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Fungal malignant external otitis
Journal of Infection (2011) 62, 226e231
www.elsevierhealth.com/journals/jinf
Fungal malignant external otitis Yaniv Hamzany a,c,*, Ethan Soudry a,c, Michal Preis a,c, Tuvia Hadar a,c, Ohad Hilly a, Jihad Bishara b,c, Ben I. Nageris a,c a
Department of Otolaryngology, Head and Neck Surgery, Rabin Medical Center, Petah Tiqwa, Israel Infectious Diseases Unit, Rabin Medical Center, Petah Tiqwa, Israel c Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel b
Accepted 5 January 2011 Available online 13 January 2011
KEYWORDS Malignant external otitis; Fungal; Hyperbaric oxygen treatment; Prognosis
Summary Objective: To investigate the clinical characteristics and outcome of fungal malignant external otitis (MEO). Methods: The files of 60 patients treated for MEO in 1990e2008 at a tertiary medical center were reviewed for clinical characteristics and outcome, and findings were compared between patients with fungal and nonfungal infection. Results: Mean duration of follow-up was 4 years. Nine patients (15%) had fungal disease; the main pathogen was Candida spp. Compared with the nonfungal MEO group, patients with a fungal infection were younger at diagnosis (average 68 vs. 74 years, p Z 0.01) and had more facial nerve palsies (55% vs. 14%, p Z 0.01), fewer positive bacterial cultures at presentation (33% vs. 75%, p Z 0.02), and higher rates of surgery (78% vs. 18%, p Z 0.0008) and hyperbaric treatment (78% vs. 4%, p Z 0.0001). Eighty-nine percent had persistent infection (>2 courses of systemic antibiotics before antifungal treatment) compared with 12% in the nonfungal group (p Z 0.0001). Fungal disease was associated with more persistently positive imaging findings (87.5% vs. 25%, p Z 0.0001). There was no significant between-group difference in survival. Conclusion: Fungal MEO probably occurs secondary to prolonged antibiotic treatment for bacterial MEO. The fungal disease is more invasive than the bacterial disease, although survival is the same. Treatment should be aggressive and hyperbaric oxygen therapy should be considered. ª 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Introduction Malignant external otitis (MEO), also known as necrotizing external otitis, is an aggressive and potentially fatal infection that originates in the external ear canal and spreads
progressively along the soft tissues and bone of the skull base, ultimately involving intracranial structures.1 This rare disorder occurs almost exclusively in elderly and diabetic patients.1,2 Since Chandler’s publication of the first comprehensive case series of MEO in 1968,1 the most commonly reported
* Corresponding author. Department of Otolaryngology, Head and Neck Surgery, Rabin Medical Center, Beilinson Campus, Petah Tiqwa 49100, Israel. Tel.: þ972 3 937 6458; fax: þ972 3 937 6467. E-mail address: [email protected] (Y. Hamzany). 0163-4453/$36 ª 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2011.01.001
Fungal malignant external otitis causative pathogen has been Pseudomonas aeruginosa (>98% of cases).3 Other pathogens include Staphylococcus aureus,4 Staphylococcus epidermidis,5 Proteus mirabilis,6 and Klebsiella oxytoca.7 Fungi are rarely involved in MEO, and have been identified particularly in immune-compromised nondiabetic patients, such as patients with AIDS or acute leukemia.2,8 Aspergillus fumigates is the most common cause of fungal MEO.8,9 The traditional and well-accepted treatment for MEO is prolonged anti-pseudomonal therapy for at least 6 weeks as well as local treatment with lavage and eardrops. When cure is not achieved after 6 weeks, the antibiotic treatment is continued and other treatment modalities are considered, such as surgery for debridement10e13 and hyperbaric oxygen chamber.14e16 Only few studies have focused on fungal MEO, and most of them are case reports. In a previous study by our group of severe MEO,11 cultures of specimens from the external canal were positive for fungi in almost half the patients with a persistent course. The aim of the present study was to describe patients with fungal infection and to further investigate the clinical characteristics and outcome of fungal MEO compared to nonfungal MEO.
Patients and methods The database of the department of otorhinolaryngology of a tertiary, university-affiliated medical center was searched for all patients hospitalized with MEO between 1990 and 2008. The diagnosis of MEO was based on the following criteria: 1. External otitis not responsive to outpatient treatment of at least one week. 2. Clinical findings of severe otalgia, edema, and exudates of the external ear canal, and/or granulation tissue at the external ear canal. 3. Positive findings on bone scan (technetium with or without gallium). 4. Histological exclusion of other causes of external otitis, such as tumors and cholesteatoma. 5. Microabscess on pathology specimens obtained at surgery, if performed. In addition, MEO was diagnosed when one criterion was not fulfilled but the disease failed to improve after one week of intravenous antibiotics and extensive local treatment. Our treatment protocol for MEO consisted of intravenous ceftazidime, local eardrops, and daily ear lavage. Patients in whom the disease improved within 2 weeks were discharged and instructed to complete 6 weeks of treatment with oral ciprofloxacin or intravenous ceftazidime at home, administered by the home-care unit. Those who did not improve remained in hospital, and their antibiotic treatment was readjusted according to the culture results. In those who failed to respond to antibiotic treatment after 4 weeks, surgical debridement or hyperbaric chamber treatment was considered, according to the clinical and radiological findings. A persistent infection was defined as failure to improve after 2 full courses of systemic antibiotic treatment (>3 months). Hyperbaric treatment, when considered necessary, was administered according to the Marx protocol,17 consisting of
227 multiple once-daily sessions of breathing 100% oxygen under 2 ATA in a multi-seat hyperbaric chamber. Each session was divided into 3 equal periods of 30 min, with a 10-min interval before and after each period for pressure compression and decompression, respectively, with air breathing. In our institution, ear tissue samples from patients with MEO are routinely cultured for both bacteria and fungi. In our patients with negative cultures who had an ongoing active disease, ear tissue samples were analyzed by panbacterial and panfungal 16sRNA polymerase chain reaction (PCR). Those with positive microbiological findings of fungal infection received antifungal treatment. Cure was defined as complete clinical resolution of symptoms and a negative gallium scan. For purposes of the study, the patients’ medical records were reviewed for medical background, clinical characteristics, culture and imaging findings, management, and outcome. Findings were compared between patients with fungal and nonfungal MEO.
Statistical analysis Continuous variables are given as mean standard deviation. Differences in mean age between groups were analyzed with the ManneWhitney U test. To analyze statistically significant differences in the distribution of the categorical variables between the two groups, chi-square or Fisher exact test was performed, as appropriate. Survival was calculated from the date of diagnosis to the date of death or last follow-up using the KaplaneMeier method; log-rank test was applied to compare survival curves between groups. P values less than or equal to 0.05 were considered statistically significant. For statistical analyses, we used SPSS 15.0.1 software (SPSS Inc., Chicago, IL, USA).
Results A total of 60 patients (39 male and 21 female) were diagnosed with MEO during the study period, of which 9 (15%) had a fungal infection. The characteristics of the patients with fungal and nonfungal disease are summarized in Table 1.
Cultures Among the 9 patients diagnosed with fungal MEO, 7 had a positive culture for fungal growth and 2 had positive results on PCR analysis of tissue samples taken from the external canal. The pathogens identified on culture were Candida spp (6 patients), Aspergillus spp (3 patients), Pseudallescheria boydii (1 patient), and Malassezia restricta (1 patient); 2 patients were positive for both Candida spp. and additional fungi. Both specimens analyzed by panfungal and panbacterial 16sRNA PCR were positive uniquely for fungi: M. restricta in one and Candida parapsilosis in the other. In each case, the PCR analysis was performed following 2 negative fungal cultures. In the patient who was positive for C. parapsilosis, a positive culture was obtained at a later stage. The mean time from hospital admission to identification of a microbiological pathogen was 77 days (range 14e229 days).
228 Table 1
Y. Hamzany et al. Characteristics of patients with fungal and nonfungal MEO.
Male Female Age (yr), mean SD Diabetes mellitus Facial nerve palsya Bilateral disease Positive CT or MRI findingb At presentation In persistent disease Positive bacterial culture at presentation Persistent disease
Fungal MEO (n Z 9)
Nonfungal MEO (n Z 51)
P value
7 (78%) 2 (22%) 67.9 7.0 (54e77) 8 (89%) 5 (55%) 3 (33%)
32 (63%) 19 (37%) 74.1 12.5 (31e99) 42 (82%) 7 (14%) 5 (10%)
NS NS 0.016 NS 0.018 NS
2 7 3 8
21 (62%) 3 (50%) 38 (75%) 6 (12%)
NS NS 0.02 0.0001
(33%) (87.5%) (33%) (89%)
CT-computed tomography, MRI-magnetic resonance imaging. Values given as n (%) unless otherwise indicated. a Facial nerve palsy was documented early during the disease course. b Values represent number of positive images out of total images done.
Cultures obtained at presentation were negative in 5 patients (55%) with fungal MEO and 13 patients (25%) with nonfungal MEO. On repeated cultures, Pseudomonas spp. grew in tissue from 2 patients (22%) in the fungal MEO group and 29 patients (57%) in the nonfungal MEO group. Other pathogens in the fungal group included S. aureus (3 patients) and Enterococcus spp. (3 patients), and in the nonfungal group, S. aureus (2 patients), Enterococcus spp (3 patients), Klebsiella spp (2 patients), and Escherichia coli (1 patient).
Computed tomography (CT) Our department began to perform CT scans for patients presenting with MEO in 1996. At the time of the present study, 40 patients had undergone CT: 6 in the fungal MEO group, of whom 2 (33%) had positive findings, and 34 in the nonfungal MEO, of whom 21 (62%) had positive findings. In the fungal MEO group, temporomandibular joint involvement was demonstrated in 2 patients and nasopharyngeal involvement in one patient; in the nonfungal group, temporomandibular joint involvement was demonstrated in 13 patients (62%), infratemporal fossa involvement in 6 (29%), and nasopharyngeal involvement in 2 (9%) (Fig. 1A,B).
Management In all 9 patients in the fungal MEO group, a positive microbiology finding for fungus was obtained before antifungal treatment was commenced. Eight had a persistent infection, and they received at least 2 courses of systemic antibiotics before antifungal treatment: 4 were given 2 courses, and 4, 3 courses (Table 2). The remaining patient, who did not have persistent disease, was given 2 short courses of systemic antibiotic treatment before a positive culture for fungus was obtained. Antifungal treatment was commenced after 80 days on average from diagnosis of MEO (range 15e230). Patients with Candida spp infection received fluconazole, and those with Aspergillus spp infection or resistant Candida spp
infection were treated with voriconazole. One had gastrointestinal side effects soon after starting fluconazole and was switched to itraconazole. One patient, who died from the disease, received a course of amphotericin B after failure of fluconazole treatment (Table 2). Two patients, who are alive with disease, continue antifungal treatment. Systemic antifungal treatment was given for a mean duration of 101 days (range 42e255). In the nonfungal MEO group, 39 patients (76%) were disease-free after one course (6 weeks) of systemic intravenous antibiotics; 6 patients (12%) required two courses, and 6 patients had persistent infection that necessitated more than 2 courses (>3 months). One patient presented with very aggressive disease, characterized by extensive involvement of the base-of-skull. He died of the disease during hospitalization, early in the course of treatment. Seven patients in the fungal MEO group (78%) underwent surgical debridement compared to 9 (18%) in the nonfungal MEO group (p Z 0.0008). Hyperbaric treatment (Marx protocol) was administered to 7 patients (78%) with fungal MEO and 2 (4%) with nonfungal MEO (p Z 0.0001). Each patient was given 30 expositions. Follow-up imaging studies with CT or magnetic resonance imaging (MRI) were performed because of persistent disease in 8 patients with a fungal infection and 6 with a nonfungal infection. The rate of persistent positive imaging findings was higher in the fungal disease group (87.5% vs 50%, p Z 0.0001). Seven patients with fungal disease showed late involvement in the base-of-skull, of whom 4 (57%) also had infratemporal fossa involvement, and 4 had nasopharyngeal involvement. In the nonfungal disease group, 3 patients showed late involvement: base-of-skull in 2 (66%), infratemporal fossa in 1 (33%), and nasopharynx in 2 (66%).
Survival The mean duration of follow-up was 4 years (2 monthse17 years). At the time of the present analysis, one of the 9 patients with fungal MEO (11%) had died of the infection, 2
Fungal malignant external otitis
229
Figure 1 A,B. Temporal bone axial CT of a patient with fungal MEO at presentation (left ear). Bone destruction is demonstrated at: carotid canal, external auditory canal, condyle, posterior wall of sphenoid sinus, floor of middle cranial fossa, Infratemporal fossa soft tissue involvement.
(22%) were alive with disease, and 6 (67%) were alive with no evidence of disease. Of the 51 patients with nonfungal MEO, 23 (45%) were alive with no evidence of disease; the other 28 had died, 4 of them (8%) from the infection and the others from unrelated causes (cerebrovascular accidents, ischemic heart disease, urosepsis, etc.). The 5-year specific survival rate was 83% for the fungal MEO group and 90% for the nonfungal MEO group (NS).
Discussion To the best of our knowledge, this is the first case series of fungal MEO reported in the English literature. As part of our department’s wide experience with MEO,10,18 we have observed that some patients have a persistent disease course (defined as >3 months of systemic antibiotic treatment), and that among this subgroup, the prevalence of fungal infection is relatively high (57%). In the present study of 9 patients diagnosed with fungal MEO over an 18-year period, we found that fungal culture at the time of admission to our department was negative. Findings converted to positive only in later samples. Therefore, we assume that the primary infection was caused by a bacterial pathogen, and owing to the prolonged course of the disease and the antibiotic treatment, the patients acquired an opportunistic fungal infection. Important principles of treatment include aggressive control of diabetes, improvement of immunocompetency when possible, and administration of combined systemic (oral/intravenous) and local anti-pseudomonal agents for at least 6 weeks. Nevertheless, various studies report a poor outcome for MEO,10,11,13 which has led to an increased
interest in alternative treatment modalities. As MEO is considered an osteomyelitic process of the skull base, some clinicians advocate a treatment approach similar to that used for limb osteomyelitis, namely, prolonged systemic antibiotics as well as debridement of the infected tissues and, in some intractable cases, hyperbaric oxygen therapy.19 Although surgical debridement of the infected soft and bony tissues is a logical and common procedure, evidence of its efficacy in MEO is lacking.10,12,16 Regarding hyperbaric oxygen, there is as yet no uniformity in treatment design (i.e., number of treatments, pressure exposure during treatment) in MEO. Several reports suggested a beneficial effect of hyperbaric oxygen for MEO, along with traditional treatment,14,15,20 whereas the Cochrane Collaboration Database21 did not find any clear data supporting its efficacy relative to antibiotics and/or surgery. Our comparison of the patients with fungal and nonfungal MEO showed that the fungal MEO group was characterized by a younger mean age, higher rate of facial nerve palsies early in the course of the disease, and need for more surgical procedures and hyperbaric treatment. There was no between-group difference in the prevalence of diabetes mellitus. The repeated imaging studies performed in the patients with persistent disease showed that the number of patients with radiological evidence of bone involvement increased in the fungal MEO group and decreased in the nonfungal MEO group. Although the difference was not statistically significant, a trend was evident, which might have become significant in a larger cohort. The trend suggests that although persistent MEO does not fully respond to antibiotic treatment, when there is no fungal pathogen, some control is achieved, and antibiotic treatment will reduce the extent
230
Table 2
Systemic treatment of fungal MEO.
Patient Prehospital number treatment
Duration In hospital treatment (days) First Duration Second (days) 42
Ceftazidime
43
2
Ciprofloxacin augmentin Augmentin
42
3
Ciprofloxacin
37
4
No data
no data
Ceftazidime ciprofloxacin Ceftazidime piperacillintazobactam Ceftazidime
5
Ciprofloxacin
14
6
Ciprofloxacin
7
Ciprofloxacin
8
Ciprofloxacin ofloxacin 60
9
Ciprofloxacin
1
a
Duration Third (days) 42
50
Voriconazole cloxacillin Voriconazole
42
Voriconazole
42
50
Ciprofloxacin ceftazidime
110
Ceftazidime
14
Fluconazole
75
36
Ceftazidime
49
Ceftazidime
78
14
Ceftazidime
26
Meropenem
40
42
Ceftazidime 30 co-trimoxazole Ceftazidime 42
Duration Fourth (days)
Duration Fifth (days)
Duration (days)
42
Voriconazole 130 co-trimoxazole Ceftazidime 42
Ceftazidime ofloxacin vancomycin Fluconazole rifampicin fusidic acid Meropenem itraconazole Fluconazole
Fluconazole ampicillin
66
Fluconazole meropenem
60
Amphotericin 30 B
30
m-55 i-255 42
Fluconazole 60a rifampicin linezolid
30a
Continue treatment.
Y. Hamzany et al.
Fungal malignant external otitis of bone involvement. However, the presence of a fungal pathogen makes the disease more invasive. This was further confirmed by the higher number of facial nerve palsies in the patients with fungal MEO. The more malignant course was also longer and warranted more surgical procedures and hyperbaric treatments until cure was achieved. In our series, 2 patients are still receiving antifungal agents without the achievement of cure and might require lifelong treatment. Fungal rhinosinusitis is also recognized for its aggressive natural course. However, diabetes mellitus is an important underlying factor in fungal rhinosinusitis,22 whereas in fungal MEO, it is not, as indicated by the similar rates of diabetes mellitus in our two groups. Patient survival was similar as well. In fungal rhinosinusitis, the worse prognosis was associated specifically with infection with Mucormycosis rather than Aspergillus.22e24 By contrast, in our series, none of the patients were positive for Mucormycosis. This might explain the lack of association in our study between the type of causative pathogen and survival.
Conclusion Fungal MEO probably occurs secondary to prolonged antibiotic treatment in patients with primary bacterial MEO. Although fungal MEO is more invasive than bacterial MEO, as evidenced by imaging studies, the higher prevalence of facial nerve palsy, the greater need for surgical procedures, and the prolonged persistent course, there is no difference between the two infections in patient survival. Since the outcome of fungal MEO is grim, aggressive treatment should be offered as early as possible. After positive results are obtained on fungal cultures or PCR tests of the biopsy specimen, appropriate antifungal treatment (systemic and local) should be administered and surgical debridement performed. We suggest that hyperbaric oxygen therapy should be considered following surgery, given the existing data suggesting its significance in this setting. However, it should be borne in mind that there is as yet no definitive evidence of the benefit of hyperbaric oxygen therapy for MEO.
Funding No funding was received for this study.
References 1. Chandler JR. Malignant external otitis. Laryngoscope 1968;78: 1257e94. 2. Slattery 3rd WH, Brackmann DE. Skull base osteomyelitis. Malignant external otitis. Otolaryngol Clin North Am 1996;29: 795e806. 3. Rubin J, Yu VL. Malignant external otitis: insights into pathogenesis, clinical manifestations, diagnosis, and therapy. Am J Med 1988;85:391e8.
231 4. Bayardelle P, Jolivet-Granger M, Larochelle D. Staphylococcal malignant external otitis. Can Med Assoc J 1982;126:155e6. 5. Barrow HN, Levenson MJ. Necrotizing "malignant" external otitis caused by Staphylococcus epidermidis. Arch Otolaryngol Head Neck Surg 1992;118:94e6. 6. Coser PL, Stamm AE, Lobo RC, Pinto JA. Malignant external otitis in infants. Laryngoscope 1980;90:312e6. 7. Garcia Rodriguez JA, Montes Martinez I, Gomez Gonzalez JL, Ramos Macias A, Lopez Alburquerque T. A case of malignant external otitis involving Klebsiella oxytoca. Eur J Clin Microbiol Infect Dis 1992;11:75e7. e S, Viard JP, 8. Parize P, Chandesris MO, Lanternier F, Poire Bienvenu B, et al. Antifungal therapy of Aspergillus invasive otitis externa: efficacy of voriconazole and review. Antimicrob Agents Chemother 2009;53:1048e53. 9. Rubin Grandis J, Branstetter BF, Yu VL. The changing face of malignant (necrotising) external otitis: clinical, radiological, and anatomic correlations. Lancet Infect Dis 2004;4:34e9. 10. Joshua BZ, Sulkes J, Raveh E, Bishara J, Nageris BI. Predicting outcome of malignant external otitis. Otol Neurotol 2008;29: 339e43. 11. Soudry E, Hamzany Y, Preis M, Joshua BZ, Hadar T, Nageris BI. Malignant external otitis - analysis of severe cases. Accepted for publication- Otolaryngol Head Neck Surg. 12. Carfrae MJ, Kesser BW. Malignant otitis externa. Otolaryngol Clin North Am 2008 Jun;41(3):537e49 [viii-ix]. 13. Chen CN, Chen YS, Yeh TH, Hsu CJ, Tseng FY. Outcomes of malignant external otitis: survival vs mortality. Acta Otolaryngol 2010;130(1):89e94. 14. Narozny W, Kuczkowski J, Stankiewicz C, Kot J, Mikaszewski B, Przewozny T. Value of hyperbaric oxygen in bacterial and fungal external otitis treatment. Eur Arch Otorhinolaryngol 2006; 263:680e4. 15. Ling SS, Sader C. Fungal malignant otitis externa treated with hyperbaric oxygen. Int J Infect Dis 2008;12:550e2. 16. Tisch M, Maier H. Malignant external otitis. Laryngorhinootologie 2006 Oct;85(10):763e9. quiz 770-773 [Article in German]. 17. Marx RE, Ames JR. The use of hyperbaric oxygen therapy in bony reconstruction of the irradiated and tissue-deficient patient. J Oral Maxillofac Surg 1982 Jul;40(7):412e20. 18. Soudry E, Joshua BZ, Sulkes J, Nageris BI. Characteristics and prognosis of malignant external otitis with facial paralysis. Arch Otolaryngol Head Neck Surg 2007;133:1002e4. 19. Goldman RJ. Hyperbaric oxygen therapy for wound healing and limb salvage: a systematic review. PMR 2009 May;1(5): 471e89. 20. Shupak A, Greenberg E, Hardoff R, Gordon C, Melamed Y, Meyer WS. Hyperbaric oxygenation for necrotizing (malignant) otitis externa. Arch Otolaryngol Head Neck Surg 1989 Dec;115 (12):1470e5. 21. Phillips JS, Jones SEM. Hyperbaric oxygen as an adjuvant treatment for malignant otitis externa (Review). The cochrane collaboration. Cochrane Database Syst Rev 2005 Apr;18(2): CD004617. 22. Epstein VA, Kern RC. Invasive fungal sinusitis and complications of rhinosinusitis. Otolaryngol Clin North Am 2008;41:497e524 [viii]. 23. Parikh SL, Venkatraman G, DelGaudio JM. Invasive fungal sinusitis: a 15-year review from a single institution. Am J Rhinol 2004;18:75e81. 24. Ferguson BJ. Mucormycosis of the nose and paranasal sinuses. Otolaryngol Clin North Am 2000;33:349e65.
www.elsevierhealth.com/journals/jinf
Fungal malignant external otitis Yaniv Hamzany a,c,*, Ethan Soudry a,c, Michal Preis a,c, Tuvia Hadar a,c, Ohad Hilly a, Jihad Bishara b,c, Ben I. Nageris a,c a
Department of Otolaryngology, Head and Neck Surgery, Rabin Medical Center, Petah Tiqwa, Israel Infectious Diseases Unit, Rabin Medical Center, Petah Tiqwa, Israel c Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel b
Accepted 5 January 2011 Available online 13 January 2011
KEYWORDS Malignant external otitis; Fungal; Hyperbaric oxygen treatment; Prognosis
Summary Objective: To investigate the clinical characteristics and outcome of fungal malignant external otitis (MEO). Methods: The files of 60 patients treated for MEO in 1990e2008 at a tertiary medical center were reviewed for clinical characteristics and outcome, and findings were compared between patients with fungal and nonfungal infection. Results: Mean duration of follow-up was 4 years. Nine patients (15%) had fungal disease; the main pathogen was Candida spp. Compared with the nonfungal MEO group, patients with a fungal infection were younger at diagnosis (average 68 vs. 74 years, p Z 0.01) and had more facial nerve palsies (55% vs. 14%, p Z 0.01), fewer positive bacterial cultures at presentation (33% vs. 75%, p Z 0.02), and higher rates of surgery (78% vs. 18%, p Z 0.0008) and hyperbaric treatment (78% vs. 4%, p Z 0.0001). Eighty-nine percent had persistent infection (>2 courses of systemic antibiotics before antifungal treatment) compared with 12% in the nonfungal group (p Z 0.0001). Fungal disease was associated with more persistently positive imaging findings (87.5% vs. 25%, p Z 0.0001). There was no significant between-group difference in survival. Conclusion: Fungal MEO probably occurs secondary to prolonged antibiotic treatment for bacterial MEO. The fungal disease is more invasive than the bacterial disease, although survival is the same. Treatment should be aggressive and hyperbaric oxygen therapy should be considered. ª 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Introduction Malignant external otitis (MEO), also known as necrotizing external otitis, is an aggressive and potentially fatal infection that originates in the external ear canal and spreads
progressively along the soft tissues and bone of the skull base, ultimately involving intracranial structures.1 This rare disorder occurs almost exclusively in elderly and diabetic patients.1,2 Since Chandler’s publication of the first comprehensive case series of MEO in 1968,1 the most commonly reported
* Corresponding author. Department of Otolaryngology, Head and Neck Surgery, Rabin Medical Center, Beilinson Campus, Petah Tiqwa 49100, Israel. Tel.: þ972 3 937 6458; fax: þ972 3 937 6467. E-mail address: [email protected] (Y. Hamzany). 0163-4453/$36 ª 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2011.01.001
Fungal malignant external otitis causative pathogen has been Pseudomonas aeruginosa (>98% of cases).3 Other pathogens include Staphylococcus aureus,4 Staphylococcus epidermidis,5 Proteus mirabilis,6 and Klebsiella oxytoca.7 Fungi are rarely involved in MEO, and have been identified particularly in immune-compromised nondiabetic patients, such as patients with AIDS or acute leukemia.2,8 Aspergillus fumigates is the most common cause of fungal MEO.8,9 The traditional and well-accepted treatment for MEO is prolonged anti-pseudomonal therapy for at least 6 weeks as well as local treatment with lavage and eardrops. When cure is not achieved after 6 weeks, the antibiotic treatment is continued and other treatment modalities are considered, such as surgery for debridement10e13 and hyperbaric oxygen chamber.14e16 Only few studies have focused on fungal MEO, and most of them are case reports. In a previous study by our group of severe MEO,11 cultures of specimens from the external canal were positive for fungi in almost half the patients with a persistent course. The aim of the present study was to describe patients with fungal infection and to further investigate the clinical characteristics and outcome of fungal MEO compared to nonfungal MEO.
Patients and methods The database of the department of otorhinolaryngology of a tertiary, university-affiliated medical center was searched for all patients hospitalized with MEO between 1990 and 2008. The diagnosis of MEO was based on the following criteria: 1. External otitis not responsive to outpatient treatment of at least one week. 2. Clinical findings of severe otalgia, edema, and exudates of the external ear canal, and/or granulation tissue at the external ear canal. 3. Positive findings on bone scan (technetium with or without gallium). 4. Histological exclusion of other causes of external otitis, such as tumors and cholesteatoma. 5. Microabscess on pathology specimens obtained at surgery, if performed. In addition, MEO was diagnosed when one criterion was not fulfilled but the disease failed to improve after one week of intravenous antibiotics and extensive local treatment. Our treatment protocol for MEO consisted of intravenous ceftazidime, local eardrops, and daily ear lavage. Patients in whom the disease improved within 2 weeks were discharged and instructed to complete 6 weeks of treatment with oral ciprofloxacin or intravenous ceftazidime at home, administered by the home-care unit. Those who did not improve remained in hospital, and their antibiotic treatment was readjusted according to the culture results. In those who failed to respond to antibiotic treatment after 4 weeks, surgical debridement or hyperbaric chamber treatment was considered, according to the clinical and radiological findings. A persistent infection was defined as failure to improve after 2 full courses of systemic antibiotic treatment (>3 months). Hyperbaric treatment, when considered necessary, was administered according to the Marx protocol,17 consisting of
227 multiple once-daily sessions of breathing 100% oxygen under 2 ATA in a multi-seat hyperbaric chamber. Each session was divided into 3 equal periods of 30 min, with a 10-min interval before and after each period for pressure compression and decompression, respectively, with air breathing. In our institution, ear tissue samples from patients with MEO are routinely cultured for both bacteria and fungi. In our patients with negative cultures who had an ongoing active disease, ear tissue samples were analyzed by panbacterial and panfungal 16sRNA polymerase chain reaction (PCR). Those with positive microbiological findings of fungal infection received antifungal treatment. Cure was defined as complete clinical resolution of symptoms and a negative gallium scan. For purposes of the study, the patients’ medical records were reviewed for medical background, clinical characteristics, culture and imaging findings, management, and outcome. Findings were compared between patients with fungal and nonfungal MEO.
Statistical analysis Continuous variables are given as mean standard deviation. Differences in mean age between groups were analyzed with the ManneWhitney U test. To analyze statistically significant differences in the distribution of the categorical variables between the two groups, chi-square or Fisher exact test was performed, as appropriate. Survival was calculated from the date of diagnosis to the date of death or last follow-up using the KaplaneMeier method; log-rank test was applied to compare survival curves between groups. P values less than or equal to 0.05 were considered statistically significant. For statistical analyses, we used SPSS 15.0.1 software (SPSS Inc., Chicago, IL, USA).
Results A total of 60 patients (39 male and 21 female) were diagnosed with MEO during the study period, of which 9 (15%) had a fungal infection. The characteristics of the patients with fungal and nonfungal disease are summarized in Table 1.
Cultures Among the 9 patients diagnosed with fungal MEO, 7 had a positive culture for fungal growth and 2 had positive results on PCR analysis of tissue samples taken from the external canal. The pathogens identified on culture were Candida spp (6 patients), Aspergillus spp (3 patients), Pseudallescheria boydii (1 patient), and Malassezia restricta (1 patient); 2 patients were positive for both Candida spp. and additional fungi. Both specimens analyzed by panfungal and panbacterial 16sRNA PCR were positive uniquely for fungi: M. restricta in one and Candida parapsilosis in the other. In each case, the PCR analysis was performed following 2 negative fungal cultures. In the patient who was positive for C. parapsilosis, a positive culture was obtained at a later stage. The mean time from hospital admission to identification of a microbiological pathogen was 77 days (range 14e229 days).
228 Table 1
Y. Hamzany et al. Characteristics of patients with fungal and nonfungal MEO.
Male Female Age (yr), mean SD Diabetes mellitus Facial nerve palsya Bilateral disease Positive CT or MRI findingb At presentation In persistent disease Positive bacterial culture at presentation Persistent disease
Fungal MEO (n Z 9)
Nonfungal MEO (n Z 51)
P value
7 (78%) 2 (22%) 67.9 7.0 (54e77) 8 (89%) 5 (55%) 3 (33%)
32 (63%) 19 (37%) 74.1 12.5 (31e99) 42 (82%) 7 (14%) 5 (10%)
NS NS 0.016 NS 0.018 NS
2 7 3 8
21 (62%) 3 (50%) 38 (75%) 6 (12%)
NS NS 0.02 0.0001
(33%) (87.5%) (33%) (89%)
CT-computed tomography, MRI-magnetic resonance imaging. Values given as n (%) unless otherwise indicated. a Facial nerve palsy was documented early during the disease course. b Values represent number of positive images out of total images done.
Cultures obtained at presentation were negative in 5 patients (55%) with fungal MEO and 13 patients (25%) with nonfungal MEO. On repeated cultures, Pseudomonas spp. grew in tissue from 2 patients (22%) in the fungal MEO group and 29 patients (57%) in the nonfungal MEO group. Other pathogens in the fungal group included S. aureus (3 patients) and Enterococcus spp. (3 patients), and in the nonfungal group, S. aureus (2 patients), Enterococcus spp (3 patients), Klebsiella spp (2 patients), and Escherichia coli (1 patient).
Computed tomography (CT) Our department began to perform CT scans for patients presenting with MEO in 1996. At the time of the present study, 40 patients had undergone CT: 6 in the fungal MEO group, of whom 2 (33%) had positive findings, and 34 in the nonfungal MEO, of whom 21 (62%) had positive findings. In the fungal MEO group, temporomandibular joint involvement was demonstrated in 2 patients and nasopharyngeal involvement in one patient; in the nonfungal group, temporomandibular joint involvement was demonstrated in 13 patients (62%), infratemporal fossa involvement in 6 (29%), and nasopharyngeal involvement in 2 (9%) (Fig. 1A,B).
Management In all 9 patients in the fungal MEO group, a positive microbiology finding for fungus was obtained before antifungal treatment was commenced. Eight had a persistent infection, and they received at least 2 courses of systemic antibiotics before antifungal treatment: 4 were given 2 courses, and 4, 3 courses (Table 2). The remaining patient, who did not have persistent disease, was given 2 short courses of systemic antibiotic treatment before a positive culture for fungus was obtained. Antifungal treatment was commenced after 80 days on average from diagnosis of MEO (range 15e230). Patients with Candida spp infection received fluconazole, and those with Aspergillus spp infection or resistant Candida spp
infection were treated with voriconazole. One had gastrointestinal side effects soon after starting fluconazole and was switched to itraconazole. One patient, who died from the disease, received a course of amphotericin B after failure of fluconazole treatment (Table 2). Two patients, who are alive with disease, continue antifungal treatment. Systemic antifungal treatment was given for a mean duration of 101 days (range 42e255). In the nonfungal MEO group, 39 patients (76%) were disease-free after one course (6 weeks) of systemic intravenous antibiotics; 6 patients (12%) required two courses, and 6 patients had persistent infection that necessitated more than 2 courses (>3 months). One patient presented with very aggressive disease, characterized by extensive involvement of the base-of-skull. He died of the disease during hospitalization, early in the course of treatment. Seven patients in the fungal MEO group (78%) underwent surgical debridement compared to 9 (18%) in the nonfungal MEO group (p Z 0.0008). Hyperbaric treatment (Marx protocol) was administered to 7 patients (78%) with fungal MEO and 2 (4%) with nonfungal MEO (p Z 0.0001). Each patient was given 30 expositions. Follow-up imaging studies with CT or magnetic resonance imaging (MRI) were performed because of persistent disease in 8 patients with a fungal infection and 6 with a nonfungal infection. The rate of persistent positive imaging findings was higher in the fungal disease group (87.5% vs 50%, p Z 0.0001). Seven patients with fungal disease showed late involvement in the base-of-skull, of whom 4 (57%) also had infratemporal fossa involvement, and 4 had nasopharyngeal involvement. In the nonfungal disease group, 3 patients showed late involvement: base-of-skull in 2 (66%), infratemporal fossa in 1 (33%), and nasopharynx in 2 (66%).
Survival The mean duration of follow-up was 4 years (2 monthse17 years). At the time of the present analysis, one of the 9 patients with fungal MEO (11%) had died of the infection, 2
Fungal malignant external otitis
229
Figure 1 A,B. Temporal bone axial CT of a patient with fungal MEO at presentation (left ear). Bone destruction is demonstrated at: carotid canal, external auditory canal, condyle, posterior wall of sphenoid sinus, floor of middle cranial fossa, Infratemporal fossa soft tissue involvement.
(22%) were alive with disease, and 6 (67%) were alive with no evidence of disease. Of the 51 patients with nonfungal MEO, 23 (45%) were alive with no evidence of disease; the other 28 had died, 4 of them (8%) from the infection and the others from unrelated causes (cerebrovascular accidents, ischemic heart disease, urosepsis, etc.). The 5-year specific survival rate was 83% for the fungal MEO group and 90% for the nonfungal MEO group (NS).
Discussion To the best of our knowledge, this is the first case series of fungal MEO reported in the English literature. As part of our department’s wide experience with MEO,10,18 we have observed that some patients have a persistent disease course (defined as >3 months of systemic antibiotic treatment), and that among this subgroup, the prevalence of fungal infection is relatively high (57%). In the present study of 9 patients diagnosed with fungal MEO over an 18-year period, we found that fungal culture at the time of admission to our department was negative. Findings converted to positive only in later samples. Therefore, we assume that the primary infection was caused by a bacterial pathogen, and owing to the prolonged course of the disease and the antibiotic treatment, the patients acquired an opportunistic fungal infection. Important principles of treatment include aggressive control of diabetes, improvement of immunocompetency when possible, and administration of combined systemic (oral/intravenous) and local anti-pseudomonal agents for at least 6 weeks. Nevertheless, various studies report a poor outcome for MEO,10,11,13 which has led to an increased
interest in alternative treatment modalities. As MEO is considered an osteomyelitic process of the skull base, some clinicians advocate a treatment approach similar to that used for limb osteomyelitis, namely, prolonged systemic antibiotics as well as debridement of the infected tissues and, in some intractable cases, hyperbaric oxygen therapy.19 Although surgical debridement of the infected soft and bony tissues is a logical and common procedure, evidence of its efficacy in MEO is lacking.10,12,16 Regarding hyperbaric oxygen, there is as yet no uniformity in treatment design (i.e., number of treatments, pressure exposure during treatment) in MEO. Several reports suggested a beneficial effect of hyperbaric oxygen for MEO, along with traditional treatment,14,15,20 whereas the Cochrane Collaboration Database21 did not find any clear data supporting its efficacy relative to antibiotics and/or surgery. Our comparison of the patients with fungal and nonfungal MEO showed that the fungal MEO group was characterized by a younger mean age, higher rate of facial nerve palsies early in the course of the disease, and need for more surgical procedures and hyperbaric treatment. There was no between-group difference in the prevalence of diabetes mellitus. The repeated imaging studies performed in the patients with persistent disease showed that the number of patients with radiological evidence of bone involvement increased in the fungal MEO group and decreased in the nonfungal MEO group. Although the difference was not statistically significant, a trend was evident, which might have become significant in a larger cohort. The trend suggests that although persistent MEO does not fully respond to antibiotic treatment, when there is no fungal pathogen, some control is achieved, and antibiotic treatment will reduce the extent
230
Table 2
Systemic treatment of fungal MEO.
Patient Prehospital number treatment
Duration In hospital treatment (days) First Duration Second (days) 42
Ceftazidime
43
2
Ciprofloxacin augmentin Augmentin
42
3
Ciprofloxacin
37
4
No data
no data
Ceftazidime ciprofloxacin Ceftazidime piperacillintazobactam Ceftazidime
5
Ciprofloxacin
14
6
Ciprofloxacin
7
Ciprofloxacin
8
Ciprofloxacin ofloxacin 60
9
Ciprofloxacin
1
a
Duration Third (days) 42
50
Voriconazole cloxacillin Voriconazole
42
Voriconazole
42
50
Ciprofloxacin ceftazidime
110
Ceftazidime
14
Fluconazole
75
36
Ceftazidime
49
Ceftazidime
78
14
Ceftazidime
26
Meropenem
40
42
Ceftazidime 30 co-trimoxazole Ceftazidime 42
Duration Fourth (days)
Duration Fifth (days)
Duration (days)
42
Voriconazole 130 co-trimoxazole Ceftazidime 42
Ceftazidime ofloxacin vancomycin Fluconazole rifampicin fusidic acid Meropenem itraconazole Fluconazole
Fluconazole ampicillin
66
Fluconazole meropenem
60
Amphotericin 30 B
30
m-55 i-255 42
Fluconazole 60a rifampicin linezolid
30a
Continue treatment.
Y. Hamzany et al.
Fungal malignant external otitis of bone involvement. However, the presence of a fungal pathogen makes the disease more invasive. This was further confirmed by the higher number of facial nerve palsies in the patients with fungal MEO. The more malignant course was also longer and warranted more surgical procedures and hyperbaric treatments until cure was achieved. In our series, 2 patients are still receiving antifungal agents without the achievement of cure and might require lifelong treatment. Fungal rhinosinusitis is also recognized for its aggressive natural course. However, diabetes mellitus is an important underlying factor in fungal rhinosinusitis,22 whereas in fungal MEO, it is not, as indicated by the similar rates of diabetes mellitus in our two groups. Patient survival was similar as well. In fungal rhinosinusitis, the worse prognosis was associated specifically with infection with Mucormycosis rather than Aspergillus.22e24 By contrast, in our series, none of the patients were positive for Mucormycosis. This might explain the lack of association in our study between the type of causative pathogen and survival.
Conclusion Fungal MEO probably occurs secondary to prolonged antibiotic treatment in patients with primary bacterial MEO. Although fungal MEO is more invasive than bacterial MEO, as evidenced by imaging studies, the higher prevalence of facial nerve palsy, the greater need for surgical procedures, and the prolonged persistent course, there is no difference between the two infections in patient survival. Since the outcome of fungal MEO is grim, aggressive treatment should be offered as early as possible. After positive results are obtained on fungal cultures or PCR tests of the biopsy specimen, appropriate antifungal treatment (systemic and local) should be administered and surgical debridement performed. We suggest that hyperbaric oxygen therapy should be considered following surgery, given the existing data suggesting its significance in this setting. However, it should be borne in mind that there is as yet no definitive evidence of the benefit of hyperbaric oxygen therapy for MEO.
Funding No funding was received for this study.
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