Gentamicin Toxicity

• What is Gentamicin Toxicity?
• Why Do Only Some People Develop Gentamicin Toxicity?
• What is the Prognosis of Gentamicin Toxicity?
• References

What is Gentamicin Toxicity?

Gentamicin is a commonly used antibiotic medication. Gentamicin toxicity is the most common single known cause of bilateral vestibulopathy, accounting for 15 to 50% of all cases. Bilateral vestibulopathy, discussed in more detail here, occurs when the balance portions of both inner ears are damaged. The symptoms typically include imbalance and visual symptoms. The imbalance is worse in the dark, or in situations where footing is uncertain. Spinning vertigo is unusual. The visual symptoms, called oscillopsia, only occur when the head is moving. Quick movements of the head are associated with transient visual blurring. This can cause difficulties with seeing signs while driving, or recognizing peoples faces while walking.

When a person has bilateral vestibular damage, such as may result from Gentamicin toxicity, they may experience oscillopsia. When the head is moving, objects blur. When driving, one may be unable to see signs clearly on a bumpy road.

Other than gentamicin, there are numerous other ototoxins, but most maily affect hearing.

Gentamicin is spelled with a terminal micin, unlike several other drugs in the same aminoglycoside family, that end with mycin. The difference in spelling from other aminoglycosides, such as streptomycin, reflects the different species of origin of this antibiotic (Begg and Barclay, 1995).

Hearing ototoxicity reportedly occurs about 5 to 10% of the time that gentamicin is given intravenously or during peritoneal dialysis. However, hearing in humans is generally affected only for high frequencies (approximately 8,000 to 12,000 Hz) or not at all. This differs from the situation in most animals.

Typical audiogram of person exposed to gentamicin. Hearing is commonly normal through 4000 Hz, and then falls off at higher frequencies. Often, persons with significant vestibular damage from gentamicin do not notice any change in their hearing.

More importantly, the vestibular system can be damaged with gentamicin. The exact incidence of vestibulotoxicity when gentamicin is administered in humans is presently uncertain. Not only have very few prospective studies of vestibular function been done, but it is also difficult to detect vestibular damage until it is profound. It seems likely that significant vestibular damage does not occur as frequently as the subtle hearing impairment reported above (5 to 10%). The author's best estimate is that between 0.1% and 1% of all two-week courses of gentamicin result in vestibular toxicity. This is only a guess, and we hope that a prospective study is done to answer this question at some point.

In pathologic studies, aminoglycoside toxicity is associated with death of inner ear hair cells (Plogar et al, 2001). The auditory ganglion is spared (Tsuji et al, 1999), suggesting that eventually it may be possible to design an inner ear prosthesis similar to a cochlear implant might be designed to remedy this condition.

Why Do Only Some People Develop Gentamicin Toxicity?

As discussed above, gentamicin toxicity is certainly not the rule, even for month-long courses of gentamicin. Why do some people react with ototoxicity and others don't? The following factors may affect toxicity:

• dose
• potentiating medications
• genetic susceptibility

Dose

One possibility is that the dose was too small. It is very uncommon for gentamicin ototoxicity to develop with less than one week of treatment. It is possible to develop bilateral vestibular toxicity from gentamicin, even when the level of the drug is not too high ifit is given for a long period. The risk may be especially high if there are other drugs being given (see below), or in certain individuals with genetic predisposition (see below).

Recent studies suggest that gentamicin ototoxicity is most closely related to total dose, rather than having inappropriately high levels. Conventionally, gentamicin is given three times per day, with a total dose per day ranging from 3 mg/kg to 5 mg/kg. These doses may need to be modified for special situations such as when kidney function is impaired. For dosers of three times per day, ordinarily a peak of 5 to 10 and a trough of less than 2 is aimed for (see Keller et al). Black et al (2001) did not find a correlation between total dose and ototoxicity. However, their numbers were small and a correlation could have easily been missed.

A recent trend is to administer gentamicin on a once per day schedule because bacterial killing is a stronger function of concentration than time. Details about how this is done using a nomogram, called the Hartford Nomogram, is found in in a paper written by Nicolau et al. Other algorithms are discussed by Begg and Barclay (1995). Peak levels are expected to be quite high, and targets for three time per day dosing as discussed above are inappropriate for once per day dosing. Instead,  levels drawn at known times from the administration are used to adjust the interval of dosing using a nomogram. According to Begg (1995), trough levels are not needed for once-daily dosing. Most evidence suggests that ototoxicity is less for once/day dosing than more frequent dosing (Begg and Barclay, 1995). This line of evidence suggests that high-peak levels are not necessarily ototoxic, but rather it is the total dose that is important. It also possible that toxicity might be related to a combination of peak dose and total dose. The studies done to date are not powerful enough to clearly distinguish between the two possibilities.

Potentiating Medications

There may be increased risk of ototoxicity from gentamicin, if other ototoxic drugs such as cisplatin (a chemotherapy agent) and vancomycin (another antibiotic) are given at the same time.  There also appears to be a synergistic effect of loop diuretics, such as furosemide or ethacrynic acid (Ding, 2001), and also loud noise (Aran et al, 1992), when combined with gentamicin. The potentiating effect of loop diuretics is likely related to a more rapid entry of gentamicin into the ear. Gentamicin is probably also toxic to the ear of the developing fetus, as related drugs (such as. streptomycin) have been shown to have this problem (see Boradori et al, 1997). Ear drops containing gentamicin, as well as related substances, may be ototoxic if given over a prolonged time to individuals with perforated ear drums. Click here for more information about this.

Genetic Susceptibility

It has been recently found that in some individuals there is unusual susceptibility to gentamicin or streptomycin ototoxicity related to a mutation of mitochondria (Fishel-Ghodsian et al, 1997;Gardner et al, 1997). This susceptibility is passed on genetically through the mother and occurs in as many as 17% of individuals with hearing loss after aminoglycoside exposure. A patient with idiopathic loss of vestibular function has also been reported with mitochondrial abnormalities (Baloh et al, 1997), and some pedigrees have been reported with both sensorineural deafness and aminoglycoside sensitivity (El-Schahawi et al, 1997). Hearing loss is also common in Kearns-Sayre, a disorder with mitochondrial DNA and other mitochondrial disorders.

What is the Prognosis of Gentamicin Toxicity?

In general the message is not very encouraging. People do recover, but the process is slow and usually incomplete. The majority of the improvement occurs at high frequencies on rotatory chair testing -- high-frequency gain may return to normal, but remain depressed for lower frequencies. Progression of vestibulotoxicity can occur for months after the last dose, and recovery can be measured out to a year or even longer (Black et al, 2001). Recovery likely is related to a combination of several factors:

1. Some "sick" inner ear hair cells get better. Nobody knows exactly how many inner ear hair cells are sick rather than being dead, but it seems reasonable to assume that they are not all dead; some remain but are not functioning at top efficiency. As gentamicin persists in the ear for somewhere between 80 days and a year, recovery from this process might reasonably stretch over the same time frame.
2. The brain adapts to the missing inner ear information. Certainly people adapt to missing sensory input using plasticity, substitution and behavioral changes.
3. There may be regeneration occurring. Birds can regenerate their hair cells. It was felt for a long time that people can't do this; however, there is a small amount of evidence that some regeneration does occur.
4. Nerve axons sprout and innervate surviving hair cells.

Please see our Bilateral Vestibulopathy Page for further information regarding diagnosis, treatment, prognosis, and research efforts related to ototoxicity in general and gentamicin toxicity in particular.

References

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• Aran J, Hiel H, Hayashida T, Erre JP, Aurousseau C, Guilhaume A, Dulon D. Noise, aminoglycosides and diuretics. In: Noise Induced Hearing Loss (Dancer, Henderson, Salvi, Hamernik, Editors), Mosby, 1992
• Baloh RW. Idiopathic bilateral vestibulopathy. Neurology, 39: 272-275, 1989
• Baloh RW and others. Clinical-pathologic correlation in a patient with selective loss of hair cells in the vestibular endorgans. Neurology 49(5) 1377-82, 1997
• Begg EJ, Barclay ML, Duffull SB. A suggested approach to once-daily aminoglycoside dosing. Br. J. Clnic Pharm 39,605-609, 1995
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• Polgar and others. Anatomic and morphometric changes to gerbil posterior cristas following transtympanic administration of gentamicin and streptomycin. JARO 02:147-158, 2001
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B. Joseph Touma, M.D. is a clinical instructor at the Marshall University School of Medicine, West Virginia. He earned his M.D. from West Virginia School of Medicine, Morgantown.