Prevention and modulation of aminoglycoside ototoxicity (Review)

Abstract

Abstract. More than 60 years after their isolation and characterization, aminoglycoside (AG) antibiotics remain powerful agents in the treatment of severe gram-negative, enterococcal or mycobacterial infections. However, the clinical use of AGs is hampered by nephrotoxicity and ototoxicity, which often develop as a consequence of prolonged courses of therapy, or of administration of increased doses of these drugs. The discovery of non-ototoxic antibacterial agents, showing a wider spectrum of activity, has gradually decreased the use of AGs as first line antibiotics for many systemic infections. However, AGs are now undergoing an unexpected revival, being increasingly indicated for the treatment of severe emerging infections caused by organisms showing resistance to most first-line agents (e.g., multidrug-resistant tuberculosis, complicated nosocomially-acquired acute urinary tract infections). Increasing adoption of aminoglycosides poses again to scientists and physicians the problem of toxicity directed to the kidneys and to the inner ear. In particular, aminoglycoside-induced deafness can be profound and irreversible, especially in genetically predisposed patients. For this reason, an impressive amount of molecular strategies have been developed in the last decade to counteract the ototoxic effect of aminoglycosides. The present article overviews: i) the molecular mechanisms by which aminoglycosides exert their bactericidal activity, ii) the mechanisms whereby AGs exert their ototoxic activity in genetically-predisposed patients, iii) the drugs and compounds that have so far proven to prevent or modulate AG ototoxicity at the preclinical and/or clinical level, and iv) the dosage regimens that have so far been suggested to decrease the incidence of episodes of AG-induced ototoxicity. Aminoglycoside antibiotics: a revival?Aminoglycoside (AG) antibiotics have been extensively used for the prophylaxis and the treatment of a wide variety of systemic infections, for the outstanding features displayed by these antibacterial agents, i.e., the concentration-dependent bactericidal activity, the post-antibiotic effect, the favorable pharmacokinetic profile, and the strong synergism with other antibiotics such as vancomycin and ß-lactams (1). More than 60 years after their isolation and characterization, these drugs remain powerful tools for treatment of severe gram-negative, enterococcal or mycobacterial infections. AGs are usually administered in combination with ß-lactam antibiotics for a variety of systemic infections (e.g., bacterial endocarditis or various pseudomonal infections), but are also used as monotherapy for infections of the urinary tract. Streptomycin, the first AG isolated and adopted for human therapy (Fig. 1), MOLECULAR MEDICINE REPORTS 1: 3-13, 2008 3 Prevention and modulation of aminoglycoside ototoxicity (Review) GIANPAOLO

Immediate Post‐Administration Safety of Bolus Gentamicin

“…While the mechanism resulting in cochlear toxicity is less clear, it is best correlated with the cumulative dose duration of treatment and repeated courses of therapy, as well as genetic predisposition. 9 The relationship with vestibular toxicity is unclear. It has been suggested that it is a process, which depends on the duration of exposure to gentamicin, and does not appear to be linked to serum concentration, although other sources maintain it can occur at any dose, with any regimen and at any serum level.…”