Journal of Antimicrobial Chemotherapy (1992) 30, 745-751

Review Malignant otitis externa: the therapeutic evolution of a lethal infection Helen Giamarefloa 1st Department Propedeutic Medicine, Athens Univeristy School of Medicine, Laiko General Hospital, GR 115 27 Athens, Greece

Malignant otitis externa (MOE) is a potentially fatal infection of the external auditory canal caused by Pseudomonas aeruginosa in a majority of cases. Treatment of MOE has changed over the years. Surgical debridement of all infected tissue is no longer considered the treatment of choice and has been replaced by localized surgical debridement supplemented with long-term antimicrobial chemotherapy. The recent availability of the fluroquinolones and in particular ciprofloxacin has opened up new therapeutic opportunities.

Introduction Meltzer & Kelemen (1959) were the first to describe the characteristics of a fatal case of otitis externa. Nine years later Chandler (1968) described 13 cases and coined the term malignant otitis externa (MOE). MOE also named necrotizing external otitis (Kraus, Rehm & Kinney, 1988), is a potentially fatal aggressive infection of the external auditory canal caused by Pseudomonas aeruginosa in more than 95% of affected patients. Staphylococccus aureus, Aspergillus fumigatus, Proteus mirabilis, Klebsiella spp. and anaerobes have been implicated in selected cases. Before 1987, 28 papers referable to MOE appeared in the English literature; a further 31 have since been published indicating increasing interest in the condition. Characteristically there is painful inflammation of the external auditory canal, worse at night, accompanied by hearing loss and a purulent discharge, with oedematous obstruction and fleshy granulation tissue of the bony-cartilaginous junction of the inferior aspect of external canal which is considered to be the most reliable hallmark of this infection (Chandler, 1977; Babiatzki & Sadc, 1987; Rubin & Yu, 1988). More than 80% of the cases occur in elderly male diabetics, although it has also been encountered rarely in those with neutropenia, leukaemia and following frostbite and in malnourished children. The disease is most commonly observed in hot and humid climates, there being several cases reported from Florida and Israel. Patbogeneds Despite the fact that P. aeruginosa is not found among the normal skin flora of the external auditory canal, colonization is facilitated by excessive moisture and minor 745 0305-7453/92/120745+07 S08.00

© 1992 The British Society for Antimkrobia] Chemotherapy


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trauma from wearing hearing devices, scratching and after ear irrigation with unsterile tap water (Rubin & Yu, 1988). Certain conditions, such as in diabetic microangiopathy, predispose to ccllulitis. The subsequent focal necrosis of adjacent tissues is the result of an invasive vasculitis and accompanying thrombosis resulting from proteolytic enzymes elastase and collagenase of P. aeruginosa. MOE is complicated by parotitis, mastoiditis, osteomyelitis of the temporal and petrous bones, cranial nerve paralyses, jugular vein thrombosis, meningitis and death. Before the availability of the antipseudomonal /Mactams the overall mortality rate was up to 32% and increased to 50% in the presence of facial nerve paralysis and 75% in cases with mulitple cranial nerve involvement Kraus et al. (1988) proposed the following clinical staging of MOE: Stage I with involvement of the external auditory canal and mastoid cells; Stage II with osteomyelitis of the base of the skull and cranial nerve involvement; Stage III with extension to the brain. Recently Levenson et al. (1991) presented a new classification which extends the disease: 'Pre-MOE' in the presence of all clinical and bacteriological criteria but a negative technetium-99m ( T c radioisotope bone scan); 'limited MOE1 as the 'Pre-MOE' plus a positive ""Tc radioisotope bone scan; 'Central-MOE', fulfilling all previous criteria with the addition of cranial nerve palsies with or without involvement of the temporomandibular joint, base of the skull, parapharyngeal space and infratemporal fossa. The differential diagnosis includes eosinophilic granuloma, Wegener's granulomatosis, squamous cell carcinoma, cholesteatoma, nasopharyngeal carcinoma and Hand-Schuller-Christian disease (Cohen & Friedman, 1987; Rubin & Yu, 1988). Swimmer's ear, is a benign form of otitis externa that is seen most often during the summer and is mostly associated with swimming in lakes in which bacterial counts are high or in inadequately chlorinated whirlpool baths contaminated with Pseudomonas spp; in general this condition, does not proceed to MOE (Pelton & Klein, 1988). However, Salit, McNeely & Chait (1985) pointed out that MOE may begin insidiously as uncomplicated otitis externa in swimmers and subsequently progress to invasive necrotizing disease associated with severe otalgia and the presence of 'polyps' at the bony-cartilaginous junction of the external canal.

Diagnostic Imaging Bony involvement in MOE cannot be assessed reliably by plain radiographs or tomography of the base of the skull because 30-50% demineralization is necessary before X-ray changes become visible (Gold et al., 1984). T c radioisotope MDP scanning although 100% sensitive has a low specificity and because it detects osteoblastic activity cannot be used for monitoring response. Gallium-67 radioisotope scanning is said to correlate more accurately with infection and is more useful for monitoring response; gallium scans have been reported to return to normal after four weeks of successful therapy (Strashun, Nejatheim & Goldsmith, 1984; Levin et al., 1986; Kraus et al., 1988). Computed tomography and magnetic resonance imaging, despite their sensitivity, have yet to be evaluated with regard to their specificity and the management of this condition (Chakeres, Kapila & LaMasters, 1985; Gherini, Brackmann & Bradley, 1986).

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Antimicrobial chemotherapy With advances in our understanding of the pathogenesis, microbiological aetiology together with new antipseudomonal agents, the treatment of MOE has undergone change over the years. Surgical debridement of all infected tissue is no longer considered the treatment of choice (Raines & Schindler, 1980; Pelton & Klein, 1988; Rubin & Yu, 1988). Surgery is now confined to localized debridement of granulation tissue and infected cartilage, simple mastoidectomy with tympanoplasty and facial nerve decompression, or the removal of sequestra and drainage of deep-seated abscesses in the case of more extensive disease. This shift from extensive to localized surgical debridement supplemented with long-term antimicrobial chemotherapy, is based on an impression that extensive surgery may encourage the spread of infection in,the absence of clearly demarcated lines of infection. The role of hyperbaric oxygen remains controversial (Mader & Love, 1982). Anti-pseudomonal agents and aminoglycosides Topical antibiotics used in the treatment of 'Swimmer's ear' have no place in the management of MOE. Systemic anti-pseudomonal antibiotics are the mainstay of therapy (Giamarellou, Tsagarakis & Daikos, 1982; Haverkos, Caparosa & Yu, 1982; Strauss et al., 1982; Uri et al., 1984; Salit et al., 1985; McShane et at., 1986; Babiatzki & Sadc, 1987; Meyers et al., 1987; Kraus et al., 1988; Kimmelman & Lucente, 1989; Johnson & Ramphal, 1990). Johnson & Ramphal (1990) reviewed therapeutic reports from the 'pre-quinolone' era. In the period 1968-1974 63 patients were reported of which 90% had diabetes mellitus and 48% cranial nerve deficits. Three (23%) of 13 patients given colistin and six (67%) of nine given an aminoglycoside were cured with an overall favourable response in 32 (55%) of 58 patients. For the period 1975-1984 most patients were treated with an aminoglycoside and/or an anti-pseudomonal penicillin which resulted in cure in 53 (74%) of 68 patients. Ticarcillin and tobramycin for 6-8 weeks was the predominant regimen. Although mortality was significantly decreased, nephrotoxicity, ototoxicity and bleeding disorders, particularly with prolonged treatment remained a concern, limiting therapy and resulting in high relapse rates. Experience with latamoxef alone produced a favourable outcome in only four of nine patients (Haverkos et al., 1982). From 1985-1989 the incidence of diabetes mellitus and cranial nerve involvement fell to 74% and 20% respectively, and was attributable to increased awareness, earlier diagnosis and treatment. One hundred (91%) of the 110 reported cases had a favourable outcome. Among these 31 (86%) of 36 were cured with a combination of an aminoglycoside and an anti-pseudomonal penicillin. Babiatzki & Sade (1987) reported an additional 50 cases of MOE, of which 68% had diabetes mellitus and 10% involvement of cranial nerves VII-XII, while 30 out of 39 who were scanned showed increased uptake; 10% died because of the infection but the remainder, although not clearly stated, were successfully treated. Anti-pseudomonal cephalosporins Since 1985 monotherapy with the anti-pseudomonal cephalosporins, cefsulodin and ceftazidime have been reported. Cefsulodin cured seven of 11 patients with 'limited MOE' while the remaining four with 'central MOE' failed (Meyers et al., 1987).


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However the daily dose was only 4 g and the role of cefsulodin in MOE has yet to be clarified. Ceftazidime 2g, 8 hourly iv, for 4-6 weeks was given to 23 patients (Kimmelman & Lucente, 1989; Johnson & Ramphal, 1990); three in combination with tobramycin. Twenty-one patients had diabetes mellitus, six osteomyelitis of the skull, and in seven the facial nerve was affected. Despite the small numbers, 17 (74%) were cured at follow-up of 10-26 months, including five with bony involvement. Despite these successes ceftazidime requires prolonged intravenous administration. Fluoroquinolones

The recent availability of the fluoroquinolones has opened up new therapeutic opportunities (Barza, 1991). Among them riprofloxacin is considered the most active in vitro against P. aeruginosa, followed by ofioxacin and pefloxacin. The latter compounds have excellent bone penetration and proven efficacy in treating Gram-negative bacillary osteomyelitis (Gilbert et al., 1987; Lesse et al., 1987; Giamarellou et al., 1988a). The availability of parenteral and oral formulations and their relative safety permits prolonged administration, and is required in the therapy of MOE. To the best of my knowledge 159 patients reported to be suffering from MOE have been treated with a fluoroquinolone. In all, surgery was limited to the removal of granulation tissue and when indicated, necrotic bone and cartilage. A favourable response was reported in 89-7% with no deaths. One hundred and one, among whom 46 had 'central MOE' with crania] nerves deficit, were given dprofloxacin (mostly 750 mg po 12 hourly); 96 (95%) were cured. About half (44 patients) were treated for six or less weeks while the remainder for periods of up to 26 weeks, without any differences in response rates or important side-effects (Scully & Neu, 1987; Giamarellou et al., 19886; Joachims, Danino & Raz, 1988; Leggett & Prendergast, 1988; Morrison & Bailey, 1988; Murphy, Phair & Daikos, 1988; Sabater et al., 1988; Fairley & Glover, 1989; Giamarellou et al., 1989; Hickey et al., 1989; Rubin et al., 1989; Sade et al., 1989; Chrysanthopoulos & Bassaris, 1990; Galanakis et al., 1990). Follow-up in most series extended to a minimum of 12 months, a time period considered adequate for the detection of relapse (Rubin & Yu, 1988). Kitzes-Cohen et al. (1989) studied the penetration of ciprofloxadn into ear tissue of patients with MOE, and reported levels of 1-13 mg/L, 6-2-10 mg/L and 2-5-13 mg/L in granulation tissue, bone and cartilage respectively, concentrations that are much higher than the mean MIC for P. aeruginosa. Ofioxacin at a dose of 400-800 mg po daily for periods of 2-20 weeks in 46 patients, 30 of whom had bone extension, was successful in 38 (82-6%) patients with MOE (Levy et al., 1990; Zikk et al., 1990; H. Giamarellou, unpublished data). Pefloxacin 800-1200 mg po daily for 2-24 weeks, has been given to 12 patients, nine (75%) of whom were cured (Boudard et al., 1990; H. Giamarellou, unpublished data). Contrary to those treated with dprofloxacin five of those receiving ofloxacin or pefloxacin, developed resistance among the pseudomonas isolates. There are no comparative studies of the fluoroquinolones with more traditional combination regimens. Sade et al (1989), published experience with 23 patients with MOE, 21 of whom were cured after six weeks of dprofloxacin, and compared this with historical records of 61 patients treated with gentamidn and an anti-pseudomonal penidllin. Ciprofloxadn was well tolerated and treatment averaged 16-8 days hospitalization with an average of seven days for bacteriological eradication; comparable figures in the control group were 49 and 15-3 days respectively, but with serious side-effects in 46% of patients.

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There is little doubt that the fluoroquinolones and in particular ciprofloxacin, are becoming the antimicrobial agents of choice in MOE. They have proved safe and well tolerated and oral availability reduces the necessity for and the duration of hospitalization with obvious cost advantages. Dosage and duration of therapy need to be individualized according to the stage of the infection and susceptibility of the causative pseudomonas; periods of 6, 12 and 24 weeks or longer are appropriate for 'pre-MOE', 'limited* and 'central-MOE' respectively. To avoid resistance emerging high doses should be prescribed and in those with extensive disease, these should be combined with ceftazidime for the first two weeks. The importance of frequent local toilet and debridement of granulation tissue should not be neglected.

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Salit, I. E., McNeely, D. J. & Chait, G. (1985). Invasive external otitis: review of 12 cases. Canadian Medical Association Journal 132, 381-4. Scully, B. E. & Neu, H. C. (1987). Treatment of serious infections with intravenous ciprofloxacin. American Journal of Medicine 82, Suppl. 4A, 369-75. Strashun, A. M., Nejatheim, M. & Goldsmith, S. J. (1984). Malignant external otitis: early scintigraphic detection. Radiology ISO, 541-5. Strauss, M., Aber, R. C , Conner, G. H. & Baum, S. (1982). Malignant external otitis: long-term (months) antimicrobial therapy. Laryngoscope 92, 397-406. Uri, N., Kitzes, R., Meyer, W. & Schuchman, G. (1984). Necrotizing external otitis. The importance of prolonged drug therapy. Journal of Laryngology and Otology 98, 1083-5. Zikk, D., Rapoport, Y., Redianu, C. H., Shaht, I. & Himelfarb, M. Z. (1990). Granulation tissue concentrations and efficacy of oral ofloxacin therapy in invasive external otitis. In Program and Abstracts of the Third International Symposium on New Qxdnolones, Vancouver, Canada. 1990. Abstract 372, p. 46Z {Received 20 January 1992; accepted 22 April 1992)

Malignant otitis externa: the therapeutic evolution of a lethal infection.

Malignant otitis externa (MOE) is a potentially fatal infection of the external auditory canal caused by Pseudomonas aeruginosa in a majority of cases...
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