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Topical tacrolimus treatment for chronic dermatitis of the ear

European Journal of Dermatology. Volume 17, Number 5, 405-11, September-October 2007, Therapy

DOI : 10.1684/ejd.2007.0238

Summary

Author(s) : Wolfgang Harth, Philipp P Caffier, Babak Mayelzadeh, Heidemarie Haupt, Benedikt Sedlmaier, Gabriele Richard , Clinic for skin diseases, Vivantes Klinikum Berlin Friedrichshain, Department of Dermatology and Phlebology, Landsberger Allee 49, 10249 Berlin, Germany. Academic Teaching Hospital of the Charité – Medical University Berlin, Germany, Department of Otorhinolaryngology, Head and Neck Surgery, Charité – Medical University Berlin, Campus Charité Mitte, Germany, Department of Dermatology & Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, and GeneDx Inc., Gaithersburg, MD, USA.

Summary : Recurrent exacerbation in chronic recalcitrant external otitis (EO) often warrants multidisciplinary treatment and collaboration with a dermatologist. The aim of this pilot study was to ascertain the efficacy of topical tacrolimus ointment application in chronic, non-infectious and therapy-resistant EO.In a prospective clinical study, the efficacy of tacrolimus ointment 0.1% was examined in 53 patients with therapy-refractory chronic EO of confirmed non-infectious etiology. Clinical examination took place prior to treatment (V1), at the end (V2) and during follow-up investigations (V3) of 28 patients over 10-22 months. Patients were evaluated for the symptoms otalgia, edema, otorrhea, erythema, pruritus and desquamation on a 6-point scale.The short-term results after topical application of tacrolimus (V2) showed a clear improvement in 85% of the patients (N \= 45) and significant drop in severity scores for all clinical parameters (p <\; 0.001). The long-term follow-up studies (V3) revealed that a one-time treatment cycle led to complete remission in 46% of patients (N \= 28). The remaining 54% had recurrent EO events, however, with significantly longer symptom-free intervals. Within the observation period, no relevant local or systemic side effects were observed, except for occasional skin burning, stinging, or itching.This interdisciplinary study between dermatologists and ENT specialists clearly demonstrates that the topical application of 0.1% tacrolimus ointment is an effective and well-tolerated new option in the treatment of chronic recalcitrant EO. Furthermore, it shows that dermatologists, with their experience in topical immunomodulatory therapy, can make valuable contributions to the treatment of inflammatory disorders in other medical fields.

Keywords : external otitis, tacrolimus, chronic inflammation, resistance to therapy, immune modulation, dermatitis

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ARTICLE

Auteur(s) : Wolfgang Harth¹, Philipp P Caffier², Babak Mayelzadeh², Heidemarie Haupt², Benedikt Sedlmaier², Gabriele Richard³

¹Clinic for skin diseases, Vivantes Klinikum Berlin Friedrichshain, Department of Dermatology and Phlebology, Landsberger Allee 49, 10249 Berlin, Germany. Academic Teaching Hospital of the Charité – Medical University Berlin, Germany
²Department of Otorhinolaryngology, Head and Neck Surgery, Charité – Medical University Berlin, Campus Charité Mitte, Germany
³Department of Dermatology & Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, and GeneDx Inc., Gaithersburg, MD, USA

accepté le 26 Avril 2007

External otitis (EO) is one of the most frequent and painful diseases in otorhinolaryngological practice worldwide [1]. EO affects 4 out of every 1000 Americans each year, and approximately 10% of the population is expected to suffer from EO at some point in their lifetime [2]. EO is defined as an inflammation of the cutis and subcutis of the external auditory canal. Other associated symptoms are otalgia (pain on tragus and helix palpation), otorrhea, pruritus and conductive hearing loss due to edematous obstruction [3]. Clinically, EO can be subdivided into a wet, secretory type and a dry, squamous (scaly) type. In the majority of cases, EO is a nonspecific diffuse inflammation of bacterial, viral, mycotic or allergic origin [4-7]. Mainstay of therapy is the local application of corticosteroids, antibiotics or antimycotics [8, 9]. The term ‘chronic EO’ is used, if, in terms of chronification, the duration of infection exceeds 4 weeks or if more than 4 episodes occur per year. Recurrent exacerbation in chronic EO represents a special therapeutic challenge for the attending physician.Tacrolimus – its name derived from ‘tsukubaensis macrolide immunsuppresivum’ - is a molecule belonging to the macrolide group, which was discovered 1984 by scientists of Fujisawa Pharmaceutical Co. Ltd. (Japan) by isolation from Streptomyces tsukubaensis [10]. It is a monohydrate with the molecular formula C₄₄H₆₉NO₁₂·H₂O and shows a strong immunosuppressive effect [11]. Since it belongs to the new generation of locally applicable immune modulators [12, 13], tacrolimus has been successfully used in dermatological diseases [14-16]. The aim of this study was to evaluate the efficacy of topical application of tacrolimus in chronic therapy-resistant dermatitis of the external auditory canal.

Materials and methods

Study design and procedure

In a clinical prospective study, the efficacy of tacrolimus ointment was examined in patients with otherwise therapy-refractory non-infectious chronic EO. After aural toilet, an ear wick containing tacrolimus ointment 0.1% (Protopic^®) was inserted into the external auditory canal every 2nd-3rd day. Application was continued until symptoms vanished. Altogether, the wick was changed not more than three times during the treatment cycle (maximum treatment duration: 9-12 days). Clinical examinations took place at days 0, 3, 6, 9, 12 when the wick was changed, and at 3-month intervals after conclusion of the treatment cycle (up to 22 months). Furthermore, patients were instructed to consult their physician in every case of EO recurrence after the tacrolimus treatment cycle was completed. Disease severity was assessed at the initial visit (V1) prior to treatment, at the end of the treatment cycle (V2: day 9-12) and at the follow-up visits (V3). Severity scores based on standardized clinical evaluation form and photo-documentation were obtained at visits V1, V2, and V3 and statistically analyzed (see below). The results were also compared to retrospective data assessed from written and electronic patient charts concerning course of disease, number of consultations, applied medication and duration of EO therapy.

Patients

A consecutive cohort of 53 patients with mono- or binaural chronic EO was recruited from the Charité University ENT outpatient clinic and 7 private ENT practices in Berlin and written informed consent was obtained. The cohort consisted of 27 men and 26 women who were subjected to clinical examination, topical tacrolimus treatment and follow-up examinations. Study inclusion criteria were: EO duration > 4 weeks or > 4 episodes per year, endaural swab with no evidence of bacteria or fungi, no preceding aural surgery, existing tympanic membrane perforation and prevailing EO being refractory to conventional medical treatment. Altogether, complete treatment documentation for all follow-up visits (V3 long-term results) was available for 28 patients.

Evaluation procedure

After taking their medical history, the patients underwent an ear-specific ENT examination including ear microscopy. An endaural swab was taken for bacteriological investigation and patients with infectious EO were excluded from the study. Digital photo-documentation was obtained using aural video endoscopy for objective evaluation and monitoring of EO and treatment results. A structured clinical evaluation form was used to document and compare the pre- and post-therapeutic data. It was standardized for clinical symptom quantification by means of a 6-point score system (0 = not existing, 1 = marginal, 2 = slight, 3 = fair, 4 = strong, 5 = very strong, 6 = maximal prevalence). With the help of the clinical picture and subjective assessment of patient’s discomfort, the attending physician had to rate the actual state of otalgia, edema, otorrhea, erythema, pruritus and desquamation.

Statistical data analysis

Means ± standard deviation (SD) or 95% confidence intervals for graphic representation were calculated for all parameters. Wilcoxon matched pairs test was used to compare the parameters before and after treatment. Log-linear analysis of frequency tables was used for testing the changes in severity scores. Significance between the groups with dry or wet EO was tested by analysis of variance (ANOVA) with repeated measurements. Subsequently, contrast analysis was used to compare individual means. Significance was set at p < 0.05. All statistical tests and graphics were made using Statistica 7.1 (StatSoft).

Results

Description of sample

In total, 53 patients (92 ears) with confirmed diagnosis and completely documented data records entered therapy and further evaluation. 27 male and 26 female patients aged 5 to 83 years (52 ± 16) were treated. Subjects of both sexes were comparable in terms of age and sociodemographic influences (marital status, education, occupation). Altogether, 14 patients suffered from unilateral chronic EO, 39 patients from a bilateral one. Medical history revealed the following predisposing and precipitating factors in 29 patients (55%): eczematous skin disease (n = 6), diabetes mellitus (n = 9), wearing hearing aids (esp. in the canal, ear molds; n = 11), exostoses (n = 4) and a preexisting allergy to cosmetics, ointment bases or other externals (n = 4). No risk factors were found in 24 patients (45%). Important patient characteristics are listed in table 1.

All 28 patients with documented preceding EO episodes who entered the long-term follow-up study (V1-V2-V3) had been previously treated with topical ear drops or ointment wicks with the following medications: cortisone (especially betamethasone and triamcinolone), antibiotics like gyrase inhibitors and aminoglycosides (e.g., ciprofoxacin; gentamicin), combination preparations (e.g., dexapolyspectran), and antimycotic agents like polyenes and imidazoles (e.g., nystatin; clotrimazole). Four patients required treatment with oral antibiotics during the latest EO event. The typical course of disease prior to tacrolimus therapy was characterized by relapsing episodes with 4 to 12 EOs per year (mean 6.2 ± 2.4). For treatment, the resulting number of ENT consultations during the last year ranged from 8 to 50 appointments per year. The total duration of complaints lay between 12 and 24 months in the majority of cases (19 out of 28), between 3 and 5 years in 8 cases and was 11 years in one patient.
Table 1 Study cohort. Unless otherwise noted, data are expressed as number of subjects in relation to all patients (N = 53: V1+V2) and to the long-term results group with documented preceding EO episodes (n = 28: V1+V2+V3)

Characteristics	All patients (n = 53)	Long-term results group (n = 28)
Gender
Male	27	14
Female	26	14
Age, year (mean ± SD)	52 ± 16	53 ± 16
Occurrence of EO
Unilateral	14	8
Bilateral	39	20
Appearance of EO
Dry, scaly	37	19
Wet, secretory	16	9
Risk factors
wearing hearing aids	11	6
diabetes mellitus	9	7
eczematous skin disease	6	4
exostoses	4	2
allergy (cosmetics, etc.)	4	2

Short-term results

The short-term results after local application of tacrolimus (V1-V2) showed a clear improvement in about 85% of the cases (45 out of 53 patients or 77 out of 92 ears). The intra-individual comparison of pre- and post-therapeutic severity score revealed a statistically significant reduction in severity for all investigated parameters (p < 0.001; figure 1). For bilateral EO, neither clinically relevant nor statistically significant differences were to be seen between either ear.

During treatment, the placement and endaural retention of the topical tacrolimus ear wick was subjectively well tolerated. The mean duration of tacrolimus treatment was 8 ± 2 days. Compared to the standard therapy of preceding EO episodes (9 ± 3 days), the mean duration of treatment showed no substantial differences. Within the observation period, no relevant local or systemic side effects were observed, except for a local feeling of heat, occasional skin burning or stinging, and temporarily increased itching. In 2 cases a bacterial superinfection was seen, leading to immediate study dropout and start of local antibiotic therapy. The endaural swabs taken provided evidence of pseudomonas aeruginosa, staphylococcus aureus and group A beta hemolytic streptococci. All individuals who developed side effects and resistance to therapy are listed in table 2.

Based on the clinical and otoscopic features at pre-therapeutic consultation (V1), 2 groups could be distinguished: 37 patients presented with a dry and squamous EO in altogether 66 ears, 16 patients with a wet and secretory EO in 26 ears. According to the standardized score sheet for the quantification of clinical symptoms, the 66 dry EO ears were mainly characterized by pruritus (severity score (SS) 4.8 ± 1.1), desquamation (SS 3.4 ± 1.4) and erythema (SS 3.1 = 1.2). In the 26 wet EO ears, the maximum ratings were obtained for otorrhea (SS 4.1 ± 1.1), pruritus (SS 3.7 ± 1.3) and edema (SS 3.2 ± 1.3). Tacrolimus therapy resulted in differing degrees of efficiency in the ears with dry or wet EO (figure 2). Edema and otorrhea decreased to greater an extent in wet EO ears than in dry EO ears, and the decease of pruritus and desquamation was more pronounced in dry EO ears (significant interaction effects). Remarkably, significant differences in the mean severity levels of the symptoms edema, otorrhea and erythrema between dry and wet ears were observed post-therapeutically, with these symptoms not being completely removed from the wet EO ears. Of all cases lacking therapeutic success (n = 8), the 2 patients with bacterial superinfection and 4 out of 6 patients without improvement had a wet and secretory EO.

On otoscopic examination, the tympanic membrane was initially invisible in 10 ears (11%), a myringitis was seen in 12% of the cases, and the remaining 77% showed a normal surface of the tympanic membrane. After tacrolimus application, all eardrums were without pathological findings. To exemplify the progressive improvement of the clinical features during the treatment cycle, photo documentation of two patients, one with dry EO and one with wet EO, is shown in figure 3.
Table 2 Incidence rate of reported or observed drug-related adverse events and resistance to therapy. Data expressed as number of patients and percentage of all patients

Side effects	Number of patients	% of all patients (N = 53)
Burning or stinging	13	24.4
Increased itching	4	7.5
Bacterial superinfection	2	3.8
No improvement	6	11.3

Long term results

The post-therapeutic observation period in 28 patients ranged from 10 to 22 months (mean 15 + 4 months). During the long-term follow-up after a single treatment cycle, the number of recurrent EO episodes was significantly reduced compared to the EO frequency prior to treatment. Thirteen of twenty eight patients (46%) remained relapse-free, while the remaining 54% experienced recurrences of EO. Nevertheless, their symptom-free intervals were significantly longer (mean 9.9 ± 4.7 month) than prior to the tacrolimus treatment cycle (mean 2.2 ± 0.7 months) (p < 0.00001). Again, the efficacy of tacrolimus therapy was significantly higher in dry EO ears than in wet EO ears. Among patients with diabetes mellitus (n = 9), 2 patients with wet EO did not profit from tacrolimus therapy and dropped out. The remaining 7 subjects (dry EO in n = 3, wet EO in n = 4) showed long term improvement. Throughout the follow-up period, 2 dry EO patients remained symptom free, and 5 patients presented with EO relapses (dry EO in n = 1, wet EO in n = 4). Due to the small sample size, no significant differences were noted with regard to other risk factors.

Discussion

The treatment of chronic external otitis (EO) usually lies in the hands of ENT specialists rather than dermatologists. Nevertheless, we strongly believe that interdisciplinary collaboration between ENT and dermatology specialists can be of great benefit to the patients suffering from this common condition, especially in its chronic form. As evidenced by our data, the dermatologist can make valuable contributions.

Tacrolimus was initially used as intravenous and oral medication in transplant medicine for the prevention of organ transplant rejection. Since it belongs to the new generation of locally applicable immune modulators, tacrolimus has been successfully used in dermatological practice for the treatment of chronic inflammatory skin diseases, especially atopic dermatitis. Furthermore, numerous reports suggest that tacrolimus ointment may provide an effective treatment for a variety of other inflammatory skin disorders, including psoriasis, lichen planus, pyoderma gangrenosum, lichen sclerosus, contact dermatitis, seborrhoeic dermatitis, leg ulcers in rheumatoid arthritis, steroid-induced rosacea, cicatricial pemphigoid, Behçet’s disease, erosive mucosal lichen planus and also granuloma annulare, necrobiosis lipoidica and alopecia areata or vitiligo [14, 17]. Taken together, dermatologists have gained great expertise and experience in this topical immunomodulatory therapy. In addition, tacrolimus has also been tested for topical use in the ophthalmology field for the treatment of ocular immune-mediated diseases [18]. Therefore, we propose that tacrolimus ointment may be also an effective treatment for a variety of other inflammatory disorders involving skin and epithelia that are refractory to conventional therapy and typically are in the domain of other medical fields, with external otitis as a case in point.

While standard medication treatment based on corticosteroids and antimicrobials is successful and established in the short-term therapy of acute EO [19, 20], it is ineffective and unsuccessful in the long-term treatment of relapsing chronic EO. Subsequently, chronic recurrent EO can lead to post-inflammatory acquired atresia of the external auditory canal, requiring surgical enlargement [21]. Recurrent exacerbation in chronic recalcitrant EO often warrants multidisciplinary treatment and collaboration with a dermatologist. Our results from this interdisciplinary study between dermatologists and ENT specialists indicate that the topical application of 0.1% tacrolimus ointment appears to be an effective and well-tolerated new option in both the short-term and long-term treatment of chronic recalcitrant EO.

Throughout a mean follow-up of 15 months, complete remission without recurrence was observed in 46% of the patients, whereas 54% of patients had recurrent EO events with on average significantly longer symptom-free intervals. Furthermore, reapplied tacrolimus treatment attenuated the relapsing course of disease and reduced the number of EO episodes significantly. Topical tacrolimus application was especially successful in patients with dry and squamous EO. Six out of eight patients with failing therapy success had a wet and secretory EO. These findings suggest that wet EO should be treated for a longer time than dry EO. It is also possible that some patients with wet EO had preexisting infectious EO with false-negative results on the endaural swabs.

In 2 of our patients, a bacterial superinfection with P. aeruginosa, S. aureus and group A beta hemolytic streptococci occurred, possibly due to the immunosuppressive local therapy. However, other studies in dermatology have shown that topical tacrolimus ointment is not associated with an increase in cutaneous infections [22]. Instead, tacrolimus demonstrated some antifungal [23] and even unspecific antibacterial activity. Skin colonization with S. aureus is reduced without any direct inhibitory effect but due to the reduction of skin inflammation (atopic dermatitis) and the resulting improvement in the barrier function [24, 25]. In contrast to steroids, topical calcineurin inhibitors result in inflammatory dendritic epidermal cell depletion and normalization of pathologically-increased activity of Langerhans’ cells without apoptosis, and therefore they do not reduce local immunity [26]. We postulate that successful topical tacrolimus application depends on specific indications: a) the exclusion of meatal infections and b) the presence of a dry, squamous type of chronic refractory EO.

Regarding adverse events, no relevant local or systemic side effects were observed, except for an initial local feeling of heat, occasional skin burning or stinging, and itching. Unlike topical corticosteroids, long-term treatment with tacrolimus ointment is not known to cause skin atrophy or other steroidal side effects [27]. The antipruritic effect of tacrolimus may be linked to the reduction of levels of the neuropeptide substance P and the nerve growth factor in keratinocytes in lesional skin [28].

Concerning safety, experience with topical tacrolimus in dermatological clinical trials of up to 4 years duration in humans has not indicated a generally increased risk for skin malignancies [29]. However, as with all immunomodulatory treatments, long-term vigilance in this regard is recommended. The physiochemical properties, such as large molecular size and lipophilic behavior, limit diffusion through the skin and into the bloodstream, providing a skin-selective treatment. Clinical trials with thousands of pediatric and adult patients have demonstrated that systemic absorption of tacrolimus from the ointment is minimal or undetectable [30, 31]. Additionally, studies have shown that percutaneous absorption decreases as treatment continues and clinical improvement occurs. Both aspects, the self-limiting facet of treatment and the skin selectivity, reflect the good safety and tolerability profile of tacrolimus ointment [32]. Altogether, our patients reported that the therapeutic success resulted in an enormous improvement of their subjective quality of life.

In summary, similar to evidence-based recommendations for the management of diffuse acute EO [33], the primary therapeutic aim in chronic EO should be the appropriate use of topical preparations, adequate pruritus and pain relief and improvement of ear hygiene (no manipulation). Before therapy, the diffuse non-infectious chronic EO has to be distinguished from other causes of otalgia, otorrhea and inflammation, infections with the presence of bacteria or fungi and factors that modify management (e.g., diabetes, immuno-compromised state). The choice of therapy must be based on infectiology, efficacy, low incidence of adverse events, likelihood of adherence to therapy, and cost. If one considers the favorable relationship between a safe and successful anti-inflammatory therapy and a minimum of unwanted side effects, the treatment with topical tacrolimus is recommended in chronic inflammatory stages of EO.

In conclusion, our results suggest that the local application of tacrolimus ointment into the external auditory canal represents an effective and well-tolerated new option in the treatment of chronic, non-infectious, refractory EO. The use of this corticosteroid-free ointment, which selectively affects the immune system of the skin, has shown promising results even in patients with long lasting, recurrent disease. Furthermore, our study underscores the benefits of interdisciplinary collaboration between ENT specialists and dermatologists, and aims to raise the awareness of dermatologists to the problem disorder External Otitis and other inflammatory disorders in neighboring medical fields.

Acknowledgements

The authors confirm the absence of financial involvement in any organization with a direct commercial interest and the absence of any off-label or investigational use. This study was conducted in cooperation with the following private ENT practices in Berlin (Germany): Bohlmann, P.; Conrad, C.; Flöttmann, T.; Jivanjee, A.; Lenk, R.; Reinke, R.; Tausch-Tremel, R.

References

1 Rowlands S, Devalia H, Smith C, Hubbard R, Dean A. Otitis externa in UK general practice: a survey using the UK General Practice Research Database. Br J Gen Pract 2001; 51: 533-8.

2 Beers SL, Abramo TJ. Otitis externa review. Pediatr Emerg Care 2004; 20: 250-6.

3 Baily BJ, Baroody F, Dohar J, Guthrie R, Harris JS. Diagnosis and treatment of otitis externa: an interdisciplinary update. Proceedings of round table discussion. Ann Otol Rhinol Laryngol 1999; 176(Suppl): 1-23.

4 Brook I, Frazier EH, Yeager JK. Microbiology of infected atopic dermatitis. Int J Dermatol 1996; 35: 791-3.

5 Martin TJ, Kerschner JE, Flanary VA. Fungal causes of otitis externa and tympanostomy tube otorrhea. Int J Pediat Otorhinol 2005; 69: 1503-8.

6 Pigatto PD, Bigardi A, Legori A, Altomare G, Troiano L. Allergic contact dermatitis prevalence in patients with otitis externa. Acta Dermato-venereol 1991; 71: 162-5.

7 Yariktas M, Yildirim M, Doner F, Baysal V, Dogru H. Allergic contact dermatitis prevalence in patients with eczematous external otitis. Asian Pacific J Allerg Immunol 2004; 22: 7-10.

8 Sander R. Otitis externa: a practical guide to treatment and prevention. American family physician 2001; 63: 927-36; (941-2).

9 Stuck BA, Riedel F, Hörmann K. Treatment of therapy refractory chronic otitis externa by local injection of triamcinolone acetate crystalline suspension. HNO 2001; 49: 199-203.

10 Tanaka H, Kuroda A, Marusawa H, Hashimoto M, Hatanaka H, Kino T, Goto T, Okuhara M. Physicochemical properties of FK-506, a novel immunosuppressant isolated from Streptomyces tsukubaensis. Transplan Proc 1987; 19(5 Suppl 6): 11-6.

11 Meier-Kriesche HU, Li S, Gruessner RW, Fung JJ, Bustami RT, Barr ML, Leichtman AB. Immunosuppression: evolution in practice and trends, 1994-2004. Am J Transplant 2006; 6: 1111-31.

12 Ruzicka T, Assmann T, Homey B. Tacrolimus: the drug for the turn of the millennium? Arch Dermatol 1999; 135: 574-80.

13 Bekersky I, Fitzsimmons W, Tanase A, Maher RM, Hodosh E, Lawrence I. Nonclinical and early clinical development of tacrolimus ointment for the treatment of atopic dermatitis. J Am Acad Dermatol 2001; 44(1 Suppl): 17-27.

14 Harth W, Linse R. Topical tacrolimus in granuloma annulare and necrobiosis lipoidica. Br J Dermatol 2004; 150: 792-4.

15 Michel JL, Gain P. Topical tacrolimus treatment for ocular cicatricial pemphigoid. Ann Dermatol Venereol 2006; 133: 161-4.

16 Shichinohe R, Shibaki A, Nishie W, Tateishi Y, Shimizu H. Successful treatment of severe recalcitrant erosive oral lichen planus with topical tacrolimus. J Eur Acad Dermatol Venereol 2006; 20: 66-8.

17 Ruzicka T, Assmann T, Lebwohl M. Potential future dermatological indications for tacrolimus ointment. Eur J Dermatol 2003; 13(4): 331-42.

18 Bertelmann E, Pleyer U. Immunomodulatory therapy in ophthalmology - is there a place for topical application? Ophthalmologica 2004; 218(6): 359-67.

19 Roland PS, Pien FD, Schultz CC, Henry DC, Conroy PJ, Wall GM, Garadi R, Dupre SJ, Potts SL, Hogg LG, Stroman DW, Ciprodex Otic AOE Study Group. Efficacy and safety of topical ciprofloxacin/dexamethasone versus neomycin/polymyxin B/hydrocortisone for otitis externa. Cur Med Res Opinion 2004; 20: 1175-83.

20 Schwartz RH. Once-daily ofloxacin otic solution versus neomycin sulfate/polymyxin B sulfate/hydrocortisone otic suspension four times a day: a multicenter, randomized, evaluator-blinded trial to compare the efficacy, safety, and pain relief in pediatric patients with otitis externa. Cur Med Res Opinion 2006; 22: 1725-36.

21 Becker BC, Tos M. Postinflammatory acquired atresia of the external auditory canal: treatment and results of surgery over 27 years. Laryngoscope 1998; 108: 903-7.

22 Fleischer Jr. AB, Ling M, Eichenfield L, Satoi Y, Jaracz E, Rico MJ, Maher RM. Tacrolimus Ointment Study Group. Tacrolimus ointment for the treatment of atopic dermatitis is not associated with an increase in cutaneous infections. J Am Acad Dermatol 2002; 47: 562-70.

23 Nakagawa H, Etoh T, Yokota Y, Ikeda F, Hatano K. Tacrolimus has antifungal activities against Malassezia furfur isolated from healthy adults and patients with atopic dermatitis. Clin Drug Invest 1996; 12: 245-50.

24 Park CW, Lee BH, Lee CH. Tacrolimus reduces staphylococcal colonization on the skin in Korean atopic dermatitis patients. Drugs Exp Clin Res 2005; 3: 77-87.

25 Remitz A, Kyllonen H, Granlund H, Reitamo S. Tacrolimus ointment reduces staphylococcal colonization of atopic dermatitis lesions. J Allerg Clin Immunol 2001; 107: 196-7.

26 Schuller E, Oppel T, Bornhovd E, Wetzel S, Wollenberg A. Tacrolimus ointment causes inflammatory dendritic epidermal cell depletion but no Langerhans cell apoptosis in patients with atopic dermatitis. J Allerg Clin Immunol 2004; 114: 137-43.

27 Alomar A, Berth-Jones J, Bos JD, Giannetti A, Reitamo S, Ruzicka T, Stalder JF, Thestrup-Pedersen K. European Working Group on Atopic Dermatitis. The role of topical calcineurin inhibitors in atopic dermatitis. Br J Dermatolog 2004; 151(Suppl 70): 3-27.

28 Katoh N, Hirano S, Yasuno H, Kishimoto S. Effects of tacrolimus ointment on facial eruption, itch and scratching in patients with atopic dermatitis. J Dermatol 2004; 31: 194-9.

29 Naylor M, Elmets C, Jaracz E, Rico JM. Non-melanoma skin cancer in patients with atopic dermatitis treated with topical tacrolimus. J Dermatol Treat 2005; 16: 149-53.

30 Harper J, Smith C, Rubins A, Green A, Jackson K, Zigure S, Bourke J, Alomar A, Stevenson P, Foster C, Undre N. A multicenter study of the pharmacokinetics of tacrolimus ointment after first and repeated application to children with atopic dermatitis. J Invest Dermatol 2005; 124: 695-9.

31 Rubins A, Gutmane R, Valdmane N, Stevenson P, Foster C, Undre N. Pharmacokinetics of 0.1% tacrolimus ointment after first and repeated application to adults with moderate to severe atopic dermatitis. J Invest Dermatol 2005; 125: 68-71.

32 Kapp A, Allen BR, Reitamo S. Atopic dermatitis management with tacrolimus ointment (Protopic). J Dermatol Treat 2003; 14(Suppl 1): 5-16.

33 Rosenfeld RM, Brown L, Cannon CR, Dolor RJ, Ganiats TG, Hannley M, Kokemueller P, Marcy SM, Roland PS, Shiffman RN, Stinnett SS, Witsell DL. American Academy of Otolaryngology--Head and Neck Surgery Foundation. Clinical practice guideline: acute otitis externa. Otolaryngol Head Neck Surg 2006; 134(4 Suppl): 4-23.