Gentamicin Toxicity

 

Edited by Tim Hain, MD 10/2012

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 faces while walking.

Oscillopsia 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.

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.

Gentamicin AudiogramTypical 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.

The current prevailing view is that aminoglycoside toxicity is associated with death of inner ear hair cells one to two days after exposure, while spiral ganglion cell loss occurs three to fifteen days post-exposure (Alharazneh et al 2011, Zilberstein et al 2012). The auditory ganglion is spared.

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. A recent study found a strong correlation between aminoglycoside dose frequency and severity of hearing loss (Tokgoz et al 2010).

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. A thorough discussion of dosage and monitoring is discussed by Roberts and associates (2012) .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 Roberts et al. (2012), trough levels are not necessarily needed for once-daily dosing. Evidence suggests that ototoxicity is less for once/day dosing than more frequent dosing (Tokgoz et al 2010). This line of evidence suggests that high-peak levels are not necessarily ototoxic, but rather it is the total dose that is important. It is 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 et al 2010), and also loud noise (Li & Steyger 2009), 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 (Touw et al 2009). Ear drops containing gentamicin, as well as related substances, may be ototoxic if given over a prolonged time to individuals with perforated ear drums.

Genetic Susceptibility

It has been found that in some individuals there is unusual susceptibility to gentamicin or streptomycin ototoxicity related to a mutation of mitochondria (Muyderman et al 2012, Qian & Guan 2009). This susceptibility is passed on genetically through the mother and occurs in as many as 17% of individuals with hearing loss after aminoglycoside exposure. Vestibular abnormalities have been demonstrated in an animals with dysfunctional mitochondria (Quintana et al 2010), and human pedigrees have been reported with both sensorineural deafness and aminoglycoside sensitivity(Rahman et al 2012). 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.

Current research has shown that vestibular hair cell regeneration may be possible with gene therapy (Albu & Muresanu 2012).

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

  • Albu S, Muresanu DF. 2012. Vestibular Regeneration – Experimental Models and Clinical Implications. Journal of cellular and molecular medicine
  • Alharazneh A, Luk L, Huth M, Monfared A, Steyger PS, et al. 2011. Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. PloS one 6: e22347
  • Black FO, Gianna-Poulin C, Pesznecker SC. 2001. Recovery from vestibular ototoxicity. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 22: 662-71
  • Ding D, Jiang H, Salvi RJ. 2010. Mechanisms of rapid sensory hair-cell death following co-administration of gentamicin and ethacrynic acid. Hearing research 259: 16-23
  • Li H, Steyger PS. 2009. Synergistic ototoxicity due to noise exposure and aminoglycoside antibiotics. Noise & health 11: 26-32
  • Muyderman H, Sims NR, Tanaka M, Fuku N, Raghupathi R, Thyagarajan D. 2012. The mitochondrial T1095C mutation increases gentamicin-mediated apoptosis. Mitochondrion 12: 465-71
  • Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. 1995. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrobial agents and chemotherapy 39: 650-5
  • Qian Y, Guan MX. 2009. Interaction of aminoglycosides with human mitochondrial 12S rRNA carrying the deafness-associated mutation. Antimicrobial agents and chemotherapy 53: 4612-8
  • Quintana A, Kruse SE, Kapur RP, Sanz E, Palmiter RD. 2010. Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome. Proceedings of the National Academy of Sciences of the United States of America 107: 10996-1001
  • Rahman S, Ecob R, Costello H, Sweeney MG, Duncan AJ, et al. 2012. Hearing in 44-45 year olds with m.1555A>G, a genetic mutation predisposing to aminoglycoside-induced deafness: a population based cohort study. BMJ open 2: e000411
  • Roberts JA, Norris R, Paterson DL, Martin JH. 2012. Therapeutic drug monitoring of antimicrobials. British journal of clinical pharmacology 73: 27-36
  • Tokgoz B, Somdas MA, Ucar C, Kocyigit I, Unal A, et al. 2010. Correlation between hearing loss and peritonitis frequency and administration of ototoxic intraperitoneal antibiotics in patients with CAPD. Renal failure 32: 179-84
  • Touw DJ, Westerman EM, Sprij AJ. 2009. Therapeutic drug monitoring of aminoglycosides in neonates. Clinical pharmacokinetics 48: 71-88
  • Zilberstein Y, Liberman MC, Corfas G. 2012. Inner hair cells are not required for survival of spiral ganglion neurons in the adult cochlea. The Journal of neuroscience : the official journal of the Society for Neuroscience 32: 405-10

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.