An Update on the Current Practice on the Management of Fungal Necrotizing Otitis Externa: A Systematic Analysis of the Literature

Abstract

Malignant otitis externa (MOE), necrotizing otitis externa (NOE), or skull base osteomyelitis (SBO) is a severe ear infection, primarily caused by Pseudomonas aeruginosa with 5%–20% of cases due to fungal species. Fungal NOE affects immunocompromised patients. This study systematically reviews fungal NOE management, addressing: (1) when to suspect it and start treatment; (2) the most appropriate anti-fungal; (3) treatment duration. We searched Medline, the Cochrane Library, PubMed, and Embase for English articles up to June 2024, supplemented by Google Scholar and manual reference checks. Using PRISMA, 516 articles were identified in which 387 were screened, 54 full texts reviewed, and 32 included after excluding duplicates and irrelevant studies. Fungal NOE is hard to diagnose. Suspect it with aggressive symptoms and sterile cultures unresponsive to antibiotics. Voriconazole is effective due to bone penetration. Treatment should be continued for > 12 weeks with multiple swabs, aural toileting, and thorough examinations.

Graphical abstract

Keywords

fungal malignant otitis externa / fungal necrotizing otitis externa / skull base osteomyelitis / temporal bone osteomyelitis / voriconazole

1 Introduction

Malignant otitis externa (MOE), necrotizing otitis externa (NOE), or skull base osteomyelitis (SBO) is interchangeable term for a serious infection of the external ear and temporal bone (TB) [1]. Pseudomonas aeruginosa (PA) is the most common pathogen responsible [1], though around 5%–20% of the cases are caused by different fungal species [2,3]. While Aspergillus and Candida species are commonly isolated from ear swabs, Scedosporium angiospermum, although uncommon, was also isolated from some cases and is particularly challenging to identify and treat [4].

Fungal NOE, the same as bacterial NOE, mostly affects immunocompromised patients. It is always a challenge to diagnose it, which subsequently delays the start of treatment and increases the risk of more serious complications such as mycotic aneurysms, cerebral infarction, cranial nerve palsies, intracranial abscesses, and sinus thrombosis or even death [5,6].

Since symptoms mirror bacterial NOE, once patients are diagnosed with bacterial NOE, they are commenced on antibiotics; later, a fungal pathogen is identified on ear swab cultures [7]. This delay in diagnosis makes the treatment more challenging.

There are no current guidelines for the management of fungal NOE. The main outlines of management are to control the risk factors, commence patients on long-term anti-fungal, regular micro suctioning of the ear canal, multiple ear swabs, imaging modality to see the extent of the disease, and surgical intervention in complex cases.

Although studies have reported the efficacy of different anti-fungal medications in management [5,8], none of the current publications reported any significant evidence regarding the most effective anti-fungals and the duration of the anti-fungal. In addition, the exact pathophysiology of fungal NOE is not well understood [9].

Clinicians struggle to treat patients due to limited research on fungal NOE and its management. We did not find any research on the treatment guidance for fungal NOE. Our study aims to systematically review the literature on managing fungal NOE and answer the following questions:

1.When to suspect fungal NOE and start anti-fungal?

2.Which anti-fungal is most appropriate for fungal NOE?

3.For how long should we continue anti-fungal?

2 Materials and Methods

We searched Medline, the Cochrane Library, PubMed, and Embase databases for relevant papers published up to June 2024. The search was made by Syed Zohaib Maroof Hussain and Syed Salman Hashmi. All abstracts were reviewed by additional authors (Syed Zohaib Maroof Hussain, Syed Salman Hashmi and Hassan Nounou). The following keywords were searched for articles; “NOE, fungal ear infection, SBO, fungal NOE, fungal MOE, Voriconazole, Scedosporium angiospermum, TB, temporal bone osteomyelitis (TBO), and skull base osteitis.” The search was limited to articles published in English only. This search was supplemented by using the “related article” function. The search was repeated on Google Scholar to locate additional abstracts. A manual search of references of eligible manuscripts was also performed. Each reference was checked and evaluated for any potential manuscripts. Duplicate articles were removed. We excluded all studies which were non-English and not related to fungal SBO/NOE/MOE/TBO/skull base osteitis and any other ear pathologies. Studies that did not mention the management of fungal NOE were also excluded. We included studies regardless of ethnicity, gender, and age (Table 1). All included abstracts were reviewed by the most senior authors (Asad Qayyum and Mohammed A. Elkrim Saad Mohammed). There was no registered protocol, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was used.

3 Results

The initial literature search identified 516 articles. Following the removal of duplicate articles, letters to the editor and conference proceedings, 387 articles were screened. Upon initial screening, 185 articles were found to be completely irrelevant and hence removed. The remaining 202 abstracts were screened, and 148 articles were removed as per the exclusion criteria. Full texts were reviewed for 54 articles, and 22 articles were further excluded, leaving 32 articles in the final analysis, as per the inclusion criteria of our study as shown in Figure 1. Our systematic analysis included 32 articles, 3 systematic reviews, 11 retrospective studies, 1 case series, and 17 case reports. A total of 74 patients were included in our study cohort.

3.1 Presentation and Microbiology

Otalgia was the main presenting complaint, followed by otorrhea. Oedematous external auditory canal (EAC) with granulation was the most common finding on examination, followed by facial nerve palsy. The specimens obtained from external ear canal swabs and biopsy, nasopharynx biopsy, and surgical swabs and excision were evaluated histopathologically, microbiologically, and via culture. In total, 25 (33.7%) of the patients were culture-positive for Aspergillus flavus, the most common pathogen. Other Aspergillus and Candida species and detailed presenting features are mentioned in Table 2.

3.2 Treatment, Duration and Outcome

All patients were started with the most suitable anti-fungal, per the swab results and microbiology advice. Most patients were started on a single anti-fungal, most commonly voriconazole (VCZ). In some cases, the anti-fungal needed to be changed or add another anti-fungal. In our study, VCZ was the most commonly used anti-fungal. A combination of intravenous (IV) and oral routes was used depending on the patient's severity and status. However, in some cases, antibiotics were commenced as well, depending on the sensitivity, as shown in Table 3. Medication was continued depending on the response and clinical condition of the patient. The mean duration of treatment in our study was 14.7 weeks. Surgery was the last resort in all studies. Variations in surgeries were noted depending on the presentation and extension of the disease. Most of the patients in our study recovered fully, but some needed a longer duration of treatment. Detailed descriptions are mentioned in Table 3.

3.3 Mortality and Complications

In our study analysis, 54 patients experienced complete resolution of symptoms. A few patients demonstrated a poor response to treatment, either due to permanent cranial nerve palsy or the presence of other comorbidities. Additionally, 3 patients died (4.7%) as a result of advanced ear infections, and one patient died at 6-month follow-up unrelated to ear infection. Detailed responses are summarized in Table 4.

3.4 Non-Aspergillus Fungi

Emerging non-Aspergillus fungi like Scedosporium and Candida non-albicans present significant treatment challenges due to their often intrinsic or rapidly acquired resistance to commonly used anti-fungals; for instance, Candida krusei is intrinsically resistant to fluconazole and Scedosporium species, particularly Scedosporium prolificans, are often resistant to multiple anti-fungal classes, including azoles and amphotericin B, making infections very challenging to treat. Voriconazole is often the preferred first-line agent for Scedosporium apiospermum complex. Consequently, accurate species identification and comprehensive anti-fungal susceptibility testing are critical for guiding therapeutic decisions, often necessitating the use of alternative anti-fungal classes like echinocandins or newer agents and potentially combination therapies, deviating from standard Aspergillus treatment approaches to ensure effective management of these increasingly encountered and resistant fungal pathogens in the local clinical setting. Authors recommend further research in the management of emerging non-Aspergillus fungi. In our study, non-Aspergillus fungi had poor outcomes compared to Aspergillus or Candida albicans as shown in Table 4.

4 Discussion

PA is the most common pathogen responsible for NOE. Consequently, patients presenting with NOE are empirically started on anti-pseudomonal antibiotics for at least 6 weeks [39]. Even in cases with negative cultures, the initial regimen consists of anti-pseudomonal antibiotics for at least 6 weeks, alongside managing other comorbidities [40]. Fungal NOE is an extremely rare condition, with most cases attributed to Aspergillus species [8,41,42]. Similarly, our study identified Aspergillus species as the most common fungal pathogen responsible, accounting for 39.18% of cases. Currently, there are no established guidelines for the diagnosis and management of fungal NOE. As a result, diagnosing fungal NOE is challenging, leading to delays in treatment. The diagnosis is often postponed for several reasons. First, it is standard practice to initiate anti-pseudomonal treatment even in the absence of growth on initial swabs, as PA is the most frequently identified causative pathogen. Second, the rate of positive results for culturing a pathogenic fungus from swabs or pus collected from tissue is very low, and when surgical debridement is not used for tissue sampling, the likelihood of identifying a fungal infection decreases. Finally, there are no clear clinical, laboratory, or radiological parameters that can differentiate fungal from bacterial infections, except through tissue sampling for direct smear or PCR [11].

Likewise, in our study, all of the patients were empirically started on antibiotics for a minimum of 6 weeks. After no improvement or further deterioration in the patient's condition, multiple swabs (average 2 swabs and more in some cases) were taken before the diagnosis of fungal NOE was made. Early recognition and effective anti-fungals can result in good outcomes. After 3–4 weeks of antibiotics, the management plan should be re-reviewed and changed accordingly. If there is no response or further deterioration in the patient's condition, the surgical option should be considered either tissue biopsy or debridement [43,44]. Tissue biopsy can be helpful in early diagnosis, as most fungal species do not grow on initial swabs or culture.

In case of aggressive or advanced disease, fungal infection should be considered, and the patient should be started on anti-fungals and where needed, surgery should be performed. Previously reported studies have summarized prognostic factors associated with advanced disease, including facial nerve paralysis, bilateral disease and advanced radiological findings (temporomandibular joint bone destruction, soft tissue involvement in the infratemporal fossa or nasopharynx). Advanced disease was associated with higher adverse disease-specific outcomes and a higher mortality rate. As a result, they suggest earlier surgical intervention in such cases [45,46].

Similarly, in our study, patients were at advanced stages both clinically and radiologically. A tissue biopsy or bone biopsy was taken in most cases. Common radiological findings in our study are demonstrated in Table 5.

In the present study, most patients underwent a surgical biopsy for diagnosis. All patients were then switched to anti-fungal as per the fungal species. However, most patients were treated with VCZ, as shown in Table 4. VCZ is a safe and effective anti-fungal [5]. Amphotericin B is another option; however, it is nephrotoxic, hence its use should be avoided where possible. Some fungal species are resistant to amphotericin B [47]. In addition, VCZ is more potent in case of central nervous system involvement due to better penetration compared to other anti-fungals [48]. Another study reported the effectiveness of VCZ in a patient who presented with fungal NOE [49]. A worldwide case series reported the impact of VCZ on Aspergillus bone infection. As per their data, more than 50% of patients showed favorable responses to VCZ [50]. Treatment depends on so many things. Similarly, another study reported, analysis suggests that a number of factors influence patient outcomes. As with aspergillosis at other sites, immunological status or underlying disease appears to influence outcomes of bone infection. Their response rate (83%) was higher than that for patients with underlying immunosuppression (6 [43%] of 14 patients) [51]. VCZ is fungicidal against Aspergillus [52,53] and is effective as first-line and salvage therapy in patients with invasive aspergillosis [54]. VCZ has excellent tissue penetration, including penetration into the CNS [51].

Similarly, in our analysis, 22 out of 32 studies commenced patients on VCZ, and all patients in their cohort showed favorable responses. In some cases, it was not suitable for patients to be started on VCZ. Hence, an alternative was used depending on the swab results and discussion with microbiology. Authors also recommend VCZ as well from their clinical practice.

The length of therapy also influenced the outcome. The length of anti-fungal has not been described for fungal NOE or bone aspergillosis [55]. However, a previous study has advocated a 6–12-month course of anti-fungal therapy with Candida bone infection [54,56]. The length of therapy was selected by the physicians on the basis of the patients' clinical and radiological responses. The 11 patients with satisfactory responses received a median duration of VCZ therapy of 180 days, compared with just 14 days for the 9 patients with unsatisfactory responses [50,57]. This suggests that factors such as underlying illnesses and comorbidities may influence response.

Authors in our study continued anti-fungal for 12 weeks or more. In some complex cases, anti-fungal drugs were continued for a long period. As per our study, the mean duration of anti-fungals was 14.7 weeks. It is prudent to start anti-fungals if the patient has not responded to antibiotics and/or negative swab results. Delays in treatment can lead to irreversible complications.

Authors recommend an anti-fungal for a minimum of 12 weeks. Management of fungal NOE necessitates a multidisciplinary team (MDT) approach. We advise consultation with microbiology regarding treatment duration while acknowledging the need for institutions to develop local protocols. Our study presented a diagnostic algorithm in Figure 2 that can help clinicians decide when to suspect fungal NOE and start the most suitable anti-fungal.

5 Conclusion

Fungal NOE is a challenge to diagnose and treat. From the systemic review, we found the answers to the questions as below: (1) Aggressive presentation with sterile cultures not responding to conventional medications should raise the suspicion of fungal NOE and prompt clinicians to investigate further and start anti-fungal. (2) Radiological findings can be helpful in the early diagnosis of fungal NOE. Key findings are mentioned in Table 5. An early tissue biopsy and cultures are crucial for prompt diagnosis and effective treatment. (3) Voriconazole (either IV or oral) is found to be an effective anti-fungal due to its good bone penetration. Fungal NOE needs extensive treatment. (4) Minimum duration should be at least 12 weeks. The mean duration of treatment in our study was 14.7 weeks. Since the process is long and complex, an MDT approach is essential. In addition, multiple ear swabs, regular aural toileting and thorough ear examination should be considered. (5) Voriconazole has some limitations such as drug interactions, hepatotoxicity, and resistance in non-Aspergillus species (e.g., Scedosporium apiospermum, which may require combination therapy).

There is limited guidance on the management of fungal NOE. Our study will help clinicians and provide further opportunities for research in this area. We recommend further research in this area to create guidelines.

References

[1] J. L. Hatch, M. J. Bauschard, S. A. Nguyen, P. R. Lambert, T. A. Meyer, and T. R. McRackan, “Malignant Otitis Externa Outcomes: A study of the University HealthSystem Consortium Database,” Annals of Otology, Rhinology & Laryngology 127, no. 8 (2018): 514–520.

[2] M. Hasibi, M. K. Ashtiani, M. Motassadi Zarandi, et al., “A Treatment Protocol for Management of Bacterial and Fungal Malignant External Otitis,” Annals of Otology, Rhinology & Laryngology 126, no. 7 (2017): 561–567.

[3] G. J. Ridder, C. Breunig, J. Kaminsky, and J. Pfeiffer, “Central Skull Base Osteomyelitis: New Insights and Implications for Diagnosis and Treatment,” European Archives of Oto-Rhino-Laryngology 272, no. 5 (2015): 1269–1276.

[4] P. Parize, M. O. Chandesris, F. Lanternier, et al., “Antifungal Therapy of Aspergillus Invasive Otitis Externa: Efficacy of Voriconazole and Review,” Antimicrobial Agents and Chemotherapy 53, no. 3 (2009): 1048–1053.

[5] P. Jalava-Karvinen, M. Nyman, M. Gardberg, I. Harju, U. Hohenthal, and J. Oksi, “Scedosporium apiospermum as a Rare Cause of Central Skull Base Osteomyelitis,” Medicine Mycology Case Reports 11 (2016): 28–30.

[6] O. McLaren and C. Potter, “Scedosporium apiospermum: A Rare Cause of Malignant Otitis Externa,” BMJ Case Reports (2016): bcr2016217015.

[7] D. Stodulski, B. Kowalska, and C. Stankiewicz, “Otogenic Skull Base Osteomyelitis Caused by Invasive Fungal Infection,” European Archives of Oto-Rhino-Laryngology 263, no. 12 (2006): 1070–1076.

[8] A. K. Johnson and P. S. Batra, “Central Skull Base Osteomyelitis: An Emerging Clinical Entity,” Laryngoscope 124, no. 5 (2014): 1083–1087.

[9] J. Rubin Grandis, B. F. 4th Branstetter, and V. L. Yu, “The Changing Face of Malignant (Necrotising) External Otitis: Clinical, Radiological, and Anatomic Correlations,” Lancet Infectious Diseases 4, no. 1 (2004): 34–39.

[10] P. M. Spielmann, R. Yu, and M. Neeff, “Skull-Base Osteomyelitis: Current Microbiology and Management,” Journal of Laryngology & Otology 127, no. Suppl 1 (2013): S8–S12.

[11] M. Gruber, A. Roitman, I. Doweck, et al., “Clinical Utility of a Polymerase Chain Reaction Assay in Culture-Negative Necrotizing Otitis Externa,” Otology & Neurotology 36, no. 4 (2015): 733–736.

[12] J. Walton and C. Coulson, “Fungal Malignant Otitis Externa With Facial Nerve Palsy: Tissue Biopsy AIDS Diagnosis,” Case Report Otolaryngology 2014 (2014): 192318.

[13] N. Le Clerc, B. Verillaud, M. Duet, J. P. Guichard, P. Herman, and R. Kania, “Skull Base Osteomyelitis: Incidence of Resistance, Morbidity, and Treatment Strategy,” Laryngoscope 124, no. 9 (2014): 2013–2016.

[14] E. Glikson, D. Sagiv, M. Wolf, and Y. Shapira, “Necrotizing Otitis Externa: Diagnosis, Treatment, and Outcome in a Case Series,” Diagnostic Microbiology and Infectious Disease 87, no. 1 (2017): 74–78.

[15] P. G. Volsky and T. A. Hillman, “Fungal Skull Base Osteomyelitis: Emerging Microbial Identification Techniques,” Laryngoscope 127, no. 1 (2017): E5–E7.

[16] S. Stephen, B. Subashini, R. Thomas, A. Philip, and R. Sundaresan, “Skull Base Osteomyelitis Caused by an Elegant Fungus,” Journal of the Association of Physicians of India 64, no. 2 (2016): 70–71.

[17] P. F. Bowles, V. Perkins, and E. Schechter, “Fungal Malignant Otitis Externa,” BMJ Case Reports (2017): bcr2016218420.

[18] M. Gruber, E. Sela, I. Doweck, et al., “The Role of Surgery in Necrotising Otitis Externa,” Ear Nose Throat 96, no. 1 (2017): E16–E21.

[19] M. Doss and D. Doss, “Skull Base Osteomyelitis Secondary to Scedosporium apiospermum Infection,” Radiology Case Reports 13, no. 4 (2018): 759–763.

[20] E. Marechal, P. Chavanet, L. Piroth, et al., “Fatal Invasive Otitis With Skull Base Osteomyelitis Caused by Saksenaea vasiformis,” QJM: An International Journal of Medicine 111, no. 7 (2018): 499–500.

[21] J. Sokolowski, E. Karchier, R. Bartoszewicz, K. Niemczyk, and M. Lachowska, “Skull Base Osteomyelitis: Factors Implicating Clinical Outcome,” Acta Neurologica Belgica 119, no. 3 (2019): 431–437.

[22] M. Moniot, M. Montava, S. Ranque, U. Scemama, C. Cassagne, and V. Arthur, “Malignant Aspergillus flavus Otitis Externa With Jugular Thrombosis,” Emerging Infectious Diseases 25, no. 4 (2019): 830–832.

[23] L. Noroy, K. Pujo, H. Leghzali-Moise, and J. Saison, “Aspergillus Necrotizing Otitis Externa With Temporomandibulozygomatic Involvement,” European Annals of Otorhinolaryngology, Head and Neck Diseases 137, no. 2 (2020): 127–129.

[24] J. Bastianpillai, S. Chaudhry, and A. Vijendren, “Rare Case of a 3-Year-Old With Candida Skull Base Osteomyelitis: Lessons to be Learnt,” BMJ Case Reports 12, no. 4 (2019): e228026.

[25] U. Singh, S. Venkitachalam, and R. Chinnusamy, “Clinical Profiling and Management Outcome of Atypical Skull Base Osteomyelitis,” British Journal of Neurosurgery 34, no. 6 (2020): 686–689.

[26] M. Krishnamoorthy, N. A. N. Othman, N. E. B. Hassan, and S. B. Hitam, “Candida Skull Base Osteomyelitis: A Case Report and Literature Review,” Acta Medica 63, no. 2 (2020): 82–85.

[27] M. Fernandez-Ruiz, M. Ruiz-Ruigomez, and J. Montojo, “Candida albicans Skull Base Osteomyelitis due to Malignant Otitis Externa: The Role of Echinocandin Therapy Associated With Surgical Debridement,” Enfermedades Infecciosas y Microbiología Clínica 38, no. 2 (2020): 89–91.

[28] A. Soleiman, N. Farhat, and M. Cosetti, “Fungal Osteomyelitis of the Temporal Bone and the Importance of Prompt Histopathologic Evaluation in Diagnosis,” Infectious Diseases in Clinical Practice 28, no. 4 (2020): 242–244.

[29] A. Khan, E. Omakobia, I. Smith, et al., “A Rare Case of Fungal Necrotising Otitis Externa Centred on the Left Temporomandibular Joint,” Case Report Otolaryngology 2020 (2020): 8874754.

[30] C. Peled, R. Novoa, S. El-Saied, D. M. Kaplan, R. Sadeh, and V. Novack, “Computer Tomography Findings in Necrotizing Otitis Externa Based on the Offending Pathogens,” European Archives of Oto-Rhino-Laryngology 278, no. 12 (2021): 4707–4713.

[31] T. M. I. T. Kamalden and K. Misron, “A 10-year Review of Malignant Otitis Externa: A New Insight,” European Archives of Oto-Rhino-Laryngology 279, no. 6 (2022): 2837–2844.

[32] A. B. Auinger, V. Dahm, I. Stanisz, U. Schwarz-Nemec, and C. Arnoldner, “The Challenging Diagnosis and Follow-Up of Skull Base Osteomyelitis in Clinical Practice,” European Archives of Oto-Rhino-Laryngology 278, no. 12 (2021): 4681–4688.

[33] A. M. D. Lullo, G. Grimaldi, P. Capriglione, et al., “Skull Base Fungal Osteomyelitis: A Case Report and Review of the Literature,” Ear Nose Throat 100, no. 10_suppl (2021): 1089S–1094S.

[34] J. Koleri, A. Al Bishawi, M. AlMaslamani, H. Abdelhadi, I. Al-Sheikh, and S. Qureshi, “Beware of Covert Enemies: Candida orthopsilosis Malignant Otitis Externa With Base of the Skull Osteomyelitis, a Case Report and Review of Literature,” IDCases 25 (2021): e01163.

[35] P. T. Nguyen, M. Bobinski, J. Chang, et al., “Skull Base Infections, Their Complications, and Management,” Neuroradiology Journal 37, no. 1 (2022): 6–16.

[36] J. W. J. Lim, T. McLean, and F. C. E. Hill, “Scedosporium apiospermum Infections in the Middle Ear and Mastoid: Case Series and Review of the Literature,” Journal of Laryngology 136, no. 10 (2022): 979–985.

[37] I. Margulis, R. Cohen-Kerem, A. Roitman, et al., “Laboratory and Imaging Findings of Necrotizing Otitis Externa are Associated With Pathogen Type and Disease Outcome: A Retrospective Analysis,” Ear Nose Throat 103, no. 11 (2022): NP644–NP650.

[38] M. A. Chaabouni, I. Achour, G. Yousfi, et al., “Culture-Negative Necrotizing Otitis Externa: Diagnosis and Management,” Egyptian Journal of Otolaryngology 39, no. 1 (2023): 30.

[39] ENT UK Guideline on Necrotising Otitis Externa.

[40] E. Hanna, G. Hughes, I. Eliachar, J. Wanamaker, and W. Tomford, “Fungal Osteomyelitis of the Temporal Bone,” Ear Nose Throat 72, no. 8 (1993): 537–541.

[41] C. C. Blyth, L. Gomes, T. C. Sorrell, M. Da Cruz, A. Sud, and S. C. Chen, “Skull-Base Osteomyelitis: Fungal vs. Bacterial Infection,” Clinical Microbiology and Infections 17, no. 2 (2011): 306–311.

[42] A. Ong, C. C. Blyth, R. Bency, et al., “Fatal Mycotic Aneurysms due to Scedosporium and Pseudallescheria Infection,” Journal of Clinical Microbiology 49, no. 5 (2011): 2067–2071.

[43] E. Soudry, B. Z. Joshua, J. Sulkes, and B. I. Nageris, “Characteristics and Prognosis of Malignant External Otitis With Facial Paralysis,” Archives of Otolaryngology–Head and Neck Surgery 133, no. 10 (2007): 1002–1004.

[44] U. Peleg, R. Perez, D. Raveh, D. Berelowitz, and D. Cohen, “Stratification for Malignant External Otitis,” Otolaryngology–Head and Neck Surgery 137, no. 2 (2007): 301–305.

[45] E. Soudry, Y. Hamzany, M. Preis, B. Joshua, T. Hadar, and B. I. Nageris, “Malignant External Otitis: Analysis of Severe Cases,” Otolaryngology–Head and Neck Surgery 144, no. 5 (2011): 758–762.

[46] S. M. Stevens, P. R. Lambert, A. B. Baker, and T. A. Meyer, “Malignant Otitis Externa: A Novel Stratification Protocol for Predicting Treatment Outcomes,” Otology & Neurotology 36, no. 9 (2015): 1492–1498.

[47] A. J. Carrillo and J. Guarro, “In Vitro Activities of Four Novel Triazoles Against Scedosporium spp,” Antimicrobial Agents and Chemotherapy 45, no. 7 (2001): 2151–2153.

[48] S. Schwartz, A. Reisman, and P. F. Troke, “The Efficacy of Voriconazole in the Treatment of 192 Fungal Central Nervous System Infections,” Infection 39, no. 3 (2011): 201–210.

[49] S. Z. M. Hussain, I. I. Haq, Z. Arshad, A. Ekunola, and S. Das, “Rare Cause of Skull Base Osteomyelitis: A Challenging Diagnosis and Management With a Literature Review,” Cureus 15, no. 9 (2023): e45838.

[50] H. Mouas, I. Lutsar, B. Dupont, et al., “Voriconazole for Invasive Bone Aspergillosis: A Worldwide Experience of 20 Cases,” Clinical Infectious Diseases 40, no. 8 (2005): 1141–1147.

[51] I. Lutsar, S. Roffey, and P. Troke, “Voriconazole Concentrations in the Cerebrospinal Fluid and Brain Tissue of Guinea Pigs and Immunocompromised Patients,” Clinical Infectious Diseases 37, no. 5 (2003): 728–732.

[52] M. A. Pfaller, S. A. Messer, R. J. Hollis, and R. N. Jones, and SENTRY Participants Group, “Antifungal Activities of Posaconazole, Ravuconazole, and Voriconazole Compared to Those of Itraconazole and Amphotericin B Against 239 Clinical Isolates of Aspergillus spp. and Other Filamentous Fungi: Report From SENTRY Antimicrobial Surveillance Program, 2000,” Antimicrobial Agents and Chemotherapy 46, no. 4 (2002): 1032–1037.

[53] W. R. Kirkpatrick, R. K. McAtee, A. W. Fothergill, M. G. Rinaldi, and T. F. Patterson, “Efficacy of Voriconazole in a Guinea Pig Model of Disseminated Invasive Aspergillosis,” Antimicrobial Agents and Chemotherapy 44, no. 10 (2000): 2865–2868.

[54] J. R. Perfect, K. A. Marr, T. J. Walsh, et al., “Voriconazole Treatment for Less-Common, Emerging, or Refractory Fungal Infections,” Clinical Infectious Diseases 36, no. 9 (2003): 1122–1131.

[55] D. W. Denning, “Invasive Aspergillosis,” Clinical Infectious Diseases 26, no. 4 (1998): 781–803.

[56] P. G. Pappas, J. H. Rex, J. D. Sobel, et al., “Guidelines for Treatment of Candidiasis,” Clinical Infectious Diseases 38, no. 2 (2004): 161–189.

[57] A. B. Auinger and C. Arnoldner, “Current Management of Skull Base Osteomyelitis,” Current Opinion in Otolaryngology & Head and Neck Surgery 29, no. 5 (2021): 342–348.

RIGHTS & PERMISSIONS

2026 The Author(s). Eye & ENT Research published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.