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First described in 1959 by Meltzer and Kelemen , skull-base osteomyelitis (SBO) is an uncommon condition associated with significant morbidity and mortality [2–4]. Subsequently, our understanding of SBO is derived from case reports or small series in the surgical literature [1–15]. The entity has been described most often as a complication of malignant otitis externa secondary to Pseudomonas aeruginosa infection [5,16]. Increasing age, diabetes mellitus and microvascular disease are common risk factors [2,9].
SBO, however, may also occur in the absence of malignant otitis externa and with pathogens other than P. aeruginosa, including fungi [3,7,8,12–14,17]. Fungal SBO has been reported to be mostly caused by Aspergillus, and less commonly, Scedosporium spp. [3,7,12]. Although underlying diabetes and primary or acquired immunodeficiencies have often been evident , fungal SBO has also occurred in the absence of these traditional risk factors [10,12,15].
Early diagnosis, identification of the causative pathogen(s), prompt initiation of appropriate antimicrobial or surgical therapies, and continuation of therapy for an adequate period are essential when managing SBO. Identification of the pathogen often requires surgical biopsy. Because this may be delayed for medical or technical reasons, clinical features or risk factors that discriminate between SBO caused by bacteria and that due to fungi could guide selection of empiric antimicrobial therapy pending definitive diagnosis. Using data from cases at a single institution over 18 years, we compared the epidemiology and clinical characteristics of bacterial and fungal SBO, aiming to identify unique risk factors and clinical associations.
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SBO, usually a complication of uncontrolled otogenic, odontogenic or sinus infection, is uncommon [3,11,14]. Large, adequately powered epidemiological studies have not been published. The prevalence of SBO and the relative contribution of bacteria and fungi are difficult to estimate from previous case series as a result of small patient numbers, the frequent inclusion of patients with malignant otitis externa without confirmed SBO and variation in the diagnostic methods used [6,9,16]. The present study, using strict case definitions for SBO, reveals that fungi accounted for a significant proportion (approximately 50%) of SBO in contemporary hospital practice. We have also identified clinical variables associated with fungal, or bacterial, SBO that may guide initiation of early diagnostic sampling and/or selection of empiric antimicrobial therapy.
The significant morbidity of SBO in the present study is consistent with previous reports [3,4,6]. Almost half (48%) of patients had persistent cranial nerve abnormalities, comparable to that reported elsewhere (21–43%) [3,6,19]. Although extension into brain was uncommon [6, present study], cerebral involvement has been associated with high mortality in reported cases despite surgical intervention; the single patient in our series succumbed to fungal infection before surgery could be considered. A large proportion of patients suffered disfiguring surgery with an attendant prolonged hospital stay (median 3 weeks). As noted in other studies [3,6,16], diabetes mellitus and chronic ear disease were predisposing factors. However, confirmation of underlying chronic sinusitis as a risk factor for SBO is required.
Otogenic P. aeruginosa infection accounted for 50% of bacterial SBO. This is consistent with the adage that SBO complicating malignant otitis externa is almost uniformly caused by this bacterium [16,20]. However, other bacteria, and fungi are also important causes of SBO [3,6]. Fungal SBO is increasingly reported in the literature [3,7,10,12,15,17,21], although no systematic long-term epidemiological studies have been conducted. This apparent rise may reflect the increasing use of immunosuppressive therapies, in parallel with the rise of other forms of invasive fungal disease (IFD) [21,22]. Indeed, four of five immunosuppressed patients in our study had fungal SBO (Table 1). Importantly, however, fungal SBO may also occur in immunocompetent individuals [10,15, present study] and should be considered in all patients presenting with symptoms/signs of SBO, especially given evidence from other forms of IFD that delay in antifungal therapy results in increased mortality [23,24].
Most cases of fungal SBO have been due to Aspergillus or Scedosporium spp., reportedly arising from contiguous spread of ear infection [7,10,12,17], although one report noted fungi to be a rare cause of invasive otitis externa . In comparison, we observed that fungal SBO occurred primarily as a result of antecedent sinus infection and that zygomycetes were the most frequent pathogen. The reasons for the relative prevalence of zygomycetes are not readily apparent but are of interest. Zygomycetes are well-known pathogens of invasive fungal sinusitis [3,17,21] and, as such, may have influenced the aetiology of SBO. Although not statistically significant, the majority (>70%) of fungal SBO patients had diabetes, which is a risk factor for zygomycosis . By using strict case definitions to determine SBO, we also excluded instances of ‘colonization’, typically with fungi (e.g. Aspergillus spp.) other than zygomycetes. It is possible that local institutional epidemiology may have influenced the prevalence of specific fungi, although there are no data to support this.
Fungal SBO is often considered only following failure of antibacterial therapy . Kountakis et al.  noted that only one of ten patients with Aspergillus SBO had received antifungal therapy prior to surgical biopsy. In our study, 55% of patients with fungal SBO were treated with antibacterial drugs for a median of 5 weeks prior to diagnosis. It remains uncertain how long one should wait prior to performing diagnostic sampling.
Previous data attempting to identify risk factors for the development of SBO have not distinguished between disease caused by different microorganisms. Although the number of cases included in the analysis is small and therefore the results need to be interpreted with caution, our analyses suggest that there may be differences in clinical risk factors and associations for bacterial and fungal SBO. Patients with fungal SBO were more likely to have underlying chronic sinus disease, symptoms attributable to invasive sinus infection (sinofacial pain, periorbital swelling, nasal stuffiness/discharge), but with a relative paucity of features attributable to ear infection. Indeed, the absence of purulent ear discharge was a sensitive (91%) predictor of underlying fungal SBO (Table 1). These associations warrant further investigation through larger prospective multi-centred epidemiological studies. Nonetheless, the results may assist in identifying patients most likely to benefit from early antifungal therapy. Given the diversity of fungal pathogens identified, diagnostic sampling should be performed, where possible, prior to commencing therapy. However, because no clinical association was 100% sensitive or specific for presence of fungal SBO, clinical failure with antibacterial therapy should also prompt similar considerations.
Antimicrobial therapy in SBO is targeted to eradication of the causative pathogen. Because P. aeruginosa infection predominates in most case series of bacterial SBO, including the present study, initiation of antibiotics with activity against P. aeruginosa is appropriate pending microbiological diagnosis. In the absence of local epidemiological data to guide empiric antifungal therapy, agents with activity against all major pathogens are necessary. Because zygomycetes were responsible for more than 50% of fungal SBO in our series, the use of regimens including high-dose amphotericin B formulations is advised pending definitive diagnosis. The role of surgical resection is likely also influenced by pathogen. Early surgery is associated with improved survival in patients with zygomycosis . Aggressive surgical debridement is recommended in fungal SBO  but is probably unnecessary in patients with bacterial SBO [6,20].
The limitations of this small retrospective study are recognized. The number of patients accessible was insufficient to fully examine significant differences. Longitudinal data were not collected beyond 180 days. The study, however, used rigorous inclusion criteria and the frequent use of biopsy to confirm SBO and identify causative pathogens was evident.
In conclusion, the present study highlights the importance of pathogens other than P. aeruginosa, including fungi, as causes of SBO. Certain clinical variables may enable recognition and differentiation of fungal from bacterial SBO, which may assist clinicians in identifying patients who are at increased risk of either type of infection and who may benefit from early diagnostic sampling.