Tobramycin Ototoxicity

Timothy C. Hain, MD • Page last modified: April 3, 2023

See also: bilat_cause• bilat_prevent• Bilat_recent• bilat_vn• gentamicin_toxicity• ototoxic_drops• ototoxins • progressive_bilateral • regeneration • sensory_substitution

Additional Disclaimer: This material is not written for legal use, including trial testimony.

Causes of Bilateral Loss
After "idiopathic", gentamicin is the most common cause of bilateral vestibular loss that we encounter in our clinical practice. Tobramycin is the second most common of aminoglycoside toxicity.

 

Tobramycin is an antibiotic medication. It is most frequently used in persons with cystic fibrosis who develop recurrent pulmonary infections with resistant organisms such as Pseudomonas. Rates of ototoxicity in cystic fibrosis units run as high as 20% (Soulsby et al, 2009). In children with more than 10 courses of intravenous aminoglyosides (of which tobramycin is the main one in CF), up to 44% had sensorineural hearing loss. Zettner and Gleser (2018) reported that "The majority of adult patients with CF are (often repeatedly) exposed to parenteral aminoglycosides and lose hearing at a rate that far exceeds that predicted from aging alone."

Ototoxicity seems mainly to be correlated with intravenous use rather than inhaled use (Chuchalin et al,  2009).   Tobramycin is rarely used in peritoneal dialysis (CAPD), where the drug may persist in the blood for 72-96 hours (Mars et al, 2000). While we know of no cases of ototoxicity reported for this protocol, it seems likely to us that this is rare only due to the infrequency of it's use for CAPD.

tobra2
. Audiogram of person with advanced tobramycin ototoxicity.  Hearing is lost at high frequencies

Tobramycin is a mixed ototoxin, causing both hearing (cochlear) and balance (vestibulotoxicity). The hearing toxicity starts at high frequencies, and extends to lower frequencies with longer or higher dose.

Some authors suggest there is no hearing loss after tobramycin use in cystic fibrosis patients (Sheenstra et al, 2010). This is somewhat contrary to our experience (e.g. see figure 1-2), as well as contrary the animal literature -- tobramycin is a mixed ototoxin in animals. Nevertheless, we have seen some examples of a "vestibular wipeout" and normal hearing, similar to the situation commonly found with gentamicin ototoxicity. Our position on this is that vestibular function is probably more sensitive to tobramycin than hearing, but neverthless, with sufficient drug, both become damaged. This is not the usual situation with gentamicin where hearing toxicity is very unusual.

It also seems likely that toxicity from tobramycin depends on the average dose over long periods of time (e.g. a year). In other words, there is likely a history effect. See this page for more detail about prediction of toxicity.

The vestibulotoxicity of Tobramycin is a 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.

Oscillopsia When a person has bilateral vestibular damage, such as may result from Tobramycin 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.

 

The visual symptoms, called "oscillopsia", only occur when the head is moving. A movie showing oscillopsia, can be seen by clicking here. Oscillopsia often occurs during walking (Freyss et al, 1988). 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.

Tobra audiogram tobra oae
Audiogram of person exposed to Tobramycin, with near complete loss of vestibular responses on rotatory chair testing. Hearing is commonly normal through 4000 hz, and then falls off at higher frequencies. OAE of same person as on left.  Although vestibular function is greatly reduced on rotatory chair testing, OAE's are normal through about 10K. See later writing on this page concerning the relative insensitivity of OAE amplitudes to Tobramycin.
tobra2 rot
Case T2 -- very low rotatory chair responses after a course of IV tobramycin. The lowest gain/phase points are not accurate (there was almost no response).
t2 audio t2 sweep
Case T2: nearly normal audiometry, with no high frequency loss. Case T2: OAE's are also reasonably good for age, although vestibular function is very poor.

 

Other than Tobramycin, there are numerous other aminoglycoside ototoxins.

Pathology

In pathologic studies, severe aminoglycoside toxicity is associated with death of inner ear hair cells (Plogar et al, 2001). Doses that are not enough to kill hair cells may damage their motion sensitive hairs (sterocilia), making them unable to respond to motion, at least for some months.( Oei, Segenhout et al. 2004).

More temporal bone studies with humans are sorely needed ! If you have Tobramycin ototoxicity, please consider donating your inner ear to the temporal bone registry, in the event of your death.

Dosing of tobramycin:

According to Bragier and Brown (1998), the half-life of tobramycin in children with cystic fibrosis is 2.3h. This is similar to the situation with gentamicin.  According to Cipolle et al (1980), the half-life varied from 0.5 to 8.6 hours.  This is more than a 10-fold variation, and suggests that monitoring of levels is prudent.

Typical initial IV dosing for Tobramycin is 10 mg/kg/day, adjusted with levels (Prescott and Nagel, 2010).  This compares with typical IV dosing for Gentamicin being roughly 5 mg/kg/day.  In other words, Tobramycin is given in higher doses. In our experience, patients with significant Tobramycin ototoxicity have had at least one intravenous course for 4 weeks or longer.

Inhaled tobramycin is not reported to be ototoxic (Chuchalin et al, 2009), although there is a single case report of it occurring in a patient who also had renal failure. Recently, Kaufman and Eliades (2019) reported a single case in a patient who did not have renal failure as well.

We would expect that peritoneal dosing of Tobramycin is very ototoxic, but we know of no case reports or series confirming this.  Nikolaidis et al (1991) found no evidence for hearing toxicity.

In pregnant women, Bourget et al (1991) suggested that there was lower clearance in the third trimester, as well as a possibility of accumulation of tobramycin in the fetus.

Like gentamicin, Tobramycin and furosemide (a loop diuretic) interact.  Kaka et al (1984) reported that furosemide reduces the volume of distribution, which may increase levels.  As furosemide is ototoxic itself, it's ototoxicity may add to that of tobramycin. Other loop diuretics are likely similar.

It seems likely that Tobramycin and Vancomycin given together in an intravenous form would increase ototoxicity, as is the case with gentamicin.  However, the literature is silent on this situation.

Gentamicin and metronidazole (Flagyl) probably have some synergy for toxicity, and we would expect that tobramycin and metronidazole would also have more combined ototoxicity than either one alone. Again, no literature.

It also seems likely that Tobramycin given topically in an ear with a perforation would, like gentamicin drops, be ototoxic. Tobradex (tobramycin plus dexamethasone) drops are marketed for use in the eyes, and eye drops are sometimes used in the ear. We do not know of any cases of ototoxicity reported from this situation.  Extrapolating from other aminoglycoside containing drops, the toxicity would likely require weeks of treatment.

See this page for more discussion about dosing. 

Diagnosis

Diagnosis is not difficult. What is required is exposure to tobramycin, documentation of substantial bilateral vestibular and/or hearing reduction, and exclusion of reasonable alternatives.

With respect to documentation of bilateral vestibular reduction (paresis), the rotatory chair test is preferred. Caloric testing can sometimes indicate absence of function when there actually is considerable function. VEMPs are reduced or absent in most cases of significant aminoglycoside ototoxicity.   Nothing has been reported so far in tobramycin ototoxicity.

There is an issue when ice-calorics are not done, or air is used, as these tests are sometimes falsely positive. Active head rotation tests such as the "Vortec" or "VAT" or the VHIT test, are inferior to rotatory chair testing. Of these, should a rotatory chair not be available, we would favor the instrumented VHIT.

Hearing testing is generally useful as Tobramycin affects both hearing and vestibular function. On the other hand, fistula testing and ABR testing have no role other than to exclude alternative diagnoses. Posturography testing has a small utility.

Alternative diagnoses that should be considered are other sensory ataxias (especially proprioceptive loss, as can be found in diabetics), cerebellar ataxias, orthostatic hypotension, BPPV, and malingering (mainly encountered in situations where people are hoping to be paid to be ill -- also see here).

Prevention -- monitoring of vestibular or auditory function

At this writing, there are no ongoing inner ear monitoring protocols that are customary and that can reliably prevent Tobramycin toxicity, and it seems unlikely that they are even possible. The difficulty is that the toxicity is delayed -- it may not cause clinical symptoms for a week after intake, and damage can progress after the drug has stopped.

Fausti and associates (1994) used high-frequency audiometry in an attempt to detect ototoxicity. Only 37% of ears tested in this way showed a significant hearing reduction, from a mean duration of 11.4 days of treatment with several different aminoglycosides.

Can high-frequency audiometry provide early warning of ototoxicity ? This study does not address this point as the drugs monitored varied in their propensity to cause hearing loss and also there was no attempt to correlate vestibulotoxicity with audiometric findings. Another problem is that older people generally lose high-frequencies anyway, leaving nothing to measure.

Otoacoustic emissions, particularly those obtained at extremely high frequencies, have a potential to detect ototoxicity. (Orts et al, 2000) We have not found them to be useful in practice after the fact, as older people generally have no OAE's, even younger people commonly have no high-frequency OAE's, and practically OAE's do not seem to be very sensitive to Tobramycin.  In fact, Katbamna et al (1999) reported that DPOAE amplitudes were not significantly different in treated patients.

In the figures above, OAE's through lower frequencies are preserved while vestibular function is lost. In other words, although super high frequency DPOAE may be sensitive to ototoxicity, so far, there is not data to be sure. Furthermore, they are unlikely to be specific because of the high rate that high-frequency DPOAE's drop out, due to things such as listening to loud music.

Katbamna et al (1998) suggested that enhanced contralateral suppression may be the first sign of a developing tobramycin ototoxicity. It is puzzling to us that enhancement of any response should be an early sign of a destructive drug.

Other approaches to prevention are discussed here.

More data

Please see our Bilateral Vestibulopathy Page for further information regarding diagnosis, treatment, prognosis, and research efforts related to vestibular ototoxicity.

References: