ONCE-DAILY DOSING OF AMINOGLYCOSIDE ANTIBIOTICS
Section snippets
PHARMACODYNAMIC RATIONALE FOR ONCE-DAILY DOSING
The pharmacodynamic characteristics of aminoglycosides that suggest the use of once-daily dosing are (1) concentration-dependent killing; (2) postantibiotic effect and postantibiotic leukocyte enhancement; and (3) adaptive resistance.
CLINICAL EFFICACY OF ONCE-DAILY DOSING
The possibility of increased efficacy with once-daily aminoglycoside dosing has been evaluated in a multitude of randomized clinical trials. The interpretation of these studies has been complicated by the fact that individual trials have had insufficient power to determine whether observed differences in efficacy between once-daily and multiple-daily dosage regimens are due to chance alone.
Meta-analysis has been used in an attempt to synthesize the data contained in these multiple studies.2, 3,
Nephrotoxicity
Aminoglycoside nephrotoxicity results from drug accumulation in proximal renal tubular cells of the renal cortex. These drugs disrupt cellular lysosomes and phospholipid metabolism and precipitate the formation of “myeloid bodies, ” which are lamellar aggregates of phospholipid.44
The uptake of aminoglycosides by renal cortical cells appears to be a saturable process26 (Fig. 2). Once proximal tubular cells are saturated with aminoglycoside, the higher peak serum concentrations seen with
COST SAVINGS WITH ONCE-DAILY DOSING
Whereas the initial impetus for once-daily dosing of aminoglycosides was based on the pharmacodynamics of these agents, the acceptance of once-daily dosing of aminoglycosides has occurred in the context of increased cost-cutting in health care.
Impressive cost reductions have been reported with the adoption of once-daily aminoglycoside administration; at Hartford Hospital, reduction in total costs of drug administration and monitoring for an average course of gentamicin were reduced by more than
Dosing of Once-Daily Aminoglycosides
In keeping with the pharmacodynamic characteristics of aminoglycosides reviewed, once-daily dosing should be performed in a manner that (1) ensures a high Cmax:MIC ratio for the pathogen being treated, and (2) ensures that trough levels are low enough to minimize toxicity and permit the loss of adaptive resistance.
Dosages used in clinical trials of once-daily administration of gentamicin, netilmicin, and tobramycin have varied from 4 to 7 mg/kg. It has been pointed out that because of
Children
Several studies have evaluated the use of once-daily dosing of aminoglycosides in pediatric populations.10, 19, 35 These studies have included children younger than 6 months35 and children with neutropenia10 and sepsis.35 Pharmacokinetic analyses have suggested that children have a higher volume of distribution than adults and that higher antibiotic doses per unit of body mass may be warranted in children.19 Once-daily dosing appears to be safe and effective in children, although further study
Infections in Individuals with Neutropenia
Postantibiotic leukocyte enhancement of bacterial killing is expected to be impaired in individuals with neutropenia, and some animal experiments have demonstrated once-daily dosing of aminoglycoside antibiotics to be less effective in neutropenic animals than in nonneutropenic animals.33 Because of this, concern has been raised that once-daily aminoglycoside dosage is inappropriate in neutropenic individuals.
Randomized trials comparing once-daily to multiple-daily dosing of netilmicin, 42
SUMMARY
Improved understanding of the pharmacodynamics and toxicity of aminoglycoside antibiotics has resulted in the study of once-daily dosing regimens. Although studies have suggested a therapeutic advantage and possibly a decrease in toxicity with once-daily administration, these effects have been modest. The cost savings associated with once-daily aminoglycoside administration, however, makes this approach appealing.
Although a syndrome of fever, tachycardia, hypotension, and rigors has been
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Cited by (50)
Amikacin population pharmacokinetics among paediatric burn patients
2014, BurnsCitation Excerpt :However, similar to other aminoglycoside antibiotics, adaptive resistance to amikacin is enhanced by continued presence of the drug [12]. Previous reports have suggested that the development of adaptive resistance may be minimized during once-daily dosing [13–15]. Additionally, amikacin toxicity may occur with sustained drug concentrations [16].
Antibacterial drugs
2012, Clinical Pharmacology: Eleventh EditionA double-blind study of the efficacy and safety of multiple daily doses of amikacin versus one daily dose for children with perforated appendicitis in Costa Rica
2011, International Journal of Infectious DiseasesCitation Excerpt :However, there is still debate, even in clinical settings where resources are not limited, as to whether these antibiotics should be given in multiple daily doses (MDD) or as a single daily dose (once daily dose, ODD). ODD has been shown to achieve higher peak plasma concentrations with relatively undetectable trough concentrations, and thus to exert a high concentration-dependent bactericidal activity, greater post-antibiotic effect, lower risk of adaptive resistance, and reduced accumulation in the inner ear and renal proximal tubules.3–5 Recent systematic reviews of the efficacy and safety of giving aminoglycosides as an ODD to children and neonates have concluded that ODD is preferable to MDD, because ODD both minimizes costs and simplifies administration while remaining efficacious and safe.6,7
Clinical Pharmacology of Anti-Infective Drugs
2011, Infectious Diseases of the Fetus and Newborn InfantClinical pharmacology of anti-infective drugs
2010, Infectious Diseases of the Fetus and Newborn: Expert Consult - Online and PrintAminoglycosides and polymyxins
2009, Enfermedades Infecciosas y Microbiologia Clinica
Address reprint requests to David N. Fisman, MD, FRCP(C), Division of Infectious Diseases, Kennedy-6, Beth Israel Deaconess Medical Center, One Deaconess Road, Boston, MA 02215, [email protected]