Topical antibiotics: strategies for avoiding ototoxicity.

Topical therapy has long played a significant role in treating ear disease. Ototopical agents offer a variety of advantages, the most significant being their ability to concentrate medication in the ear. For example, the two currently available fluoroquinolone drops--ciprofloxacin/ dexamethasone and ofloxacin otic--can deliver a concentration of 3,000 [micro]g/ml, which far exceeds the tissue concentration delivered to the middle ear via systemic administration and far exceeds the minimum inhibitory concentration for treating known ear pathogens.

Other advantages associated with ototopical therapy are rapid delivery, good patient compliance, a broad spectrum of activity, low cost, and the capacity to combine different medications into one solution. Yet for all their advantages, net all ototopical agents are completely safe. Many carry the potential for cochlear and/or vestibular ototoxicity.

Increasing awareness of ototoxicity

It has long been known that the aminoglycoside antibiotics have ototoxic and nephrotoxic potential when given systemically. This finding first came to light shortly after the discovery of streptomycin was reported in 1944. (1) Neomycin and gentamicin were subsequently developed in the hopes that they could be useful as less toxic alternatives, but such did net prove to be the case. Multiple animal studies have shown that topically applied aminoglycosides can be ototoxic. (2-4)

Still, for many years otolaryngologists were net completely aware of the true clinical incidence of ototoxicity from topical aminoglycosides. In 1993, Lundy and Graham published their nationwide survey of 2,235 otolaryngologists. (5) They reported that 94% of respondents used ototopicals in the presence of post-tympanostomy tube otorrhea, 84% used them in the presence of a draining perforation, and 75% used them with intraoperative packing. Yet, despite such widespread use in inflamed ears, only 3.4% of the respondents reported that they had witnessed irreversible inner ear damage that had been unequivocably caused by an ototopical drug.

A year later, Roland published an analysis of reports in the American and European literature (including the Lundy and Graham survey) and calculated the reported incidence of topical aminoglycoside toxicity. (6) Even with the broadest possible criteria for defining ototoxicity, the incidence of ototoxicity was determined to be approximately only 1 in 10,000.

Of note, the primary indicator of ototoxicity in many of these earlier studies was hearing loss; vestibular symptoms and other complications were often net taken into account because they were either unrecognized or unreported (unilateral compensation might explain the failure to recognize vestibulotoxicity).

During the past decade, we have come to learn more about the true incidence and nature of ototoxicity. It is not a coincidence that the initial concern for ototoxicity with regard to aminoglycoside-containing eardrops arose in Canada. The most widely prescribed eardrop there is gentamicin/hydrocortisone. It is well known that gentamicin causes a greater degree of vestibulotoxicity than cochleotoxicity. Otolaryngologists in Canada began reporting vestibular complaints in patients who were using aminoglycoside-containing drops as early as 1994. (7-10) These complaints included dizziness, dysequilibrium, and even ataxia in seine cases. Bath et al published the largest series ever reported of patients (n = 29) with true, unmitigated ototoxicity caused by commercially available aminoglycoside-containing drops applied topically to the ear. (9) Of interest was the fact that the average duration of aminoglycoside use in that series was 16 days. A number of those patients, in fact, had used these drops for several months. In this group, 9 patients developed ataxia, 7 never returned to work, and 5 were confined to a wheelchair.

These reports led Health Canada to issue warnings regarding the potential ototoxic effects of aminoglycoside eardrops and to recommend that aminoglycoside drops should net be used in an open infected ear for more than 7 days. (7,11) A longer duration of therapy in these patients might play a significant role in causing ototoxicity. It is suspected that as the infection clears with therapy, the round window becomes more permeable in the new-normal middle ear space, which increases the ototoxic potential of continued application of aminoglycoside drops.

"Therapeutic toxicity"

As long ago as 1957, Schuknecht used intratympanic streptomycin for vestibular ablation in patients with Meniere's disease. (12) Since then, others have reported success with the use of transtympanic gentamicin to ablate vestibular function in Meniere's patients. (13,14) Gentamicin is the preferred aminoglycoside for transtympanic vestibular ablation because it is more vestibulotoxic than cochleotoxic and therefore it may ablate vestibular function while preserving hearing.

The findings on inadvertent ototoxicity from ototopical agents led researchers to conduct an interesting study of intentional vestibular ablation for therapeutic purposes using commercially prepared ototopical agents. Kaplan et al used the commercial gentamicin/betamethasone preparation to treat 20 patients with incapacitating Meniere's disease. (14) They inserted a ventilation tube into the ear of each patient and instructed each to instill 3 drops four times a day until they began to experience dizziness. Most patients experienced ototoxicity by day 12, and half of them exhibited no response to ice-water calorics. None of the 20 patients experienced any hearing loss.

An important point to keep in mind is that these patients already had an existing vestibular deficit secondary to Meniere's disease, and they did not have evidence of chronic ear disease. But this study clearly proved two points: (1) that ototopical drops w ill enter the middle ear space through a tympanostomy tube (a fact that has been doubted by some physicians) and (2) that commercially available aminoglycoside eardrops clearly have ototoxic potential.

Other ototopical agents

Many antibiotics or antiseptic agents used in ototopical therapy have been implicated as having ototoxic potential when tested in animals, including gentian violet, acetic acid, ethanol, and chlorhexidine, among others. (2,15-17) Interestingly, there is no evidence that the off-label use of topical antifungal agents (e.g., miconazole, clotrimazole, tolnaftate, and nystatin) is ototoxic. (18) It is well known that the differences in cochlear anatomy and physiology among species makes extrapolation to humans difficult at best.

The introduction of the quinolone otic drops in 1998 launched a new era in ototopical therapy. Clinical trials of the quinolones in adults and children have shown no evidence of ototoxicity. (19-20) Nor have animal studies implicated quinolone drops as being ototoxic. (3,4)

Quinolone-containing eardrops are not only safe, but they also are highly effective against known ear pathogens. (21-23) Quinolones in general have a broader spectrum of activity than aminoglycosides, and they are highly effective against Pseudomonas spp. and other ear pathogens, especially at the middle ear concentrations that can be achieved with topical therapy.

The safety profile of the quinolones is all the more consequential in light of data indicating that some patients are highly susceptible to aminoglycoside toxicity as a result of an inherited mitochondrial gene abnormality. (24) Patients with such a mutation--it is most common in Asian and Middle Eastern populations--can experience significant hearing loss after exposure to relatively small amounts of systemic aminoglycosides. Genetic susceptibility to topically applied aminoglycosides is unknown.

Medicolegal issues

Another ongoing development that has led us to readdress the issue of ototoxicity is the ever-increasing amount of malpractice litigation in the United States and Canada. It has been difficult to accurately ascertain exactly how many of these cases exist. It is known that in some cases of suspected ototoxicity, there was no evidence of hearing loss; vestibular complaints were the primary issue in these patients. These kinds of cases have led to an increased awareness of the potential for ototoxicity of aminoglyco-side-containing eardrops.

Summary

As we continue to learn more about ototoxicity from ototopical drugs, there are several key points we must keep in mind:

* Aminoglycoside antibiotics used in ototopical agents do have ototoxic potential.

* Reported cases of ototoxicity are relatively uncommon, but the potential for serious complications does exist.

* Subclinical unilateral vestibular deficits do go unrecognized.

* Superior alternatives to aminoglycoside drops, particularly the quinolone drops, are readily available.

* The quinolones are superior to the aminoglycosides in terms of safety, bacterial eradication, and clinical cure and are therefore the drops of choice for treating otorrhea in an open infected ear.

References

(1.) Schatz A, Bugie E, Waxman SA. Streptomycin, a substance exhibiting antibiotic activity against gram positive and gram negative bacteria. Proc Soc Exp Biol Med 1944;55:66-9.

(2.) Morizono T, Johnstone BM. Ototoxicity of topically applied gentamicin using a statistical analysis of electrophysiological measurement. Acta Otolaryngol 1975;80:389-93.

(3.) Barlow DW, Duckert LG, Kreig CS, Gates GA. Ototoxicity of topical otomicrobial agents. Acta Otolaryngol 1995; 115:231-5.

(4.) Russell PT, Church CA, Jinn TH, et al. Effects of common topical otic preparations on the morphology of isolated cochlear outer hair cells. Acta Otolaryngol 2001;121:135-9.

(5.) Lundy LB, Graham MD. Ototoxicity and ototopical medications: A survey of otolaryngologists. Arn J Otol 1993; 14:141-6.

(6.) Roland PS. Clinical ototoxicity of topical untibiotic drops. Otolaryngol Head Neck Surg 1994; 110:598-602.

(7.) Helal A. Aminoglycoside ear drops and ototoxicity. CMAJ 1997; 156:1056-8.

(8.) Wooltorton E. Ototoxic effects from gentamicin ear drops. CMAJ 2002; 167:56.

(9.) Bath AP, Walsh RM, Bance ML, Rutka JA. Ototoxicity of topical gentamicin preparations. Laryngoscope 1999; 109: 1088-93.

(10.) Longridge NS. Topical gentamicin vestibular toxicity. J Otolaryagol 1994;23:444-6.

(11.) Canadian Adverse Reaction Newsletter 2001;11:7-8.

(12.) Schuknecht HF. Ablation therapy in the management of Meniere's disease. Acta Otolaryngol 1957; 132(Suppl): 1-42.

(13.) Blakley BW. Update on intratympanic gentamicin for Meniere's disease. Laryngoscope 2000; 110:236-40.

(14.) Kaplan DM, Hehar SS, Bance ML, Rutka JA. Intentional ablation of vestibular function using commercially available topical gentamicin-betamethasone eardrops in patients with Meniere's disease: Further evidence for topical eardrop ototoxicity. Laryngoscope 2002;112:689-95.

(15.) Aursnes J. Vestibular damage from chlorhexidine in guinea pigs. Acta Otolaryngol 1981;92:89-100.

(16.) Spandow O, Anniko M, Moller AR. The round window us access route for agents injurious to the inner ear. Am J Otolaryngol 1988;9:327-35.

(17.) Morizono T. Toxicity of ototopical drugs: Animal modeling. Ann Otol Rhinol Laryngol Suppl 1990;148:42-5.

(18.) Tom LW. Ototoxicity of common topical antimycotic preparations. Laryngoscope 2000;110:509-16.

(19.) Force RW, Hart MC, Plummer SA, et al. Topical ciprofloxacin for otorrhea after tympanostomy tube placement. Arch Otolaryngol Head Neck Surg 1995; 121:880-4.

(20.) Tutkun A, Ozagar A, Koc A, et al. Treatment of chronic ear disease. Topical ciprofloxacin vs topical gentamicin. Arch Otolaryngol Head Neck Surg 1995; 121:1414-16.

(21.) Esposito S. Noviello S, D'Errico G, Montanaro C. Topical ciprofloxacin vs intramuscular gentamicin for chronic otitis media, Arch Otolaryngol Head Neck Surg 1992;118:842-4.

(22.) Yuen AP, Chau PY, Wei WI. Bacteriology of chronic suppurative otitis media: Ofloxacin susceptibility. J Otolaryngol 1995;24: 206-8.

(23.) Goldblatt EL. Efficacy of ofloxacin and other otic preparations for acute otitis media in patients with tympanostomy tubes. Pediatr Infect Dis J 2001;20:116-19.

(24.) Fischel-Ghodsian N, Prezant TR, Bu X, Oztas S. Mitochondrial ribosomal RNA gene mutation in a patient with sporadic aminoglycoside ototoxicity. Am J Otolaryngol 1993; 14:399-403.