Topical aminoglycosides? Yes. The case for using these agents in chronic ear disease. (Debate).

As a personal preference, I do not use aminoglycoside-containing otic drops for chronic ear disease in my practice. But this does not necessarily mean that no one should. There are very few cases in the literature in which aminoglycoside-containing drops have been implicated as a cause of ototoxicity when they are used to treat chronic ear disease.

I have testified in several court cases that involved ototoxicity caused by an intravenous aminoglycoside. I have also served as an expert witness for the defense in one of the few cases in the United States in which an otolaryngologist was accused of causing irreversible ototoxicity as a result of using a topical aminoglycoside. My involvement in the latter case led me to conduct an extensive review of the literature and perform other research, which will form the basis of my arguments.

Indications for topical aminoglycoside treatment

Topical aminoglycosides have been used for the treatment of chronic suppurative otitis media (CSOM). The definition of CSOM is somewhat controversial, but for the purposes of this discussion, I define it as a tympanic membrane perforation accompanied by otorrhea that persists for 6 weeks or longer (although there is debate over the duration of the persistence). The incidence of CSOM has been reported to be 39 per 100,000 children. An estimated 2 million tympanostomy tubes are placed in the United States each year, and approximately 20% of the patients require treatment for post-tympanostomy tube otorrhea. Nunez and Browning reported that the overall incidence of intracranial brain abscess in patients with CSOM is 1 in 10,000; however, the lifetime risk in a 30-year-old patient is much greater: 1 in 200. (1)

Schuknecht reported the use of intratympanic streptomycin for the treatment of Meniere's disease in 1957. (2) Dr. Rutka's group in Toronto recently reported their success using gentamicin transtympanically to ablate vestibular function in patients with Meniere's disease. (3)

Fears of ototoxicity are not supported in the literature

Aminoglycoside antibiotics can be ototoxic; of that, there is no argument. The medicolegal literature is replete with expert testimony of this fact, as is the otolaryngology literature. The ototoxic potential of streptomycin was recognized soon after it was first used in the 1940s. Neomycin was developed in 1949 and gentamicin in 1963 in an attempt to avoid ototoxicity but, of course, neither effort succeeded in this regard.

Nevertheless, the question remains: Are aminoglycoside antibiotics ototoxic when they are used to treat a chronically infected ear? This question has yet to be satisfactorily answered because the literature is somewhat confusing. Researchers who have conducted animal studies have used different species, different dosages, and different ways of measuring results, and most have studied uninfected ears. What's more, animal data are difficult to extrapolate to humans. The anatomic differences between animals and humans are many. For example, the round window membrane is much thicker in humans than in animals. And, of course, there are physiologic differences among the different species.

In humans, very few studies have implicated topical aminoglycosides in ototoxicity. Most of those that have are single case reports, most involved prolonged therapy, and many involved the use of framycetin (also known as neomycin II), which was never approved for use in the United States. Moreover, some of these findings in these reports are tenuous at best, because the treated patients had prolonged infections. Finally, otic drops were implicated in some studies even though the treated patients had also undergone surgery.

The 30 patients that Dr. Rutka and colleagues treated for inadvertent ototoxicity caused by commercially available gentamicin/betamethasone drops represent by far the largest such population ever reported. (4) There are few well-controlled studies of note in the literature. In one large study published in 1976, Gyde reported that of 300 patients with otorrhea who had been treated with gentamicm for 3 weeks prior to surgery, none showed any evidence of ototoxicity. (5) In 1993, Lundy and Graham published the results of their survey of 2,235 otolaryngologists. (6) They reported that 94% of the respondents used ototopical agents to treat post-tympanostomy tube otorrhea, 84% did so to treat draining perforations, 75% used them intraoperatively, and 30% used them to treat dry perforations. Of the 2,235 respondents, only 3.4% reported that they had ever observed any ototoxicity.

Widespread use attests to safety

The widespread use of aminoglycoside-containing eardrops is a testament to their safety. In the 1990s, the manufacturer of polymyxin/neomycin/hydrocortisone (PNH) otic suspension reported that it had sold 1.5 million bottles over a 2-year period. Furthermore, many otolaryngologists in leadership positions in the United States continue to use aminoglycoside drops; some use them exclusively, and some even use them with intraoperative packing.

PNH accounts for a large share of the eardrop market in Nashville, Tenn., which I consider to be a progressive medical city. (Nashville has a major university, four large private hospitals, and a strong otology and neurotology presence). In July 2001, PNH's share of the Nashville market was 51%. By comparison, sales of the fluoroquinolones ciprofloxacin and ofloxacin, which are not ototoxic at all, represented 19 and 16%, respectively, of total sales.

How does Nashville compare with the rest of the nation? The combined market share of ciprofloxacin and ofloxacin nationwide is 55%. Not surprisingly, otolaryngologists use topical quinolones more than primary care physicians do and less than pediatricians do. In fact, I first learned about ciprofloxacin ophthalmic drops from a referring pediatrician who was treating patients with CSOM.

Effect of medicolegal concerns on prescribing

A number of factors influence our decisions as to which otic drops we prescribe. As caregivers, we are quick to point out that our decisions are guided by clinical experience and evidence-based medicine. We are less enthusiastic about admitting that economic and medicolegal concerns also play an important role. I have contacted a number of colleagues around the country and have learned that there are at least four cases currently in litigation in which aminoglycoside drops are being blamed for causing ototoxicity. In Canada, there are seven such cases.

Informed consent. These cases illustrate in a most profound way the importance of obtaining informed consent. In Canada, it has been suggested that all patients be warned of the possibility of ototoxicity--specifically, hearing loss and vertigo--before they receive any aminoglycoside-containing drop. Similarly, many clinics are now obtaining written informed consent from patients who are being treated with steroids for sudden hearing loss, because of the possibility that some of these patients might develop avascular necrosis of the hip.

As surgeons, we are all familiar with the necessity of obtaining written informed consent, but as prescribers of eardrops, obtaining such consent is new territory. If we do begin obtaining informed consent before prescribing eardrops, however, should we also do so before prescribing other medications? Based on my own review of the literature, I have concluded that the incidence of topical aminoglycoside-induced ototoxicity is no greater than 1 in 10,000--that is, 0.01%. Most medications carry some degree of risk, and many have complication rates that are much higher than 0.01%.

Malpractice. If a physician treating CSOM prescribes an otic drop that is used by more than 50% of his colleagues, is the physician liable for any subsequent drug-related complication? If a patient with sudden hearing loss experiences avascular necrosis of the hip after receiving properly administered treatment, is the complication the fault of the physician? In some areas of the United States, a failure to treat sudden hearing loss might constitute negligence. Conversely, an adverse reaction to treatment might constitute malpractice. It happens again and again.

In conclusion, aminoglycoside drops do have some potential for ototoxicity, but such cases are rare, and these agents continue to be widely used. They can be prescribed with confidence--but not overconfidence; consider obtaining informed consent.

References

(1.) Nunez DA, Browning GG. Risks of developing an otogenic intracranial abscess. J Laryngol Otol 1990;104:468-72.

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

(3.) 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.

(4.) Marais J, Rutka JA. Ototoxicity of topical eardrops. Clin Otolaryngol 1998;23:360-7.

(5.) Gyde MC. When the weeping stopped: An otologist views otorrhea and gentamicin. Arch Otolaryngol 1976;102:542-6.

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