Safety and efficacy of topical steroids with and without topical antibiotics.

Science is built up with facts, as is a house with stones. But a collection of facts is no more a science than a heap of stones is a house.

--Henri Poincare, La Science l'Hypothese, 1908

Introduction

Dr. Joseph E. Dollar: The latest advance in ototopical therapy is the development of a potent topical steroid formulated with a topical quinolone. Of course, the addition of a steroid "adds" additional questions about safety and efficacy. In this article, we examine both.

Pharmacokinetics of steroids

Dr. John Rutka: Parnes et al reported that systemically administered hydrocortisone, dexamethasone, and methylprednisolone all cross the blood-labyrinthine barrier. (1) Methylprednisolone by and large was found to have the greatest concentration in the inner ear of their guinea pig model. In another study of guinea pigs, Chandrasekhar et al demonstrated that compared with systemic administration, instillation of topical dexamethasone to the middle ear resulted in much higher concentrations in the inner ear. (2)

Dr. Zorik Spektor: We must keep in mind that the round window membrane in animals is significantly thinner than the round window membrane in humans.

Dr. Patrick J. Antonelli: The round window is thickened in acute and chronic suppurative otitis media, which would attenuate diffusion of steroids into the inner ear. (3) Animal studies have shown transient suppression of adrenal function with ototopical administration of steroids, indicating systemic absorption. (4,5) However, systemic effects have not been observed in humans.

Safety of steroids

Dr. Rutka: Are topical steroids ototoxic? I conducted an Ovid MEDLINE search of English-language articles about humans that had been published from 1996 through the first week of March 2005 (table). I found 2,256 articles that contained the keyword ototoxicity and 1,005 articles that contained the keywords topical steroids. I did not find a single article that contained both ototoxicity and topical steroids as keywords.

I also found 171 articles that contained the keywords ear drops, but none of these led to any references associated with ototoxicity and topical steroids.

We have some data on the effects of intratympanic steroids in the middle ear in animal models. These data indicate that these agents improve mucosal clearance via upregulation of transepithelial sodium transport. (6) Intratympanic steroids obviously counteract the effects of histamine--that is, the release of inflammatory mediators--and thereby reduce inflammation.

We also have evidence from animal studies that different topical steroids--hydrocortisone, dexamethasone, and betamethasone--have different effects on the middle ear mucosa, which is interesting.

Spandow et al reported that the administration of topical 2% hydrocortisone suspension delayed healing in rats with perforated tympanic membranes (TMs). (7) In the treated ears, the keratinizing squamous epithelial cells appeared to be hypertrophic and, compared with untreated ears, hyperplasia (signifying healing) was less prominent. The connective tissue layer of the treated TMs had been invaded by abundant inflammatory cells, primarily polymorphonuclear leukocytes. In other words, instead of exerting an antiinflammatory effect in the middle ear, hydrocortisone actually had a proinflammatory effect that led to thickening of the mucosa. When hydrocortisone was applied to intact TMs, it caused hypertrophy of the epidermal cells and, again, an inflammatory reaction within the TM. High-frequency inner ear hair cell loss at frequencies great than 3,000 Hz was also noted. This was the only article I found that implicated a topical steroid in ototoxicity.

Dr. Antonelli: In another study, Spandow et al found that intratympanlc hydrocortisone also caused hearing loss in rat ears. (8) Obviously, that's not been the human experience with other steroids, which have shown hearing improvement with their use.

Dr. Billy Giles: One guinea pig study revealed that administration of generally prescribed doses of ototopical hydrocortisone caused a slight decrease in mitotic activity in the skin of the ear canal. (9) Another showed a systemic effect in some dogs. (4) Adrenocorticotrophic hormone (ACTH) stimulation was seen as long as 2 weeks following administration in these animals.

Dr. Rutka: Parker and James studied dexamethasone in guinea pigs and found no evidence of ototoxicity. (10) Likewise, Shirwany et al administered transtympanic dexamethasone to guinea pigs and found that it was safe. (11) In addition, they noted that the steroid led to a significant and sustained increase in cochlear blood flow.

Dr. Giles: One animal study revealed that dexamethasone actually arrested the development of tympanosclerosis following myringotomy. (12) Also, the literature appears to indicate that dexamethasone is less irritating to the round window membrane in the middle ear than is hydrocortisone. (13)

Dr. Spektor: That is correct. Nordang et al compared morphologic changes in the round window membrane of rats following administration of hydrocortisone or dexamethasone. (13) They found that despite its antiinflammatory effect, hydrocortisone actually provoked inflammation of the round window membrane, while dexamethasone exerted no such effect.

Dr. Rutka: At my institution, we have used low-concentration gentamicin with and without betamethasone to ablate inner ear function in patients with incapacitating unilateral Meniere's disease. (14) Unfortunately, we found that the steroid did not protect against ototoxicity in the inner ear when used with the aminoglycoside.

Dr. Giles: The possibility that TM healing will be delayed is one of the biggest concerns we have when contemplating intratympanic steroid therapy in children with tympanostomy tubes. But we should soon have some retrospective human studies that we hope will settle the issue.

Dr. Rutka: Some otolaryngologists believe, based on scattered evidence, that an intratympanic steroid injection into the middle ear might increase the risk of otitis media as well as the risk of a TM perforation that will not heal. In humans, other complications include pain, transient vertigo, and perhaps hearing loss, although the role that intratympanic steroids might play in hearing loss is unclear. During the treatment of Meniere's disease, sudden sensorineural heating loss (SNHL), and immune-mediated SNHL, hearing levels fluctuate, and it is difficult to know whether periods of diminished hearing are the result of the primary disease itself or its treatment.

Dr. Antonelli: In their study of noninflamed rat middle ears, Spandow and Hellstrom showed that the use of intratympanic steroids can indeed lead to permanent perforations. (15) But, of course, we know that the physiology of the inflamed middle ear is much different than that of the noninflamed middle ear. Magnuson et al found that healing in inflamed tympanic membranes was much more exuberant than healing in noninflamed tympanic membranes. (16) In inflamed middle ears, steroid use may lead to more normal healing. At our institution, we are in the process of assessing the response to ciprofloxacin/dexamethasone following myringotomy in a chinchilla model of acute otitis media.

Dr. Dohar: Thus far, the only concern I have heard relative to ototoxicity is that high-potency steroids administered intraoperatively might hinder wound healing. And there are some data to suggest that this is so. Nevertheless, intratympanic steroids do not appear to pose any risk to the inner ear.

Dr. Antonelli: Agreed. But because I have had so much success using ciprofloxacin/dexamethasone--for example, in patients with granulation tissue following tympanostomy tube placement--I began to use it in almost all postoperative patients. And I have found that there are more cases of persistent exposed bone in patients undergoing tympanoplasty with mastoidectomy or canaloplasty. Previously, I had been routinely using ciprofloxacin alone. I'm unaware of any formal studies of ototopical steroids after middle ear reconstruction.

Dr. Giles: Many primary care physicians harbor a misconception that topical steroids promote infection. Yet some of them use steroids alone to treat external otitis. (17)

Dr. Antonelli: Yes, but the data argue strongly against this.

Dr. Dohar: The biggest objection I hear from the pediatricians I work with is that steroids can lead to growth suppression. They have been inundated with material on this, primarily with respect to the use of topical steroids for asthma and rhinitis. These concerns are also expressed in the dermatology literature and the ophthalmology literature. Endocrinologists would expect that the amount of steroid they administer would cause pituitary axis suppression in children. But that is not relevant to otolaryngology because pituitary axis suppression is a concern only in children who undergo long-term steroid therapy--for example, children with allergic rhinitis who take a topical nasal steroid for months or even years. We certainly need not be concerned about any untoward effects in terms of growth in children who take an ototopical steroid in the small doses that we prescribe.

Dr. Spektor: You raise an interesting point in that physicians in different specialties have different expectations and attitudes about steroids. Rheumatologists, for example, have little practical interest in such low steroid levels; these levels are not within the realm of their practice.

We conducted a study of the pharmacokinetic effects of ciprofloxacin/dexamethasone by instilling a single dose of 4 drops in 25 randomly selected children, aged 1 to 14 years, who had received a tympanostomy tube; most of these children exhibited effusion. 18 The total dose was 840 lag of the antibiotic and 280 lag of the steroid. Blood was drawn at the time of tube placement prior to instillation (baseline) and periodically up to 6 hours after drug administration.

We used validated high-performance liquid chromatography/tandem mass spectrometry to measure ciprofloxacin plasma levels. Peak levels were seen within 1 hour (mean: 1.33 [+ or -] 0.96 ng/ml; range: <0.5 to 3.45). The mean level was approximately 570-fold lower than the mean of 760 ng/ml that was previously reported 19 following a therapeutic 250-mg dose of oral ciprofloxacin in adults. The estimated half-life of ciprofloxacinin our study was 3.0 hours ([+ or -] 1.2). (18) Peak dexamethasone plasma levels were observed within 2 hours (mean: 0.90 [+ or -] 1.04 ng/ml; range: <0.05 to 5.10); the mean was approximately 8.8-fold lower than the mean of 7.9 ng/ml previously reported (19) after a 0.5-mg oral dose of dexamethasone in adults. The estimated half-life of dexamethasone was 3.9 hours ([+ or -] 2.9). At 6 hours, we were able to detect ciprofloxacin in only 4 of the 25 patients (16%). Our study demonstrated that the degree of systemic exposure to both ciprofloxacin and dexamethasone following ototopical administration in pediatric patients is low. We did not investigate ACTH levels, but it is unlikely that the steroid triggered any significant suppression.

Beneficial effects of steroids

Dr. Rutka: Intratympanic steroids have been used for the treatment of many conditions. The most common are Meniere's disease, immune-mediated SNHL, and sudden idiopathic SNHL. They have also been used to treat tinnitus and idiopathic VIIth cranial nerve paralysis and to minimize aminoglycoside-induced cochleotoxicity during chemical ablation.

Doyle et al reviewed the literature on the use of intratympanic steroids for the treatment of Meniere's disease and sudden SNHL. (20) They made a "weak" recommendation in favor of using intratympanic steroids for treating sudden idiopathic SNHL if oral steroid therapy fails or is contraindicated. They concluded that intratympanic steroids appear to be safe and that their potential for causing hearing loss is low. They reached no conclusion on the use of topical steroids for Meniere's disease.

Dr. Dollar: Is there any reason to believe that topical steroids exert a beneficial effect in treating otitis media? The conventional wisdom with regard to using a steroid in patients with acute otitis media through tympanostomy tubes (AOMT) is that it provides an early benefit. Might there also be a late benefit in terms of protecting the inner ear?

Dr. Antonelli: Yes. Look, for example, at the presence of Pseudomonas exotoxin A in the inner ear, which has been shown to have lasting deleterious effects on the inner ear. Steroids attenuate those effects. (21) Steroids also provide a benefit in patients with other types of inner ear injuries, such as acoustic trauma. Some investigators have theorized that steroids have some antioxidant-type properties, although we do not yet know if that is the principal mechanism of action. But overall, there is evidence that steroids do have a lasting protective effect in patients with a variety of insults.

Dr. Spektor: Park et al investigated the protective effect of corticosteroids against the cytotoxicity of aminoglycoside otic drops in the outer hair cells of chinchillas. (22) They found that dexamethasone exerted a significant protective effect against tobramycin as determined by the time to cell death and the change in cell length.

Elsewhere, Russell et al reported on the effect of common ototopical preparations on isolated cochlear hair cells in chinchillas. (23) They found that the combination agent neomycin/polymyxin B/hydrocortisone was more ototoxic than ofloxacin, which in turn was more ototoxic than either ciprofloxacin or ciprofloxacin/hydrocortisone. The criteria for establishing ototoxicity were the time to cell death and the effect on morphology as determined by cinemicrography after the outer hair cells were bathed in a standard solution of each preparation. Another interesting finding was that there was no significant difference in the ototoxicity of ciprofloxacin alone and ciprofloxacin/hydrocortisone.

Dr. Antonelli: What are the mechanisms of hearing loss after the inner ear is violated by, say, a pathologic process or an iatrogenic semicircular canal transection? We have done a fair amount of work with guinea pig models, and we have found that Pseudomonas aeruginosa and its exotoxin A appear to be the primary factors responsible for hearing loss in a transected ear. Obviously, we need to prevent this, which is difficult because we do not generally anticipate a transection. We conducted a comparison study wherein we rinsed the middle and inner ear with either ciprofloxacin/ dexamethasone or saline after transections occurred. (24) We found that hearing actually improved in the animals in the ciprofloxacin/dexamethasone group, whereas it worsened in the saline group. We usually observe a 20- to 30-dB hearing loss with transection and saline irrigation.

Dr. Dohar: Do in vitro studies of outer hair cells have any value?

Dr. Antonelli: Of course they do. Although they do not yield absolute findings, they do provide relative values. The fact that a hair cell dies in the presence of ciprofloxacin does not mean anything because that cell would die in the presence of any substance. But when they die is relative, and this is more germane to what we see in our patients.

Combined effects of steroids and antibiotics

Dr. Antonelli: Anytime we administer an antibiotic, we may aggravate the inflammatory response and precipitate unintended consequences, such as hearing loss. This risk is widely accepted in the treatment of otosyphilis and meningitis. (25,26) The same response is found in otitis media. (27,28) But if we administer a steroid at the same time, we can lower that risk and improve outcomes with treatment.

Let's look at three studies by Roland and colleagues that demonstrate the benefit of adding a steroid to a quinolone:

* In 2003, they reported their comparison of topical ciprofloxacin/dexamethasone and topical ciprofloxacin alone in 201 children with AOMT. (29) Patients were randomized to receive 3 drops of either medication twice daily for 7 days. Clinical signs and symptoms were evaluated on day 1 (baseline), day 3, day 8 (end of therapy), and day 14 (test of cure). Among the 167 patients who were culture-positive, the mean time to cessation of otorrhea was significantly shorter in the ciprofloxacin/dexamethasone group (4.22 vs. 5.31 days; p = 0.004). Furthermore, clinical responses in the combination group were better at 3 and 8 days (p < 0.0001 and p = 0.0499, respectively), although no significant differences were seen at day 14. The authors concluded that the 20% reduction in the time to cessation of otorrhea (i.e., 1.1 day) is clinically as well as statistically significant and that it represents an important advance over monotherapy.

* In 2004, they published their comparison of ciprofloxacin/dexamethasone and ofloxacin alone in 599 children with AOMT. (30) Patients were randomized to receive either 4 drops of ciprofloxacin/dexamethasone twice daily for 7 days or 5 drops of ofloxacin twice daily for 10 days. At the test-of-cure visit (day 18), patients in the combination group had significantly higher rates of clinical cure (90 vs. 78%) and microbiologic cure (92 vs. 82%). Moreover, those in the combination group also experienced fewer treatment failures (4.4 vs. 14.1%; p = 0.0017) and a shorter duration to cessation of otorrhea (4 vs. 6 days; p = 0.0209). Ciprofloxacin/dexamethasone was significantly superior in terms of clinical cure at follow-up visits on day 3 (p < 0.0001), day 11 (p < 0.0001), and day 18 (p = 0.0023). Finally, the combination was superior in terms of absence of otorrhea at each visit and reduction of otorrhea at each visit.

* Later that year, Roland et al reported on the efficacy of ciprofloxacin/dexamethasone and ofloxacin alone in the management of granulation tissue in the same population of 599 patients; granulation tissue was present in 90 of these patients. (31) The combination agent was significantly superior to monotherapy as determined by reductions in granulation tissue at the day-11 end-of-therapy visit (81.3 vs. 56.1%; p = 0.0067) and the day-18 test-of-cure visit (91.7 vs. 73.2%; p = 0.0223).

Similar benefits have been reported with the use of a combination of steroids and other antibiotics or antiseptics. (32-35) As Dr. Giles indicated, the beneficial effects of steroids in otitis externa may even outweigh those of the antibiotic itself. (17,36)

Dr. Dohar: Another reason to treat AOMT with a combination of a quinolone and a steroid rather than with monotherapy--beyond the combination's superiority in the short term--is to prevent chronic disease. We are far less likely to see our patients progress to chronic disease if we use a steroid. Certainly, we do not have any direct evidence to prove this, but all of the indirect evidence we have suggests that this is true.

References

(1.) Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids: An animal study followed by clinical application. Laryngoscope 1999; 109(7 Pt 2): 1-17.

(2.) Chandrasekhar SS, Rubinstein RY, Kwartler JA, et al. Dexamethasone pharmacokinetics in the inner ear: Comparison of route of administration and use of facilitating agents. Otolaryngol Head Neck Surg 2000;122:521-8.

(3.) Sahni RS, Paparella MM, Schachern PA, et al. Thickness of the human round window membrane in different forms of otitis media. Arch Otolaryngol Head Neck Surg 1987;113:630-4.

(4.) Ghubash R, Marsella R, Kunkle G. Evaluation of adrenal function in small-breed dogs receiving otic glucocorticoids. Vet Dermatol 2004;15:363-8.

(5.) Moriello KA, Fehrer-Sawyer SL, Meyer DJ, Feder B. Adrenocortical suppression associated with topical otic administration of glucocorticoids in dogs. J Am Vet Med Assoc 1988;193:329-31.

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

(7.) Spandow O, Hellstrom S, Schmidt SH. Hydrocortisone delay of tissue repair of experimental tympanic membrane perforations. Ann Otol Rhinol Laryngol 1990;99:647-53.

(8.) Spandow O, Hellstrom S, Anniko M. Impaired hearing following instillation of hydrocortisone into the middle ear. Preliminary report from an animal study. Acta Otolaryngol Suppl 1988;455:90-3.

(9.) Monkhouse WS, Moran P, Freedman A. The histological effects on the guinea pig external ear of several constituents of commonly used aural preparations. Clin Otolaryngol 1988; 13:121-31.

(10.) Parker FL, James GW. The effect of various topical antibiotic and antibacterial agents on the middle and inner ear of the guinea-pig. J Pharm Pharmacol 1978;30:236-9.

(11.) Shirwany NA, Seidman MD, Tang W. Effect of transtympanic injection of steroids on cochlear blood flow, auditory sensitivity, and histology in the guinea pig. Am J Otol 1998;19:230-5.

(12.) Mattsson C, Stierna P, Hellstrom S. Treatment with dexamethasone arrests the development of myringosclerosis after myringotomy. Am J Otol 2000;21:804-8.

(13.) Nordang L, Linder B, Anniko M. Morphologic changes in round window membrane after topical hydrocortisone and dexamethasone treatment. Otol Neurotol 2003;24:339-43.

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

(15.) Spandow O, Hellstrom S. Animal model for persistent tympanic membrane perforations. Ann Otol Rhinol Laryngol 1993; 102:467-72.

(16.) Magnuson K, Hermansson A, Hellstrom S. Healing of tympanic membrane after myringotomy during Streptococcus pneumoniae otitis media. An otomicroscopic and histologic study in the rat. Ann Otol Rhinol Laryngol 1996;105:397-404.

(17.) Tsikoudas A, Jasser P, England RJ. Are topical antibiotics necessary in the management of otitis externa? Clin Otolaryngol 2002;27: 260-2.

(18.) Spektor Z, Jasek MC, Jasheway D, et al. Pharmacokinetics of topical CiproDex otic suspension in pediatric and adolescent patients after tympanostomy tube surgery. Presented at the annual meeting of the American Society of Pediatric Otolaryngology; May 2-3, 2004; Phoenix.

(19.) Tartaglione TA, Raffalovich AC, Poynor WJ, et al. Pharmacokinetics and tolerance of ciprofloxacin after sequential increasing oral doses. Antimicrob Agents Chemother 1986;29:62-6.

(20.) Doyle KJ, Bauch C, Battista R, et al. Intratympanic steroid treatment: A review. Otol Neurotol 2004;25:1034-9.

(21.) Takeuchi N, Anniko M. Dexamethasone modifies the effect of Pseudomonas aeruginosa exotoxin A on hearing. Acta Otolaryngol 2000;120:363-8.

(22.) Park SK, Choi D, Russell P, et al. Protective effect of corticosteroid against the cytotoxicity of aminoglycoside otic drops on isolated cochlear outer hair cells. Laryngoscope 2004; 114:768-71.

(23.) 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.

(24.) Shefelbine SE, Young LJ, Antonelli PJ. Mitigation of hearing loss from semicircular canal transection in Pseudomonas otitis media with ciprofloxacin-dexamethasone irrigation. Otol Neurotol [in press].

(25.) Chan YM, Adams DA, Kerr AG. Syphilitic labyrinthitis--An update. J Laryngol Otol 1995;109:719-25.

(26.) Rappaport JM, Bhatt SM, Burkard RF, et al. Prevention of hearing loss in experimental pneumococcal meningitis by administration of dexamethasone and ketorolac. J Infect Dis 1999; 179:264-8.

(27.) Kawana M, Kawana C, Giebink GS. Penicillin treatment accelerates middle ear inflammation in experimental pneumococcal otitis media. Infect Immun 1992;60:1908-12.

(28.) Sato K, Quartey MK, Liebeler CL, Giebink GS. Timing of penicillin treatment influences the course of Streptococcus pneumoniae-induced middle ear inflammation. Antimicrob Agents Chemother 1995;39:1896-8.

(29.) Roland PS, Anon JB, Moe RD, et al. Topical ciprofloxacin/dexamethasone is superior to ciprofloxacin alone in pediatric patients with acute otitis media and otorrhea through tympanostomy tubes. Laryngoscope 2003; 113:2116-22.

(30.) Roland PS, Kreisler LS, Reese B, et al. Topical ciprofloxacin/dexamethasone otic suspension is superior to ofloxacin otic solution in the treatment of children with acute otitis media with otorrhea through tympanostomy tubes. Pediatrics 2004; 113(1 Pt 1):e40-6.

(31.) Roland PS, Dohar JE, Lanier BJ, et al. Topical ciprofloxacin/dexamethasone otic suspension is superior to ofloxacin otic solution in the treatment of granulation tissue in children with acute otitis media with otorrhea through tympanostomy tubes. Otolaryngol Head Neck Surg 2004;130:736-41.

(32.) Alper CM, Dohar JE, Gulhan M, et al. Treatment of chronic suppurative otitis media with topical tobramycin and dexamethasone. Arch Otolaryngol Head Neck Surg 2000; 126:165-73.

(33.) Gananca MM, Albernaz PL. Topical use of tobramycin, gentamycin, neomycin + pelymyxin B, dexamethasone, and lidocaine in the treatment of otitis. In: Myers E, ed. New Dimensions in ORL and Head and Neck Surgery. (Proceedings of the XIIIth World Congress of Otorhinolaryngology; May 26-31, 1985; Miami Beach, Fla.) New York: Elsevier, 1985:237-8.

(34.) Kaygusuz I, Karlidag T, Gok U, et al. [Efficacy of topical ciprofloxacin and tobramycin in combination with dexamethasone in the treatment of chronic suppurative otitis media]. Kulak Burun Bogaz Ihtis Derg 2002;9:106-11.

(35. Park SN, Yeo SW. Effects of antibiotics and steroid on middle ear mucosa in rats with experimental acute otitis media. Acta Otolaryngol 2001;121:808-12.

(36.) Emgard P, Hellstrom S. A group III steroid solution without antibiotic components: An effective cure for external otitis. J Laryngol Otol 2005; 119:342-7.

Table. Results of the MEDLINE search

Search   Search                                                No.
no.      target                                                articles

#1       All English-language articles about humans with the   2,256
         keyword "ototoxicity"

#2       All English-language articles about humans with the   1,005
         keywords "topical steroids"

#3       #1 and #2                                             0

#4       All English-language articles about humans with the   171
         keywords "ear drops"

#5       #1, #2, and #4                                        0