Editorials
Pharmacology
Volume 196 - Issue 11

Gentamicin and ototoxicity: why this drug is still in use

Authors:  John D Turnidge and John A Waterston

Med J Aust 2012; 196 (11): 665-666. || doi: 10.5694/mja12.10733
Published online: 18 June 2012
The fine line between therapeutic benefit and toxicity. In this issue of the Journal, Ahmed and colleagues1 focus our attention on the very real problem of gentamicin-induced ototoxicity, and especially on the frequently unrecognised problem of severe vestibulotoxicity. Their retrospective analysis of gentamicin-treated patients presenting to a balance disorders clinic found delayed clinical detection of vestibulotoxicity and an apparent lack of a relationship between toxicity and ...
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The fine line between therapeutic benefit and toxicity

In this issue of the Journal, Ahmed and colleagues1 focus our attention on the very real problem of gentamicin-induced ototoxicity, and especially on the frequently unrecognised problem of severe vestibulotoxicity. Their retrospective analysis of gentamicin-treated patients presenting to a balance disorders clinic found delayed clinical detection of vestibulotoxicity and an apparent lack of a relationship between toxicity and dose. While hearing loss can be a feature of gentamicin ototoxicity, it is uncommon and usually clinically insignificant. The most concerning aspect of the analysis is the authors’ inability to demonstrate any relationship between vestibulotoxicity and gentamicin doses, dosing schedules or exposure (ie, peaks and/or troughs).1

While the pharmacodynamics of aminoglycosides and the toxicodynamics of nephrotoxicity have been well defined,2 much less is known about the toxicodynamics of ototoxicity; namely, the relationship between drug exposure and ototoxicity. The only available data are from one animal model, amikacin toxicity in the guinea pig cochlea, which showed a relationship between hearing loss and the area under the concentration versus time curve (AUC) of drug exposure in plasma and perilymph.3,4 It is uncertain whether these results can be extrapolated to gentamicin in vestibular endolymph. There is, however, indirect evidence that the AUC of drug exposure may play a role in aminoglycoside cochlear toxicity. This evidence comes from a range of studies comparing once-daily versus multiple daily doses (same total daily dose and therefore the same AUC), but the paucity of cases of documented vestibular toxicity in these studies has prevented us from reaching any conclusion about dosing and this form of toxicity.5 Hence, we are currently unable to determine whether there are dosing regimens of gentamicin that can ensure efficacy, but prevent vestibular toxicity. Furthermore, the finding of six cases in Ahmed et al’s study1 in which toxicity occurred after a single dose of gentamicin suggests that determining this may be impossible.

The authors found an almost universal failure to recognise vestibulotoxic symptoms among prescribers of gentamicin.1 It is often not appreciated that gentamicin vestibulotoxicity does not cause spontaneous vertigo and that, in severely ill bed-bound patients, its symptoms may be minimal. The cardinal symptoms — motion-induced dizziness, oscillopsia and gait ataxia — may not become apparent until patients start to mobilise. Prescribers need to be more vigilant in monitoring for evidence of vestibulotoxicity in conscious patients and, as soon as is practical after starting gentamicin, using methods such as the dynamic visual acuity test.1 Early recognition of vestibulotoxicity and cessation of gentamicin therapy may prevent further progression and potentially lead to some recovery of vestibular function.1,6 If possible, it is also important to avoid or limit the use of gentamicin in patients with a history of pre-existing inner ear or balance disorders.

Aminoglycosides, and gentamicin in particular, have been the mainstay of empirical therapy of serious gram-negative infections for more than 50 years.7 For almost all that time it has been known that this antimicrobial class is associated with kidney and inner-ear toxicity. As ototoxic effects can be lifelong, it would seem obvious that this drug class should have been relegated long ago to the very last line of treatment: to be used when its potentially life-saving benefits for an individual patient outweigh the risk of toxicity. Why has this not happened, when there are clearly newer antimicrobial classes with appropriate broad-spectrum gram-negative activity and excellent safety profiles?

Replacement of aminoglycosides was certainly the hope when third-generation cephalosporins, then fluoroquinolones and, most recently, the carbapenems were introduced. However, within a few years of the introduction of each of these, their high potential for selection of resistance and multiresistance in both gram-negative and gram-positive bacteria was recognised. This contrasts sharply with the experience with aminoglycosides in which widespread resistance selection has not been observed.

This has led to a consensus that aminoglycosides should still play a role as initial therapy, and that in hospitals the newer antimicrobial classes should be subject to stewardship to control indiscriminate use and minimise amplification of multiresistant organisms, such as methicillin-resistant Staphylococcus aureus and extended-spectrum β-lactamase-producing enteric gram-negative bacteria. Therapeutic guidelines: antibiotic presents the latest thinking: retain the therapeutic benefit of low rates of resistance and known efficacy, while attempting to minimise the risk of toxicity.8 Essentially this means prescribing aminoglycosides as empirical therapy for up to 48 hours, pending culture results, and then changing to appropriate but safer therapy when the results of tests are known.9

Authors

  • John D Turnidge FRACP, FRCPA, FASM1
  • John A Waterston MB BS, MD, FRACP2
  • 1. Schools of Pathology, Paediatrics and Molecular and Biomedical Science, University of Adelaide, Adelaide, SA.
  • 2. Neuroscience Department and Monash University Department of Medicine, Alfred Hospital, Melbourne, VIC.

Correspondence: john.turnidge@health.sa.gov.au

Competing interests

No relevant disclosures.

References

Provenance: Commissioned; externally peer reviewed.

View this article on Wiley Online Library

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