ONCE-DAILY DOSING OF AMINOGLYCOSIDE ANTIBIOTICS

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The aminoglycosides are a class of bactericidal antibiotics characterized by the presence of a six-carbon aminocyclitol ring covalently bonded to multiple amino sugar groups.24 Aminoglycosides commonly used for the treatment of serious bacterial infections in the United States include gentamicin, tobramycin, amikacin, netilmicin, and streptomycin.18

These drugs act in part by impairing bacterial protein synthesis through irreversible binding to the 30S subunit of the bacterial ribosome.24 Since the introduction of streptomycin in the 1940s, aminoglycosides have proved extremely useful in the treatment of infections caused by gram-negative bacilli, including Pseudomonas aeruginosa, and infections caused by staphylococci, mycobacteria, and several other pathogens.18

The Food and Drug Administration (FDA) approved dosing regimens for aminoglycoside antibiotics require multiple daily doses in individuals with normal renal function. Improvements in the understanding of the pharmacodynamics of aminoglycoside efficacy and mechanisms of toxicity, however, have prompted the evaluation of once-daily dosing regimens in clinical studies.

In the pages that follow, we review the rationale behind once-daily dosing of aminoglycoside therapy as well as clinical data on the efficacy and toxicity of once-daily dosing of aminoglycosides. We also review practical aspects of dosing and monitoring once-daily aminoglycoside therapy and issues complicating the use of these regimens in special populations (including children, adults with an altered volume of distribution for aminoglycosides, and individuals with renal dysfunction) and in certain illnesses (including bacterial endocarditis, neutropenia and fever, and cystic fibrosis).

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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    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]

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