Efficacy and Safety of a Single Daily Dose of Aminoglycoside Therapy

Abstract

Despite the well-recognized renal toxicity and ototoxicity of aminoglycosides, they are still commonly used in the treatment of gram-negative infections, alone or in combination with beta lactam antibiotics. Various approaches have been proposed to reduce aminoglycoside toxicity. These rely on manipulating and correcting for either patient-related factors or drug-related factors. Drug-related risk factors can be corrected for by choosing the appropriate aminoglycoside, adapting the dose and duration of treatment or by co-administration of nephroprotectants.Aminoglycosides have two virtues: 1) concentration-dependent killing and 2) post-antibiotic effect. Aminoglycosides demonstrate dose-dependent killing, i.e., the higher the level, the more rapid the killing of bacteria. The other property of aminoglycosides is the so-called postantibiotic effect. This effect is defined as the delay in regrowth of antibiotic-treated organisms following antibiotic removal. In practice, the effect of postantibiotic effect is the suppression of bacterial growth after cessation of exposure to aminoglycoside concentrations above the minimal inhibitory concentrations (MIC). The duration of this effect is dependent on the aminoglycoside serum concentration achieved and the duration of exposure. It has therefore been suggested that the administration of a large dose once daily could maximize the rate of bacterial killing, and the post-antibiotic effect, preventing regrowth of bacteria during the period of low antibiotic concentration in the serum. 1A narrow therapeutic margin and low predictability of plasma concentrations are the main reasons for drug monitoring during aminoglycoside treatment. Gentamicin, tobramycin, amikacin and netilmicin can now be accurately and rapidly measured by radioenzymatic and radio and enzyme immunoassays. Routine determinations of peak (one to two hours post dose) and trough levels are recommended to ensure adequate dosage in all patients with serious gram-negative infections, especially when renal function is impaired. However, maintaining aminoglycoside concentration within a given range is frequently difficult and will reduce but not entirely eliminate the risk of toxicity. The pharmacokinetic behavior of the aminoglycosides leads to a progressive drug accumulation in the renal tissue and the inner ear, which depends on both dosage and duration of treatment. Nephrotoxicity to aminoglycosides has been estimated to occur in up to 5% to 25% of patients, while hearing loss (cochlear) is observed in about 3% to 14% and vestibular toxicity affecting about 4% to 6% of patients when multiple daily doses of the aminoglycosides are used for therapy. In vitro and animal studies suggest that a oncedaily regimen could reduce the risk of side effects with equal or even improved efficacy of the aminoglycosides in bacterial eradication. 1,2A large number of animal data have demonstrated that the single daily administration of an aminoglycoside is less toxic than administration twice, thrice or by continuous infusion ...