The evolution of aminoglycoside therapy: a single daily dose

Author: Robert L. Deamer, Lanyard K. Dial
Date: April, 1996

Aminoglycosides have been used for 50 years with remarkable efficacy in the treatment of gram-negative infections. The recent availability of generic preparations of gentamicin and tobramycin have made their use quite inexpensive. In fact, these agents are frequently the lowest-cost parenteral antibiotics in an institution's drug formulary. Nonetheless, aminoglycoside use has been increasingly supplanted by the more recently developed cephalosporins, penicillins, carbapenems and monobactams, antibiotics perceived to be less problem-prone in clinical use. This article discusses aminoglycoside pharmacotherapeutics and the development of a once-daily aminoglycoside dosing protocol.

Much of the hesitancy about the use of aminoglycoside therapy stems from concerns over the risks of nephrotoxicity and ototoxicity.[1] Over the past decade, considerable research has been conducted to determine the underlying mechanisms of these toxicities and strategies by which they may be avoided. The standard practice of measuring peak and trough serum levels has given clinicians empiric guidance in modifying aminoglycoside dosing but has increased the problems and costs of therapy. Furthermore, clinical evidence is equivocal as to whether these pharmacokinetic dosing strategies actually prevent toxicity.[2,3]

Recently, pharmacologic and clinical research has suggested that once-daily administration of aminoglycosides is highly effective, with comparable (or even reduced) toxicity. This dosing strategy also significantly simplifies the use of aminoglycosides, allowing family physicians to use this highly effective class of drugs with confidence.

Pharmacologic Basis

for Once-Daily Dosing

EFFICACY

Certain characteristics of aminoglycoside pharmacology provide a scientific foundation for once-daily dosing (Table 1). Prominent among these is the concentration-dependent rate of bactericidal activity: there is a linear relationship between aminoglycoside serum concentrations and the rate of killing of gram-negative bacteria.[4,5] The clinical implication of this in vitro finding is illustrated by studies demonstrating lower mortality rates from gram-negative bacteremia,[6] sepsis[7] and pneumonia[8] when peak aminoglycoside levels are in the upper therapeutic range (e.g., gentamicin levels above 6 to 8 [mu]g per mL) versus lower peak levels (e.g., gentamicin levels below 4 [mu]g per mL). The higher peak levels obtainable with once-daily aminoglycoside regimens may be expected to further enhance bacterial killing and clinical response.

TABLE 1

REFERENCES

[1.] John JF Jr. What price success? The continuing saga of the toxic:therapeutic ratio in the use of aminoglycoside antibiotics. J Infect Dis 1988;158:1-6. [2.] Kemme DJ, Daniel CI. Aminoglycoside dosing: a randomized prospective study. South Med J 1993;86:46-51. [3.] Leehey DJ, Braun BI, Tholl DA, Chung LS, Gross CA, Roback JA, et al. Can pharmacokinetic dosing decrease nephrotoxicity associated with aminoglycoside therapy. J Am Soc Nephrol 1993;4:81-90. [4.] Kapusnik JE, Hackbarth CJ, Chambers HF, Carpenter T, Sande MA. Single, large, daily dosing versus intermittent dosing of tobramycin for treating experimental pseudomonas pneumonia. J Infect Dis 1988;158:7-12 [Published erratum appears in J Infect Dis 1988;158:911]. [5.] Davis BD. Mechanism of bactericidal action of aminoglycosides. Microbiol Rev 1987;51:341-50 [Published erratum appears in Microbiol Rev 1988;52:153]. [6.] Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in patients with gram-negative bacteremia. J Infect Dis 1984;149:443-8. [7.] Noone P, Parsons TM, Pattison JR, Slack RC, Garfield-Davies D, Hughes K. Experience in monitoring gentamicin therapy during treatment of serious gram-negative sepsis. Br Med J 1974;1:477-81. [8.] Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med 1984;77:657-62. [9.] Vogelman B, Craig WA. Kinetics of antimicrobial activity. J Pediatr 1986;108(5 Pt 2):835-40. [10.] Vogelman BS, Craig WA. Postantibiotic effects. J Antimicrob Chemother 1985;15(Suppl):37-46. [11.] MacKenzie FM, Gould IM. The post-antibiotic effect. J Antimicrob Chemother 1993;32:519-37. [12.] Vogelman B, Gudmundsson S, Turnidge J, Leggett J, Craig WA. In vivo postantibiotic effect in a thigh infection in neutropenic mice. J Infect Dis 1988;157:287-98. [13.] Nicolau D, Quintiliani R, Nightingale CH. Once-daily aminoglycosides. Conn Med 1992;56:561-3 [Published erratum appears in Conn Med 1992;56:694]. [14.] Levison ME. New dosing regimens for aminoglycoside antibiotics [Editorial]. Ann Intern Med 1992;117:693-4. [15.] Chan GL. Alternative dosing strategy for aminoglycosides: impact on efficacy, nephrotoxicity, and ototoxicity. DICP 1989;23:788-94. [16.] Bates RD, Nahata MC. Once-daily administration of aminoglycosides. Ann Pharmacother 1994;28:757-66. [17.] Giamarellou H, Yiallouros K, Petrikkos G, Moschovakis E, Vavouraki E, Voutsinas D, et al. Comparative kinetics and efficacy of amikacin administered once or twice daily in the treatment of systemic gram-negative infections. J Antimicrob Chemother 1991;27(Suppl C):73-9. [18.] Hansen M, Achen F, Carstensen C, Collidge J, Dahlager J, Frimodt-Moller N, et al. Once- versus thrice-daily dosing of netilmicin in febrile immunocompromized patients: a randomized, controlled study of efficacy and safety. J Drug Dev 1988;1(Suppl 3):119-24. [19.] Tulkens PM. Efficacy and safety of aminoglycosides once-a-day: experimental and clinical data. Scand J Infect Dis Suppl 1990;74:249-57. [20.] Prins JM, Buller HR, Kuijper EJ, Tange RA, Speelman P. Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993;341:335-9. [21.] Raz R, Adaui A, Romano S, Elhanan K. Gentamicin once vs. thrice daily in children and adults. In: Program and abstracts of the thirty-third Interscience Conference on Antimicrobial Agents and Chemotherapy: 17-20 October 1993, New Orleans, Louisiana. Washington, D.C.: American Society for Microbiology, 1993. [22.] Aguado JM, Gonzalez P, Martin MA, Fernandez-Chacon T, Ortuno B, Noriega AR. Once daily gentamicin is less toxic for the tubule cells than thrice daily dosing. In: Program and abstracts of the thirty-third Interscience Conference on Antimicrobial Agents and Chemotherapy: 17-20 October 1993, New Orleans, Louisiana. Washington, D.C.: American Society for Microbiology, 1993. [23.] Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995;39:650-5. [24.] Gilbert DN. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother 1991;35:399-405.

The Authors

ROBERT L. DEAMER, PHARM.D. is director of Clinical Pharmacy Services at Cedars-Sinai Medical Center, Los Angeles. He was formerly director of pharmacotherapy education and research in the family practice residency program at the Ventura County Medical Center. He is an assistant professor of family medicine at the UCLA School of Medicine, Los Angeles, and assistant professor of pharmacy practice at the University of Southern California School of Pharmacy. Dr. Deamer received his doctor of pharmacy degree from the University of Southern California and completed a residency in pharmacotherapy at the University of California, San Francisco, School of Medicine.

LANYARD K. DIAL, M.D. is director of the family practice residency program at Ventura County Medical Center and director of geriatric services for Ventura County, Calif. He is an associate professor of family medicine at the UCLA School of Medicine. Dr. Dial received his medical degree from the Washington University School of Medicine in St. Louis, and completed a residency in family practice at the Ventura County Medical Center.

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