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. 1996 Feb 10;312(7027):338–345. doi: 10.1136/bmj.312.7027.338

Single or multiple daily doses of aminoglycosides: a meta-analysis.

M Barza 1, J P Ioannidis 1, J C Cappelleri 1, J Lau 1
PMCID: PMC2350289  PMID: 8611830

Abstract

OBJECTIVE--To assess relative efficacy and toxicity of aminoglycosides given by single daily dose compared with multiple daily doses. DESIGN--Meta-analysis of 21 randomised trials identified through MEDLARS (1966 to January 1995). Data were overviewed with fixed effects and random effects models and with meta-regression analysis. SUBJECTS--Total of 3091 patients with bacterial infection, most without pre-existing renal disease. INTERVENTIONS--Patients were randomized to receive aminoglycosides once daily or multiple times daily with similar total daily dose. MAIN OUTCOME MEASURES--Clinical failure of treatment, nephrotoxicity, ototoxicity, and mortality. RESULTS--Single daily dose regimen produced a non-significant decrease in risk of antibiotic failures (random effects risk ratio 0.83 (95% confidence interval 0.57 to 1.21)). Benefit of once daily dosing was greater when the percentage of pseudomonas isolates in a trial was larger. Once daily administration reduced risk of nephrotoxicity (fixed effects risk ratio 0.74 (0.54 to 1.00)). Similar trends were noted for patients with febrile neutropenia and for children. There was no significant difference in ototoxicity between the two dosing regimens, but the power of the pooled trials to detect a meaningful difference was low. There was no significant difference in mortality. CONCLUSIONS--Once daily administration of aminoglycosides in patients without pre-existing renal impairment is as effective as multiple daily dosing, has a lower risk of nephrotoxicity, and no greater risk of ototoxicity. Given the additional convenience and reduced cost, once daily dosing should be the preferred mode of administration.

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Selected References

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  1. Anderson E. T., Young L. S., Hewitt W. L. Simultaneous antibiotic levels in "breakthrough" gram-negative rod bacteremia. Am J Med. 1976 Oct;61(4):493–497. doi: 10.1016/0002-9343(76)90328-4. [DOI] [PubMed] [Google Scholar]
  2. Aronoff G. R., Pottratz S. T., Brier M. E., Walker N. E., Fineberg N. S., Glant M. D., Luft F. C. Aminoglycoside accumulation kinetics in rat renal parenchyma. Antimicrob Agents Chemother. 1983 Jan;23(1):74–78. doi: 10.1128/aac.23.1.74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bamonte F., Dionisotti S., Gamba M., Ongini E., Arpini A., Melone G. Relation of dosing regimen to aminoglycoside ototoxicity: evaluation of auditory damage in the guinea pig. Chemotherapy. 1990;36(1):41–50. doi: 10.1159/000238747. [DOI] [PubMed] [Google Scholar]
  4. Bennett W. M., Plamp C. E., Gilbert D. N., Parker R. A., Porter G. A. The influence of dosage regimen on experimental gentamicin nephrotoxicity: dissociation of peak serum levels from renal failure. J Infect Dis. 1979 Oct;140(4):576–580. doi: 10.1093/infdis/140.4.576. [DOI] [PubMed] [Google Scholar]
  5. Blaser J., Stone B. B., Groner M. C., Zinner S. H. Comparative study with enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance. Antimicrob Agents Chemother. 1987 Jul;31(7):1054–1060. doi: 10.1128/aac.31.7.1054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brummett R. E., Fox K. E., Bendrick T. W., Himes D. L. Ototoxicity of tobramycin, gentamicin, amikacin and sisomicin in the guinea pig. J Antimicrob Chemother. 1978 May;4 (Suppl A):73–83. doi: 10.1093/jac/4.suppl_a.73. [DOI] [PubMed] [Google Scholar]
  7. Chalmers T. C., Lau J. Meta-analytic stimulus for changes in clinical trials. Stat Methods Med Res. 1993;2(2):161–172. doi: 10.1177/096228029300200204. [DOI] [PubMed] [Google Scholar]
  8. Davis R. R., Brummett R. E., Bendrick T. W., Himes D. L. Dissociation of maximum concentration of kanamycin in plasma and perilymph from ototoxic effect. J Antimicrob Chemother. 1984 Sep;14(3):291–302. doi: 10.1093/jac/14.3.291. [DOI] [PubMed] [Google Scholar]
  9. Feld R., Rachlis A., Tuffnell P. G., Duncan I., Moran L., Pinfold P., DeBoer G. Empiric therapy for infections in patients with granulocytopenia. Continuous v interrupted infusion of tobramycin plus cefamandole. Arch Intern Med. 1984 May;144(5):1005–1010. [PubMed] [Google Scholar]
  10. Gerber A. U., Feller-Segessenmann C. In-vivo assessment of in-vitro killing patterns of Pseudomonas aeruginosa. J Antimicrob Chemother. 1985 Jan;15 (Suppl A):201–206. doi: 10.1093/jac/15.suppl_a.201. [DOI] [PubMed] [Google Scholar]
  11. Gerber A. U., Kozak S., Segessenmann C., Flückiger U., Bangerter T., Greter U. Once-daily versus thrice-daily administration of netilmicin in combination therapy of Pseudomonas aeruginosa infection in a man-adapted neutropenic animal model. Eur J Clin Microbiol Infect Dis. 1989 Mar;8(3):233–237. doi: 10.1007/BF01965266. [DOI] [PubMed] [Google Scholar]
  12. Gibson J., Johnson L., Snowdon L., Joshua D., Young G., MacLeod C., Sader C., Iland H., Vincent P., Kronenberg H. Single daily ceftriaxone and tobramycin in the empirical management of febrile neutropenic patients: a randomised trial. Int J Hematol. 1993 Aug;58(1-2):63–72. [PubMed] [Google Scholar]
  13. Gilbert D. N. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother. 1991 Mar;35(3):399–405. doi: 10.1128/aac.35.3.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gonzalez P., Aguado J. M., Martin M. A., Fernandez-Chacon T., Ortuño B. Once-daily aminoglycoside dosing. Lancet. 1993 Apr 3;341(8849):895–895. [PubMed] [Google Scholar]
  15. Herscovici L., Grise G., Thauvin C., Lemeland J. F., Fillastre J. P. Efficacy and safety of once daily versus intermittent dosing of tobramycin in rabbits with acute pyelonephritis. Scand J Infect Dis. 1988;20(2):205–212. doi: 10.3109/00365548809032439. [DOI] [PubMed] [Google Scholar]
  16. Hollender L. F., Bahnini J., De Manzini N., Lau W. Y., Fan S. T., Hermansyur K., Benny P., Husni A. N., Sutjipto, Lorber R. R. A multicentric study of netilmicin once daily versus thrice daily in patients with appendicitis and other intra-abdominal infections. J Antimicrob Chemother. 1989 May;23(5):773–783. doi: 10.1093/jac/23.5.773. [DOI] [PubMed] [Google Scholar]
  17. Kapusnik J. E., Hackbarth C. J., Chambers H. F., Carpenter T., Sande M. A. Single, large, daily dosing versus intermittent dosing of tobramycin for treating experimental pseudomonas pneumonia. J Infect Dis. 1988 Jul;158(1):7–12. doi: 10.1093/infdis/158.1.7. [DOI] [PubMed] [Google Scholar]
  18. Klastersky J., Prévost J. M., Meunier-Carpentier F., Daneau D., Gerard M. Comparative trial of single-dose versus twice-daily sisomicin in bacteriuric patients. J Clin Pharmacol. 1977 Aug-Sep;17(8-9):520–528. doi: 10.1002/j.1552-4604.1977.tb05645.x. [DOI] [PubMed] [Google Scholar]
  19. Labovitz E., Levison M. E., Kaye D. Single-dose daily gentamicin therapy in urinary tract infection. Antimicrob Agents Chemother. 1974 Oct;6(4):465–470. doi: 10.1128/aac.6.4.465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Maller R., Ahrne H., Holmen C., Lausen I., Nilsson L. E., Smedjegård J. Once- versus twice-daily amikacin regimen: efficacy and safety in systemic gram-negative infections. Scandinavian Amikacin Once Daily Study Group. J Antimicrob Chemother. 1993 Jun;31(6):939–948. doi: 10.1093/jac/31.6.939. [DOI] [PubMed] [Google Scholar]
  21. Marik P. E., Lipman J., Kobilski S., Scribante J. A prospective randomized study comparing once- versus twice-daily amikacin dosing in critically ill adult and paediatric patients. J Antimicrob Chemother. 1991 Nov;28(5):753–764. doi: 10.1093/jac/28.5.753. [DOI] [PubMed] [Google Scholar]
  22. Mauracher E. H., Lau W. Y., Kartowisastro H., Ong K. H., Genato V. X., Limson B., Yusi G. M., Liu C. Y., Suwangool P. Comparison of once-daily and thrice-daily netilmicin regimens in serious systemic infections: a multicenter study in six Asian countries. Clin Ther. 1989 Sep-Oct;11(5):604–613. [PubMed] [Google Scholar]
  23. McCormack J. P., Jewesson P. J. A critical reevaluation of the "therapeutic range" of aminoglycosides. Clin Infect Dis. 1992 Jan;14(1):320–339. doi: 10.1093/clinids/14.1.320. [DOI] [PubMed] [Google Scholar]
  24. Mendes da Costa P., Kaufman L. Amikacin once daily plus metronidazole versus amikacin twice daily plus metronidazole in colorectal surgery. Hepatogastroenterology. 1992 Aug;39(4):350–354. [PubMed] [Google Scholar]
  25. Moore R. D., Smith C. R., Lietman P. S. The association of aminoglycoside plasma levels with mortality in patients with gram-negative bacteremia. J Infect Dis. 1984 Mar;149(3):443–448. doi: 10.1093/infdis/149.3.443. [DOI] [PubMed] [Google Scholar]
  26. Mordenti J. J., Quintiliani R., Nightingale C. H. Combination antibiotic therapy: comparison of constant infusion and intermittent bolus dosing in an experimental animal model. J Antimicrob Chemother. 1985 Jan;15 (Suppl A):313–321. doi: 10.1093/jac/15.suppl_a.313. [DOI] [PubMed] [Google Scholar]
  27. Noone P., Parsons T. M., Pattison J. R., Slack R. C., Garfield-Davies D., Hughes K. Experience in monitoring gentamicin therapy during treatment of serious gram-negative sepsis. Br Med J. 1974 Mar 16;1(5906):477–481. doi: 10.1136/bmj.1.5906.477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nordström L., Lerner S. A. Single daily dose therapy with aminoglycosides. J Hosp Infect. 1991 Jun;18 (Suppl A):117–129. doi: 10.1016/0195-6701(91)90013-x. [DOI] [PubMed] [Google Scholar]
  29. Nordström L., Ringberg H., Cronberg S., Tjernström O., Walder M. Does administration of an aminoglycoside in a single daily dose affect its efficacy and toxicity? J Antimicrob Chemother. 1990 Jan;25(1):159–173. doi: 10.1093/jac/25.1.159. [DOI] [PubMed] [Google Scholar]
  30. Oakes M. The logic and role of meta-analysis in clinical research. Stat Methods Med Res. 1993;2(2):147–160. doi: 10.1177/096228029300200203. [DOI] [PubMed] [Google Scholar]
  31. Olier B., Viotte G., Morin J. P., Fillastre J. P. Influence of dosage regimen on experimental tobramycin nephrotoxicity. A biochemical approach. Chemotherapy. 1983;29(6):385–394. doi: 10.1159/000238225. [DOI] [PubMed] [Google Scholar]
  32. Powell S. H., Thompson W. L., Luthe M. A., Stern R. C., Grossniklaus D. A., Bloxham D. D., Groden D. L., Jacobs M. R., DiScenna A. O., Cash H. A. Once-daily vs. continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin, and tobramycin. J Infect Dis. 1983 May;147(5):918–932. doi: 10.1093/infdis/147.5.918. [DOI] [PubMed] [Google Scholar]
  33. Prins J. M., Büller H. R., Kuijper E. J., Tange R. A., Speelman P. Once versus thrice daily gentamicin in patients with serious infections. Lancet. 1993 Feb 6;341(8841):335–339. doi: 10.1016/0140-6736(93)90137-6. [DOI] [PubMed] [Google Scholar]
  34. Reiner N. E., Bloxham D. D., Thompson W. L. Nephrotoxicity of gentamicin and tobramycin given once daily or continuously in dogs. J Antimicrob Chemother. 1978 May;4 (Suppl A):85–101. doi: 10.1093/jac/4.suppl_a.85. [DOI] [PubMed] [Google Scholar]
  35. Roosendaal R., Bakker-Woudenberg I. A., van den Berghe-van Raffe M., Vink-van den Berg J. C., Michel B. M. Impact of the dosage schedule on the efficacy of ceftazidime, gentamicin and ciprofloxacin in Klebsiella pneumoniae pneumonia and septicemia in leukopenic rats. Eur J Clin Microbiol Infect Dis. 1989 Oct;8(10):878–887. doi: 10.1007/BF01963774. [DOI] [PubMed] [Google Scholar]
  36. Rozdzinski E., Kern W. V., Reichle A., Moritz T., Schmeiser T., Gaus W., Kurrle E. Once-daily versus thrice-daily dosing of netilmicin in combination with beta-lactam antibiotics as empirical therapy for febrile neutropenic patients. J Antimicrob Chemother. 1993 Apr;31(4):585–598. doi: 10.1093/jac/31.4.585. [DOI] [PubMed] [Google Scholar]
  37. Sturm A. W. Netilmicin in the treatment of gram-negative bacteremia: single daily versus multiple daily dosage. J Infect Dis. 1989 May;159(5):931–937. doi: 10.1093/infdis/159.5.931. [DOI] [PubMed] [Google Scholar]
  38. Thompson S. G. Controversies in meta-analysis: the case of the trials of serum cholesterol reduction. Stat Methods Med Res. 1993;2(2):173–192. doi: 10.1177/096228029300200205. [DOI] [PubMed] [Google Scholar]
  39. Tran Ba Huy P., Bernard P., Schacht J. Kinetics of gentamicin uptake and release in the rat. Comparison of inner ear tissues and fluids with other organs. J Clin Invest. 1986 May;77(5):1492–1500. doi: 10.1172/JCI112463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Van der Auwera P., Meunier F., Ibrahim S., Kaufman L., Derde M. P., Tulkens P. M. Pharmacodynamic parameters and toxicity of netilmicin (6 milligrams/kilogram/day) given once daily or in three divided doses to cancer patients with urinary tract infection. Antimicrob Agents Chemother. 1991 Apr;35(4):640–647. doi: 10.1128/aac.35.4.640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Vanhaeverbeek M., Siska G., Douchamps J., Herchuelz A. Comparison of the efficacy and safety of amikacin once or twice-a-day in the treatment of severe gram-negative infections in the elderly. Int J Clin Pharmacol Ther Toxicol. 1993 Mar;31(3):153–156. [PubMed] [Google Scholar]
  42. Verpooten G. A., Giuliano R. A., Verbist L., Eestermans G., De Broe M. E. Once-daily dosing decreases renal accumulation of gentamicin and netilmicin. Clin Pharmacol Ther. 1989 Jan;45(1):22–27. doi: 10.1038/clpt.1989.4. [DOI] [PubMed] [Google Scholar]
  43. Viganò A., Principi N., Brivio L., Tommasi P., Stasi P., Villa A. D. Comparison of 5 milligrams of netilmicin per kilogram of body weight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram-negative pyelonephritis in children. Antimicrob Agents Chemother. 1992 Jul;36(7):1499–1503. doi: 10.1128/aac.36.7.1499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Vogelman B., Gudmundsson S., Turnidge J., Leggett J., Craig W. A. In vivo postantibiotic effect in a thigh infection in neutropenic mice. J Infect Dis. 1988 Feb;157(2):287–298. doi: 10.1093/infdis/157.2.287. [DOI] [PubMed] [Google Scholar]
  45. Wood C. A., Norton D. R., Kohlhepp S. J., Kohnen P. W., Porter G. A., Houghton D. C., Brummett R. E., Bennett W. M., Gilbert D. N. The influence of tobramycin dosage regimens on nephrotoxicity, ototoxicity, and antibacterial efficacy in a rat model of subcutaneous abscess. J Infect Dis. 1988 Jul;158(1):13–22. doi: 10.1093/infdis/158.1.13. [DOI] [PubMed] [Google Scholar]
  46. de Vries P. J., Verkooyen R. P., Leguit P., Verbrugh H. A. Prospective randomized study of once-daily versus thrice-daily netilmicin regimens in patients with intraabdominal infections. Eur J Clin Microbiol Infect Dis. 1990 Mar;9(3):161–168. doi: 10.1007/BF01963832. [DOI] [PubMed] [Google Scholar]
  47. ter Braak E. W., de Vries P. J., Bouter K. P., van der Vegt S. G., Dorrestein G. C., Nortier J. W., van Dijk A., Verkooyen R. P., Verbrugh H. A. Once-daily dosing regimen for aminoglycoside plus beta-lactam combination therapy of serious bacterial infections: comparative trial with netilmicin plus ceftriaxone. Am J Med. 1990 Jul;89(1):58–66. doi: 10.1016/0002-9343(90)90099-y. [DOI] [PubMed] [Google Scholar]

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