, Carney Hospital, Boston, MA, USA. FAX 617-298-1547.

*Numbers calculated from data in article.


Updated Commentary

Meta-analysis: A single daily dose of aminoglycosides is as effective as multiple daily dosing in immunocompetent adults

These 2 systematic reviews provide solid evidence to support once-daily dosing of aminoglycosides, a practice which is now generally accepted. Each team of investigators used a different strategy for identifying and selecting individual studies, and they reached slightly different conclusions. But both meta-analyses strongly support the general conclusion that once-daily dosing is as effective as, and less toxic than, multiple daily dosing.

These meta-analyses show the extent to which estimates of clinical efficacy vary among individual studies, most of which favor once-daily dosing, but a few favor multiple daily dosing (in epidemiologic terms, individual trial results were heterogeneous). When results are "all over the board," it is risky to attempt an "overall" estimate, but once-daily dosing appears to be at least as effective as multiple daily dosing. Barza and colleagues included 2 studies among pediatric patients and 4 studies among neutropenic patients, which also suggested that the 2 dosing regimens are equivalent. The individual studies are reasonably consistent in showing that once-daily dosing results in less nephrotoxicity and ototoxicity.

Although these meta-analyses strongly support the use of once-daily dosing, several important problems remain unresolved. First, data about how particular dosing regimens may benefit different subgroups of patients remain limited (2, 3), as does the evidence on how to calculate doses and monitor patients given once daily dosing. A lesson that can be learned from these 2 meta-analyses is that a few large, multicenter trials would be far more helpful than numerous small studies in answering these remaining questions.

Peter S. Millard, MD, PhD
Family Practice Residency ProgramBangor, Maine, USA


References

1. Levison ME. New dosing regimens for aminoglycoside antibiotics. Ann Intern Med. 1992;117:693-4.

2. Hatala R, Dinh TT, Cook DJ. Single daily dosing of aminoglycosides in immunocompromised adults: a systematic review. Clin Infect Dis. 1997;24:810-5.

3. Tan K, Bunn H. Once daily versus multiple daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev. 201(2):CD002009 (latest version 18 Aug 2000.)