Timothy C. Hain, MD Page last modified: December 29, 2012
Additional Disclaimer: This material is not written for legal use, including trial testimony.
|Inner ear. For ear drops to cause ototoxicity they must enter the middle ear, and then the inner ear. Entry into the middle ear generally requires a perforation in the eardrum, either from an injury, or a tube placed for ventilation (see below). Drugs enter the inner ear via the round window (unlabeled).|
Some of the treatments given for various ear conditions, particularly infections, have the potential to injure the inner ear. In recent years considerable attention has been focused on aminoglycoside antibotics, as many common ear drops contain these drugs. Examples of aminoglycosides are gentamicin, streptomycin, kanamycin, tobramycin, and neomycin. Gentamicin and streptomycin are toxic to the vestibular (balance) part of the inner ear. Neomycin is very toxic to the hearing part of the inner ear. Some of the solvents for the antibiotics have also been reported as being ototoxic. Propylene glycol is an example (Morizono et al, 1980). As you can see below, numerous commonly used ear preparations contain these drugs.
Even drops given as "otic anticeptics", such as Burow's solution (acetic acid plus aluminum sulfate), has been reported to cause toxicity in animal models when delivered into the middle ear (Suzuki et al, 2012).
In some situations a perforation may be present but unknown to the treating doctor. For example, in otitis externa, the ear canal may be so swollen that one cannot see a perforation. The treater may not see the perforation, or might not have even looked. Another possible route for antibiotics to reach the middle ear is via an open mastoid cavity -- this is generally post-surgical. The literature suggests that between 7 and 15% of children on Medicaid with tubes or new TM perforation are given ototoxic drops containing neomycin. Multiple prescriptions increase risk. (Winterstein et al, 2012 a and b). In part, this prescribing pattern may be related to the higher cost of non-toxic drops.
|Example of a ventilation tube being placed in the ear drum, that could allow drops to enter into middle ear. This artists drawing, while a good depiction of the tube itself, does not include many normal anatomical landmarks.|
For a drop placed in the external auditory canal to do damage, it must traverse the ear drum (usually via a perforation), and also traverse the middle ear and diffuse across the round window membrane.
Factors that might reasonably influence whether or not a topical aminoglyocoside might be ototoxic include:
(Adapted from Rutka, 2006)
There is clear evidence for toxicity in animals. Roland and others reviewed 61 articles concerning animal ototoxicity. In rodents, gentamicin toxocity has been found to be "persistently, reliably, and significantly ototoxic" (Roland et al, 2004).Tobramycin has been little studied and so far it has not been shown to be ototoxic in the few studies performed. Vosol also is ototoxic. A single dose of a commonly used preparation containing neomycin, hydrocortisone and polymyxin (Cortisporin) can destroy hearing in a rodent. Aminoglycosides are also ototoxic in cats and primates, although apparently less toxicity occurs than in rodents (Roland et al, 2004).
An antifungal, Gentian violet has the potential for severe damage (Tom, 2000), and it's use seems generally unreasonable in persons with perforations.
A recent review by Matz and associates (2004) provided the following general conclusions: Numerous authors have shown vestibular or cochlear toxicity or both when neomycin/polymyxin B drops are used in patients with either tympanic perforations or open mastoid cavities. No cases have been reported of toxicity in persons with intact tympanic membranes.
In humans, toxicity does not occur as often as would be expected from animal data. As it is not felt that the hearing organ in humans differs intrinsically from that of animals, the lessened toxicity is attributed to differences in delivery. Entry into the inner ear is generally attributed to diffusion across the round window membrane. While this membrane is usually easily accessible within the middle ear of rodents, in humans it is covered by a "false" second membrane in 20% of cases. In an additional 11% there is a fatty or fibrous plug covering the round window. The membrane is also thicker in humans than in rodents. All of these factors might reduce toxicity of drops in the middle ear as well as limit therapeutic effectiveness for drops meant to enter the inner ear.
There are presently available drops that are not ototoxic -- in particular the fluoroquinolone topical drops are not ototoxic and are equally effective as aminoglycoside drops. (Manolidis et al, 2004). Other safe antibiotics, at least for hearing, include Amoxicillin, ceftazadine and ticarcillin (Roland et al, 2004).
Several topical antifungal preparations --Ciclopirox, clotrimazole, miconazole, and tolnaftate, are safe in animals (Tom, 2000; Baylancicek et al, 2008), and probably are safe in humans too as animals are generally more sensitive than humans.
The components of ear drops for ear wax removal are generally unstudied. Of course, ototoxicity for this situation requires an opening in the ear drum. Peleva et al (2011) reported that almond oil was not toxic in chinchillas. Nader et al (2011) found that docusate was severely ototoxic, and mineral oil was not ototoxic in Guinea pigs.
These recommendations are also from Matz et al (2004). If polymyxin B, neomycin, or gentamicin drops are used for longer than 2 weeks in patients with tympanic membrane perforations or open mastoid cavities, patients should be warned of the risk of either vestibular or cochlear toxicity. The use of ototopical drops should be discontinued if the patients report symptoms associated with ototoxicity.
There are presently available drops that are not ototoxic -- in particular the fluoroquinolone topical drops are not ototoxic and are equally effective as aminoglycoside drops. (Manolidis et al, 2004). In our opinion, it is prudent that these drops should be used whenever possible and use of drops with ototoxic components should be avoided.
What if the infection does not respond to fluoroquinolones ? Can one use aminoglycosides ? Well, yes with the cautions noted above, as one has to weigh the risk of hearing/vestibular loss from the antibiotic vs. the risk of hearing/vestibular loss from the infection in this situation. As tobramycin has so far not been shown to have topical ototoxicity, and because it is less ototoxic systemically than gentamicin or neomycin, it's use might be preferable to the more usual Cortisporin drops.
Unfortunately, there are no data to show that monitoring patients with vestibular function tests or serial audiograms would prevent toxicity. Procedures that selectively assess high-frequency hearing, outer-hair cell function (perhaps OAE's ?), and irregular vestibular afferent function (VEMPs ?) would theoretically be the ones most likely to be productive. We have had considerable success in using VEMP's to diagnose bilateral loss. More research is needed !
While ototoxicity from intravenous aminoglycoside administration is well documented, there is considerable controversy regarding the significance of ototoxicity from topical preparations. The literature reviewed here suggests that ear drops containing aminoglycosides (such as gentamicin or neomycin), can occasionally cause hearing loss if administered over a long period of time to a person with a perforated ear drum. There is also evidence for vestibultoxicity from gentamicin topical drops as well as evidence for toxicity for select non-aminoglycoside preparations. As nontoxic ear drops are currently available (e.g. Ofloxin (ofloxacin) or ciprofloxin containing products), it would seem prudent in the future to use these agents instead of potentially toxic drugs, when there is a perforation and when the organism in question is sensitive to these drugs.
There are many things we don't know about ototopicals and their toxicity. Why do gentamicin drops cause hearing toxicity when given topically, but rarely when given systemically ? What is the true prevalence of genetic susceptibility to aminoglycosides in the population at large and in genetic subgroups ? How can one monitor for topical antibiotic ototoxicity ?
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