Once-daily dosing of aminoglycosides

  • J. Blaser
  • C. König


Since their introduction one or more decades ago, aminoglycosides have generally been administered in multiple daily (i.e. twiceor thrice-daily) dosing regimens. However, nephrotoxicity can be reduced in animal models by administering the same total daily dose as one large dose instead of as multiple small doses. In addition, in vitro and in vivo studies that considered the impact of dosing regimens on efficacy suggest that once-daily dosing is equally or more effective compared to multiple daily dosing. Once-daily versus multiple daily dosing regimens have been compared for amikacin, netilmicin, and gentamicin in 24 randomized, clinical trials including a total of 3,181 patients. An analysis of these studies revealed superior results for once-daily regimens with respect to clinical efficacy (89.5 % vs. 84.7%, p<0.001) as well as bacteriological efficacy (88.6% vs. 83.4%, p<0.01). No statistically significant differences were noted for toxicity. Nevertheless, both nephrotoxicity and ototoxicity occurred less frequently during once-daily dosing (4.5% vs. 5.5% and 4.2% vs. 5.8%, respectively). Finally, once-daily dosing is more economical, since less nursing time and infusion material are required and the efforts for drug monitoring can be reduced. In conclusion, amikacin, netilmicin, and gentamicin can be administered once a day.


Gentamicin Clinical Efficacy Dose Regimen Large Dose Aminoglycosides 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Moore RD, Lietman PS, Craig RS: Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. Journal of Infectious Diseases 1987, 155: 93–99.Google Scholar
  2. 2.
    Blaser J, Stone BB, Groner MC, Zinner SH: 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. Antimicrobial Agents and Chemotherapy 1987, 31: 1054–1060.Google Scholar
  3. 3.
    Craig WA, Reddington J, Ebert SC: Pharmacokinetics of amikacin in vitro and in mouse thigh and lung infection. Journal of Antimicrobial Chemotherapy 1991, 27, Supplement C: 29–40.Google Scholar
  4. 4.
    Vogelman B, Craig WA: Kinetics of antimicrobial activity. Journal of Pediatrics 1986, 108: 835–840.Google Scholar
  5. 5.
    Blaser J, Stone BB, Zinner SH: Efficacy of intermittent versus continuous administration of netilmicin in a two compartment in vitro model. Antimicrobial Agents and Chemotherapy 1985, 27: 343–349.Google Scholar
  6. 6.
    Daikos GL, Lolans VT, Jackson GG: First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use. Antimicrobial Agents and Chemotherapy 1991, 35: 117–123.Google Scholar
  7. 7.
    Gerber AU, Craig WA: Aminoglycoside selected subpopulations ofP. aeruginosa. Characterisation and virulence in normal and leukopenic mice. Journal of Laboratory and Clinical Medicine 1982, 100: 671–681.Google Scholar
  8. 8.
    Gerber AU, Kozak S, Segessenmann C, Flückiger U, Bangerter T, Greter U: Once-daily versus thrice-daily administration of netilmicin in combination therapy ofPseudomonas aeruginosa infection in a man-adapted neutropenic animal model. European Journal of Clinical Microbiology & Infectious Diseases 1989, 8: 233–237.Google Scholar
  9. 9.
    Bundtzen RW, Gerber AU, Cohn DL, Craig WA: Postantibiotic suppression of bacterial growth. Reviews in Infectious Diseases 1981, 3: 28–37.Google Scholar
  10. 10.
    Vogelman B, Gudmundsson S, Turnidge J, Leggett J, Craig WA: In vivo postantibiotic effect in a thigh infection in neutropenic mice. Journal of Infectious Diseases 1988, 157: 287–297.Google Scholar
  11. 11.
    Cars O, Odenholt-Tornqvist I: The post-antibiotic sub-MIC effect in vitro and in vivo. Journal of Antimicrobial Chemotherapy 1993, 31, Supplement D: 159–166.Google Scholar
  12. 12.
    Schlaeffer F, Blaser J, Laxon J, Zinner S: Enhancement of leucocyte killing of resistant bacteria selected during exposure to aminoglycosides or quinolones. Journal of Antimicrobial Chemotherapy 1990, 25: 941–948.Google Scholar
  13. 13.
    Blaser J: Efficacy of once-versus thrice-daily dosing of aminoglycosides in in-vitro models of infection. Journal of Antimicrobial Chemotherapy 1991, 27, Supplement C: 21–28.Google Scholar
  14. 14.
    Vergères P, Blaser J: Amikacin, ceftazidime and flucloxacillin against suspended and adherentPseudomonas aeruginosa andStaphylococcus epidermidis in an in vitro model of infection. Journal of Infectious Diseases 1992, 165: 281–289.Google Scholar
  15. 15.
    Blaser J, Stone BB, Groner MC, Zinner SH: Impact of netilmicin regimens on the activity of ceftazidime-netilmicin combinations againstPseudomonas aeruginosa in an in vitro pharmacokinetic model. Antimicrobial Agents and Chemotherapy 1985, 28: 64–68.Google Scholar
  16. 16.
    Powell SH, Thompson WL, Luthe MA, Stern RC, Grossniklaus DA, Bloxham DD, Groden DL, Jacobs MR, Discenna AO, Cash HA, Klinger JD: Once-daily vs. continuous aminoglycoside dosing: efficacy and toxicity in animal studies of gentamicin, netilmicin, and tobramycin. Journal of Infectious Diseases 1983, 147: 918–932.Google Scholar
  17. 17.
    Gerber AU, Craig WA, Brugger HP, Feller C, Vastola AP, Brandel J: Impact of dosing intervals on activity of gentamicin and ticarcillin againstPseudomonas aeruginosa in granulocytopenic mice. Journal of Infectious Diseases 1983, 147: 910–917.Google Scholar
  18. 18.
    Kapusnik JE, Hackbarth CJ, Chambers HF, Carpenter T, Sande MA: Single, large daily dosing versus intermittent dosing of tobramycin for treating experimentalPseudomonas pneumonia. Journal of Infectious Diseases 1988, 158: 7–12.Google Scholar
  19. 19.
    Fantin B, Carbon C: Importance of the aminoglycoside dosing regimen in the penicillin-netilmicin combination for treatment ofEnterococcus faecalis-induced experimental endocarditis. Antimicrobial Agents and Chemotherapy 1990, 34: 2387–2391.Google Scholar
  20. 20.
    Gerber AU, Vastola AP, Brandel J, Craig WA: Selection of aminoglycoside-resistant subpopulations ofPseudomonas aeruginosa in an in vivo model. Journal of Infectious Diseases 1982, 146: 691–697.Google Scholar
  21. 21.
    Olson B, Weinstein RA, Nathan C, Chamberlin W, Kabins SA: Occult aminoglycoside resistance inPseudomonas aeruginosa: epidemiology and implications for therapy and control. Journal of Infectious Diseases 1985, 152: 769–774.Google Scholar
  22. 22.
    Gerber AU, Brugger H-P, Feller C, Stritzko T, Stalder B: Antibiotic therapy of infections due toPseudomonas aeruginosa in normal and granulocytopenic mice: comparison of murine and human pharmacokinetics. Journal of Infectious Diseases 1986, 153: 90–97.Google Scholar
  23. 23.
    Kahlmeter G, Dahlager JI: Aminoglycoside toxicity — a review of clinical studies published between 1975 and 1982. Journal of Antimicrobial Chemotherapy 1984, 13, Supplement A: 9–22.Google Scholar
  24. 24.
    Bennet WM, Plamp CE, Gilbert DN, Parker RA, Porter GA: The influence of dosage regimen on experimental gentamicin nephrotoxicity: dissociation of peak serum levels from renal failure. Journal of Infectious Diseases 1979, 140: 576–680.Google Scholar
  25. 25.
    Frame PT, Phair JP, Watanakunakorn C, Bannister TWP: Pharmacologic factors associated with gentamicin nephrotoxicity in rabbits. Journal of Infectious Diseases 1977, 135: 952–957.Google Scholar
  26. 26.
    Reiner NE, Bloxham DD, Thompson WL: Nephrotoxicity of gentamicin and tobramycin given once daily or continuously in dogs. Journal of Antimicrobial Chemotherapy 1978, 4, Supplement A: 85–101.Google Scholar
  27. 27.
    Wood CA, Norton DR, Kohlhepp SJ, Kohnen PW, Porter GA, Houghton DC, Brummett RE, Bennett WM, Gilbert DN: The influence of tobramycin dosage regimens on nephrotoxicity, ototoxicity and antibacterial efficacy in a rat model of subcutaneous abscess. Journal of Infectious Diseases 1988, 158: 13–22.Google Scholar
  28. 28.
    Giuliano RA, Paulus GJ, Verpooten GA, Pattyn VM, Pollet DE, Nouwen EJ, Laurent G, Carlier M-B, Maldague P, Tulkens PM, De Broe ME: Recovery of cortical phospholipidoses and necrosis after acute gentamicin loading in rats. Kidney International 1984, 26: 838–847.Google Scholar
  29. 29.
    Giuliano RA, Verpooten GA, Verbist L, Wedeen R, De Broe ME: In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats. Journal of Pharmacology and Experimental Therapy 1986, 236: 470–475.Google Scholar
  30. 30.
    de Broe ME, Giuliano RA, Verpooten GA: Choice of drug and dosage regimen: two important risk factors for aminoglycoside nephrotoxicity. American Journal of Medicine 1986, 80, Supplement 6B: 115–118.Google Scholar
  31. 31.
    Verpooten GA, Giuliano RA, Verbist L, Eestermans G, De Broe ME: Once-daily dosing decreases renal accumulation of gentamicin and netilmicin. Clinical Pharmacology and Therapy 1989, 45: 22–27.Google Scholar
  32. 32.
    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. Journal of Clinical Investigation 1986, 77: 1492–1500.Google Scholar
  33. 33.
    Tran Ba Huy P, Defrennes D: Aminoglycoside binding sites in the inner ears of guinea pigs. Antimicrobial Agents and Chemotherapy 1988, 32: 467–472.Google Scholar
  34. 34.
    Tran Ba Huy P: Aminoglycoside ototoxicity: influence of dosage regimen on drug uptake, correlation between membrane binding and clinical features. Journal of Drug Development 1988, 1: 93–95.Google Scholar
  35. 35.
    Noone P, Parson TMC, Pattison JR, Slack RCB, Garfield-Davies D, Hughes K: Experience in monitoring gentamicin therapy during treatment of serious gram-negative sepsis. British Medical Journal 1974, 1: 477–481.Google Scholar
  36. 36.
    Moore RD, Smith CR, Lietman PS: Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. American Journal of Medicine 1984, 77: 657–662.Google Scholar
  37. 37.
    Muijsken MA, Vreede RW, Van Dijk WC, Haverkorn MJ, Kaufman L, Drede MP: A randomized clinical study of efficacy and safety of once daily dosing versus conventional dosing of netilmicin in patients with severe infections. Journal of Drug Development 1988, 1, Supplement 3: 145–146.Google Scholar
  38. 38.
    Hansen M, Achen F, Carstensen C, Coolidge J, Dahlager J, Frimodt-Möller N, Kjaersgaard E, Larsen H, Wilkenschildt M, Zador G, Hippe E: Once versus thrice daily dosing of netilmicin in febrile immunocompromised patients: a randomized, controlled study of efficacy and safety. Journal of Drug Development 1988, Supplement 3: 119–124.Google Scholar
  39. 39.
    Fan ST, Lau WY, Teoh-Chan CH, Lau KF, Mauracher EH: Once daily administration of netilmicin compared with thrice daily, both in combination with metronidazole, in gangrenous and perforated appendicitis. Journal of Antimicrobial Chemotherapy 1988, 22: 69–74.Google Scholar
  40. 40.
    Hollender LF, Bahnini J, De Manzini N, Lau WY, Fan ST, Hermansyur K, Benny P, Husni AN, Sutjpto, Lorber RR: A multicentric study of netilmicin once daily versus thrice daily in patients with appendicitis and other intraabdominal infections. Journal of Antimicrobial Chemotherapy 1989, 23: 773–783.Google Scholar
  41. 41.
    Mauracher EH, Lau WY, Kartowisastro H, Ong KH, Genato VX, Limson B, Yusi GM, Liu CY, Suwangool P: Comparison of once-daily and thrice-daily netilmicin regimens in serious systemic infections: a multicenter study in six Asian countries. Clinical Therapeutics 1989, 11: 604–613.Google Scholar
  42. 42.
    Sturm AW: Netilmicin in the treatment of gram-negative bacteremia: single daily versus multiple daily dosage. Journal of Infectious Diseases 1989, 159: 931–937.Google Scholar
  43. 43.
    Ibrahim S, Derde MP, Kaufman L, Clerckx-Braun F, Jacqim P, Brulein V, Donnez J, Tulkens PM: Safety, pharmacokinetics and efficacy of once-a-day netilmicin and amikacin versus their conventional schedules in patients suffering from pelvic inflammatory disease. Renal Failure 1990, 12: 199–203.Google Scholar
  44. 44.
    Ter Braak EW, De Vries PJ, Bouter P, Van Der Vegt SG, Dorrestein GC, Nortier JW, Van Dijk A, Verkooyen RP, Verbrugh HA: Once-daily dosing regimen for aminoglycoside plus beta-lactam combination therapy of serious bacterial infections: comparative trial with netilmicin plus ceftriaxone. American Journal of Medicine 1990, 89: 58–66.Google Scholar
  45. 45.
    de Vries PJ, Verkooyen RP, Leguit P, Verbrugh HA: Prospective randomized study of once-daily netilmicin regimens in patients with intraabdominal infections. European Journal of Clinical Microbiology & Infectious Diseases 1990, 9: 161–168.Google Scholar
  46. 46.
    Rozdzinski E, Kern WV, 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. Journal of Antimicrobial Chemotherapy 1993, 31: 585–598.Google Scholar
  47. 47.
    Blaser J, Simmen HP, Thurnheer U, König C, Lüthy R: Nephrotoxicity, high frequency ototoxicity, efficacy and serum kinetics of once versus thrice daily dosing of netilmicin in patients with serious infections. Journal of Antimicrobial Chemotherapy 1995, 36: 803–814.Google Scholar
  48. 48.
    Giamarellou H, Yiallouros K, Petrkkos G, Moschovakis E, Vavouraki E, Voutsinas D: Comparative kinetics and efficacy of amikacin administered once or twice daily in the treatment of systemic gram-negative infections. Journal of Antimicrobial Chemotherapy 1991, 27, Supplement C: 73–79.Google Scholar
  49. 49.
    Marik PE, Lipman J, Kobilski S, Scribante J: A prospective randomized study comparing once versus twice daily amikacin dosing in critically ill adult and paediatric patients. Journal of Antimicrobial Chemotherapy 1991, 28: 753–764.Google Scholar
  50. 50.
    Mendes da Costa P, Kaufman L: Amikacin once daily plus metronidazole versus amikacin twice daily plus metronidazole in colorectal surgery. Hepato-Gastroenterology 1993, 39: 350–354.Google Scholar
  51. 51.
    Maller R, Ahrne H, Holmen C, Lausen I, Nilsson LE, Smedjegard J, the Scandinavian Amikacin Once Daily Study Group: Onceversus twice-daily amikacin regimen: efficacy and safety in systemic gram-negative infections. Journal of Antimicr- obial Chemotherapy 1993, 31: 939–948.Google Scholar
  52. 52.
    Vanhaeverbeek M, Siska G, Douchamps J, Herchuelz: Comparison of the efficacy and safety of amikacin once or twice-a-day in the treatment of severe gram-negative infections in the elderly. International Journal of Clinical Pharmacology, Therapy and Toxicology 1993, 31: 153–156.Google Scholar
  53. 53.
    Angelov A, Barrientos G, Gutensohn G, Lenzner A: Die tägliche Einmaldosis von Gentamicin bei der Behandlung von Harnwegsinfektionen. Münchner Medizinische Wochenschrift 1980, 122: 212–214.Google Scholar
  54. 54.
    Prins JM, Büller HR, Kuijper EJ, Tange RA, Speelman P: Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993, 341: 335–339.Google Scholar
  55. 55.
    Raz R, Adawi M, Romano S: Gentamicin intravenous administration of once daily versus thrice daily in adults. European Journal of Clinical Microbiology & Infectious Diseases 1995, 14: 88–91.Google Scholar
  56. 56.
    Tulkens PM, Clerckx-Braun F, Donnez J, Ibrahim S, Kallay Z, Jacqmin P, Gersdorff M: Safety and efficacy of aminoglycosides once-a-day: experimental data on randomized, controlled evaluation in patients suffering from pelvic inflammatory disease. Journal of Drug Development 1988, 1, Supplement 3: 71–82.Google Scholar
  57. 57.
    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? Journal of Antimicrobial Chemotherapy 1990, 25: 159–173.Google Scholar
  58. 58.
    Van der Auwera P, Meunier F, Ibrahim S, Kaufman L, Derde MP, Tulkens PM: 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. Antimicrobial Agents and Chemotherapy 1991, 35: 640–647.Google Scholar
  59. 59.
    The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer: Efficacy and toxicity of single doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime for infection in patients with cancer and granulocytopenia. Annals of Internal Medicine 1993, 119: 584–593.Google Scholar
  60. 60.
    Frass M, Traindle O, Podolsky A, Leithner C, Graninger W: Comparison of once-daily versus thrice-daily dosage of netilmicin in critically ill patients. Wiener Klinische Wochenschrift 1991, 103: 101–104.Google Scholar
  61. 61.
    Leoni F, Ciolli S, Pascarella A, Fanci R, Caporale R, Ferrini PR: Ceftriaxone plus conventional or single-daily doses of amikacin versus ceftazidime/amikacin as empiric therapy in febrile neutropenic patients. Chemotherapy 1993, 39: 147–152.Google Scholar
  62. 62.
    Heininger U, Böwing B, Stehr K, Solbach W: A comparative trial of single versus triple dose of aminoglycosides in patients with cystic fibrosis and pulmonary exacerbation. Klinische Pädiatrie 1993, 205: 18–22.Google Scholar
  63. 63.
    Proctor L, Petty B, Thakor R, Lietman P, Glackin R, Shimizu H: A study on the potential vestibulotoxic effects of once daily versus thrice daily administration of tobramycin. Laryngoscope 1987, 97: 1443–1449.Google Scholar
  64. 64.
    Labovitz E, Lewison ME, Kaye D: Single-dose daily gentamicin therapy in urinary tract infection. Antimicrobial Agents and Chemotherapy 1974, 6: 465–470.Google Scholar
  65. 65.
    Cohen B, Saginur R, Clecner B, Mendelson J, Kavalec E: Double-blind comparative trial of once- versus twice-daily netilmicin therapy in severe acute urinary tract infections. Current Therapeutic Research 1985, 38: 880–884.Google Scholar
  66. 66.
    Vigano A, Principi N, Brivio L, Tommasi P, Stasi P, Villa AD: Comparison of 5 milligrams of netilmicin per kilogram of bodyweight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram negative pyelonephritis in children. Antimicrobial Agents and Chemotherapy 1992, 36: 1499–1503.Google Scholar
  67. 67.
    Gibson J, Johnson L, Snowdon L, Joshua D, Young G, MacLeod C, Sader C, Jland H, Vincent P, Kronenberg H: Single daily ceftriaxone and tobramycin in the empirical management of febrile neutropenic patients: a randomized trial. International Journal of Hematology 1993, 58: 63–72.Google Scholar
  68. 68.
    Feld R, Rachlis A, Tuffnell P, Duncan I, Moran L, Pinfold P, DeBoer G: Empiric therapy for infections in patients with granulocytopenia: continuous vs. interrupted infusions of tobramycin and cefamandole. Archives of Internal Medicine 1984, 144: 1005–1010.Google Scholar
  69. 69.
    Skopnik H, Wallraf R, Nies B, Tröster K, Heimann G: Pharmocokinetics and antibacterial activity of daily gentamicin. Archives of Disease in Childhood 1992, 67: 57–61.Google Scholar
  70. 70.
    Konrad F, Wagner R, Neumeister B, Rommel H, Georgieff M: Studies on drug monitoring in thrice and once daily treatment with aminoglycosides. Intensive Care Medicine 1993, 19: 215–220.Google Scholar
  71. 71.
    Janknegt R: Aminoglycoside monitoring in the once- or twice-daily era. The Dutch situation considered. Pharmacy World & Science 1993, 15: 151–155.Google Scholar
  72. 72.
    Parker SE, Davey PG: Practicalities of once-daily aminoglycoside dosing. Journal of Antimicrobial Chemotherapy 1993, 31: 4–8.Google Scholar
  73. 73.
    Blaser J, König C, Simmen HP, Thurnheer U: Monitoring serum concentrations for once-daily dosing regimens of netilmicin. Journal of Antimicrobial Chemotherapy 1994, 33: 341–348.Google Scholar
  74. 74.
    MacGowan AP, Reeves DS: Serum monitoring and practicalities of once-daily aminoglycoside dosing. Journal of Antimicrobial Chemotherapy 1993, 33: 349–350.Google Scholar
  75. 75.
    Reeves DS, MacGowan AP: Commentary on once-daily aminoglycoside dosing. Lancet 1993, 341: 896–897.Google Scholar
  76. 76.
    Blaser J, König C, Fatio R, Follath F, Cometta A, Glauser M, members of the IATCG-EORTC: Multicenter quality control study of amikacin assay for monitoring once-daily dosing regimens. Therapeutic Drug Monitoring 1995, 17: 133–136.Google Scholar

Copyright information

© MMV Medizin Verlag 1995

Authors and Affiliations

  • J. Blaser
    • 1
  • C. König
    • 1
  1. 1.Departement für Innere MedizinUniversitätsspital, D Pol 40ZürichSwitzerland

Personalised recommendations