Gentamicin ototoxicity: a 23-year selected case series of 103 patients

Over the 23-year period, 552 patients were diagnosed with severe, symmetrical, selective (ie, normal hearing for age), bilateral vestibular loss. Of these, 263 patients had gentamicin vestibulotoxicity (GVT). In the remainder, the vestibular loss was caused by cisplatinum ototoxicity (9), meningitis (6), hereditary factors (29), or bilateral sequential vestibular neuritis (61); in 184 the condition was idiopathic.8

Patients with GVT who had severe bilateral vestibular loss after having gentamicin in hospital were interviewed and examined, and hospital records for the “gentamicin admission” were obtained. Our study included 103 patients with normal renal function at the start of gentamicin treatment (serum creatinine level, < 121 µmol/L [eGFR, > 59 mL/min/1.73 m2]) and for whom the following data were available: (i) total dose and dosage regimen of gentamicin; (ii) renal function before and during treatment; (iii) serum gentamicin level; (iv) indications (clinical and microbiological) for using gentamicin; (v) when imbalance was first noted by the patient; and (vi) when bilateral vestibular loss was first clinically recognised.

Ethics approval was not required for this retrospective review.

We reviewed patients’ clinical diagnoses to determine (i) whether gentamicin therapy complied with contemporary (at the time of admission to hospital) or with current (2010) Australian antibiotic guidelines;13 and (ii) whether the treatment was empirical, but appropriate, or based on results of cultures.

The delay to diagnosis of bilateral vestibular loss ranged from 4 days (the only patient in whom GVT was diagnosed during treatment) to 15 years. GVT was diagnosed less than 12 months after treatment in 69 patients, and more than 12 months after treatment in 34 patients.

Only three of the 103 patients with GVT complained of hearing impairment after gentamicin treatment, in each case while still in hospital. No patient had audiometry at the time gentamicin was given, but all had audiometry later as part of the assessment of vestibular loss. For the 73 patients whose audiograms were retrieved, hearing loss at each frequency, averaged for each age group and both ears, was not different from accepted age-group means (Box 2).15,16 Audiometry in the three patients who complained of hearing loss also showed thresholds consistent with age. The pure-tone thresholds in the 30 descriptive reports were reported as normal or showing only high-frequency hearing loss, consistent with age and noise exposure. We were unable to retrieve audiometry data from before gentamicin treatment for any of the patients.

During gentamicin treatment 43 of 103 patients developed nephrotoxicity, defined as a serum creatinine level > 120 µmol/L (range, 121–841 µmol/L) and eGFR < 60 mL/min/1.73 m2 (range, 59–< 6 mL/min/1.73 m2) on two sequential daily measurements.

The gentamicin dose ranged from 160 to 320 mg/day, equivalent to 1.5 to 5.6 mg/kg/day (mean, 3.5 mg/kg/day). The total gentamicin dose ranged from 160 to 16 520 mg, equivalent to 2– 318 mg/kg (mean, 3639 mg or 52 mg/kg). The mean total dose in the 43 patients who developed nephrotoxicity was 4363 mg, in contrast to 3240 mg in the 60 who did not. The gentamicin doses our patients with GVT received in hospital, between 1975 and 2010, indicate that there was no change in the total dose or daily dose of gentamicin given in this period. Box 3 shows total dose (mg/kg) versus daily dose (mg/kg/day) for each patient.

Fifty-five patients received only one daily dose of gentamicin; 14 received three doses per day, nine received two to three doses per day, 11 received two doses per day, one received a combination of one and three doses per day, and two received four doses per day. For 11 patients, we were unable to obtain reliable data on doses per day given. The total number of doses over the treatment period ranged from one to 129 (mean, 30). Twenty-six patients received five or fewer doses of gentamicin and six patients received a single dose only.

Duration of treatment ranged from 1 day (the six patients who had only a single dose) to 80 days (mean, 17 days).

It was not possible from the treatment chart information to determine the exact method of intravenous administration used: slow infusion (recommended) or bolus injection.

Serum gentamicin levels (trough or peak or both) were retrieved in 82 patients; in 23, a trough or a peak level was above the recommended range. Peak levels were higher in those who developed nephrotoxicity than in those who did not (Box 4).

Adherence to contemporary or current antibiotic guidelines for gentamicin use13 is shown by patient diagnosis in Box 5 and by clinician subspecialty in Box 6.

Culture results were available in 73 of 103 patients; 44 showed no growth. An organism was isolated in 29 cultures, sensitive to gentamicin in 11; in another 11 gentamicin was not indicated for treatment of the organism isolated (eg, methicillin-sensitive Staphylococcus aureus); and in seven gentamicin sensitivity was not tested or reported.

All these patients developed symptoms and signs of bilateral vestibular impairment after treatment with gentamicin, but only three noted any hearing impairment. Audiometric thresholds in the all patients were not significantly different from age-matched thresholds.15,16 Unless pre-gentamicin audiometry is available, high-frequency (4–8 kHz) hearing loss, especially in elderly men, cannot be assumed to be due to gentamicin; noise and ageing are much more common causes of hearing loss.1 Measuring hearing before and after gentamicin treatment17,18 shows only slight (about 15 dB) high-frequency (4–8 kHz), asymptomatic hearing loss. This suggests that any hearing loss from gentamicin ototoxicity would not be noticed by patients with normal hearing,19,20 and certainly not by those with pre-existing, high-frequency hearing loss. By contrast, symptoms of vestibular loss are obvious to patients, as are the clinical signs to the aware clinician.

All patients noted imbalance either during hospital admission or immediately after discharge. We were able to confirm that they had received gentamicin and had no other potential cause for bilateral vestibular loss. Even though it has been known since 195221 that certain aminoglycosides, including streptomycin and gentamicin, can cause severe, selective loss of vestibular function,1,2,3,4,5,6,7,8 prescribers rarely recognise GVT.3,4

Because vestibular loss is, at least initially, bilateral and symmetrical, patients will develop imbalance and oscillopsia, not vertigo, the hallmark of acute, unilateral vestibular loss. Bed-bound patients will be unaware of their imbalance until they walk again. Unless clinicians know how to test for bilateral vestibular loss, gentamicin treatment will not be stopped and vestibulotoxicity will most likely be aggravated. Bilateral vestibular loss can now be objectively confirmed at the bedside using video-vestibulometry (Box 7; Video 3, Video 4),22 dynamic visual acuity10 and the foam Romberg test (in ambulant patients) (Video 6).11

Even when patients report that imbalance developed after hospital admission, gentamicin is rarely considered as the possible cause. With delayed diagnosis, it is difficult without a subpoena23 to obtain hospital drug treatment charts to confirm that gentamicin was given.

There has not been any change in the overall gentamicin dose given to patients who develop GVT since 1994.3 We found that regardless of total dose, daily dose, number of doses per day or duration of treatment, patients can still develop GVT. We also confirmed that GVT can occur even when serum trough or peak levels are at or below the recommended range.3,4

In all but one of our patients, GVT was not diagnosed during treatment, and six patients had only a single gentamicin dose. Thus, 96 of our patients would have continued being given gentamicin after developing vestibulotoxicity (many were bed-bound), so that the total dose given to these 96 patients must have exceeded the toxic dose.

A study of 33 patients with GVT also found no relationship between daily dose, total dose or serum levels and GVT, and 32 of their patients were diagnosed after hospital discharge.4

The mean total dose and serum levels of gentamicin in the 43 patients with GVT who developed nephrotoxicity24,25 were substantially higher than in the 60 who did not. Patients who develop vestibulotoxicity seem more likely to develop nephrotoxicity (42%) than patients in general receiving gentamicin (5%–17%),26 suggesting a common mechanism or predisposing factor.

The current (2010) Australian antibiotic guidelines advise that use of gentamicin for empirical treatment should be limited to 48 hours, pending the results of microbiological investigations. Directed therapy is indicated only for infections in which there is resistance to other, safer, antimicrobials; for combination therapy in serious Pseudomonas aeruginosa and Brucella infections; and as synergistic treatment for streptococcal or enterococcal endocarditis. It should be considered for prophylactic use only in patients at specific risk of developing endocarditis from genitourinary or gastrointestional procedures.13

Gentamicin was given according to current antibiotic guidelines13 in 47% of our 103 patients; 52% were given empirical gentamicin for longer than the recommended 48 hours; and in only 46% of patients was gentamicin given in accordance with contemporary antibiotic guidelines. Few medical and surgical specialists prescribed gentamicin based on culture results, and in some cases continued it even when culture showed that it was not indicated.

Previous studies have examined the inappropriate use of aminoglycosides;27,28 in one, 10.2% of antibiotic-days were deemed inappropriate.29 An education program for junior medical officers improved appropriate prescribing of gentamicin from 52% to 78%.30

As our study did not include a control group, it is not possible, from our data alone, to establish an unequivocal causal link between gentamicin and vestibulotoxicity. However, published clinical1,2,3,4,5,6,7,8 and experimental31,32 studies remove any doubt.

As there is always a risk of vestibulotoxicity with gentamicin, regardless of dose or serum level, it should be given only as recommended by antibiotic guidelines13 and when there is no safer alternative. Clinicians prescribing gentamicin should use bedside methods to monitor for vestibulotoxicity,10,22 although this is possible only in conscious, cooperative patients. Stopping gentamicin treatment early could prevent further damage, allowing some hair cell regeneration and recovery of vestibular function.33

Our report of 103 cases seen over 23 years suggests that vestibulotoxicity is rare (Addendum). However, our criteria excluded patients in whom we were unable to obtain dosing and clinical details, those with pre-existing renal failure, and those with partial bilateral9 or unilateral vestibulotoxicity.34

GVT can occur with any dose, in any regimen, at any serum level, and is often not recognised. Vestibulotoxicity can be devastating and conscious patients should be warned of this risk before being treated with gentamicin.