Le Infezioni in Medicina, n. 3, 340-351, 2024
doi: 10.53854/liim-3203-8
ORIGINAL ARTICLES
Microbial spectrum, management challenges, and outcome in patients with otogenic skull base osteomyelitis
Salma S. AlSharhan1, Marwan J. Alwazzeh2, Mona K. ALRammah1, Wasan F. ALMarzouq1, Aishah A AlGhuneem3, Afnan J Alshrefy3, Nada A Albahrani1, Lena S Telmesani1, Amal A. AlGhamdi4, Laila M. Telmesani1
1Department of Otorhinolaryngology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia;
2Infectious Disease Division, Department of Internal Medicine, Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Dammam & King Fahad Hospital of the University, Al Khobar, Saudi Arabia;
3College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia;
4Division of Epidemiology and Biostatistics, Department of Family and Community Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
Article received 28 May 2024, accepted 9 August 2024
Corresponding author
Marwan Jabr Alwazzeh
E-mail: mjalwazzeh@iau.edu.sa
SummaRY
Objectives: The study aimed to explore the spectrum and trend of causative microbial agents and to identify management challenges and the risk factors for poor outcomes in patients with confirmed otogenic skull base osteomyelitis.
Methods: A retrospective observational study was conducted at a tertiary-care academic center from 1999 through 2019 and included 28 adult patients with confirmed otogenic skull base osteomyelitis. Relevant data was extracted from electronic and hard patient medical files. The microbial spectrum of involved microbes was identified and correlated to management options. Deterioration risk factors were investigated using suitable statistical analysis tests.
Results: Twenty-eight patients with confirmed skull base osteomyelitis were included; most were males (78.6%) and Saudis (78.6%). All patients were ≥50 years of age (mean ± SD is 69.0±10.2.4). Of 41 identified microbial isolates, 56% were bacterial, 44% were fungal. 32.1% of patients had polymicrobial infections, most patients (92.8%) had received ≥2 systemic antibiotics, 57.1% received systemic antibiotic combinations, and 32.1% underwent surgical interventions. The mean antibiotic and antifungal therapy duration was 58.3 and 45.8 days, respectively. The identified risk factors of deterioration were advanced age and concomitant cardiac failure, with P-values of .006 and .034, respectively.
Conclusions: The study findings highlight the microbiological spectrum and trend of otogenic skull base osteomyelitis-causative microbes over two decades, present the management challenges, identify deterioration risk factors, and suggest tissue biopsy as the golden standard for accurately identifying causative microbes.
Keywords: Skull base osteomyelitis, malignant otitis externa, microbial spectrum, management, poor outcome.
INTRODUCTION
Skull base osteomyelitis (SBO) is a rare but devastating bone infection that can affect temporal, sphenoid, or occipital bones with significant morbidity and mortality. It was first described by Toulmouche in 1838 as progressive osteomyelitis in the temporal bone with otorrhea [1, 2]. More than 100 years later, Meltzer and Kelemen described in 1959 the association between external otitis and osteomyelitis in the external auditory canal and temporal bone [3]. However, the diagnostic criteria for SBO are still controversial [4]. It is mainly considered as a complication of neglected malignant external otitis (MOE) (or necrotizing external otitis); however, the differentiation between MOE and SBO relies on the exact extension of infectious processes, which is not well defined frequently, and a robust case definition is still needed [5].
SBO is usually presented as a result of the extension of neighboring structure infections, mainly ears, paranasal sinuses, or nasal infections [1, 6]. It affects mainly immunocompromised elderly individuals, especially diabetic patients [6]. The leading causative agent of SBO is Pseudomonas aeruginosa; however, the spectrum of SBO microbes showed a wide range of bacteria agents such as Proteus spp, Klebsiella spp, Salmonella spp, Mycobacterium spp, Staphylococcus spp, and Streptococcus spp among others, in addition to different fungi that had involved in SBO etiology, such as Candida spp, Aspergillus spp, Cryptococcus neoformans, and Rhizopus spp. [1, 7-10]. Furthermore, more involvement of opportunistic agents is suspected as most affected patients are immunocompromised, and microbiological diagnostics improve contentiously.
Previous studies frequently document the management challenges of SBO, which started from subtle and atypical symptoms and signs combined with negative or misleading microbiological results and occasionally nonspecific radiological presentations, especially in the atypical (central) forms of SBO [6, 11-14]. Moreover, there are no evidence-based management guidelines yet and no consensus on the empiric antimicrobial regimen, the antimicrobial therapy duration, or the correct timing to switch from parenteral to oral antimicrobial regimen.
The main body of SBO-related literature consists of case reports of single or few cases of SBO; the determinants or risk factors of deterioration and poor outcomes are crudely defined. Prolonged hospitalization of SBO patients was linked to some co-morbidities, such as diabetes mellitus, renal disease, aplastic anemia, cranial nerve paresis, and neural involvement, in addition to disease severity and the need for surgical interventions [6, 15].
This study, aimed to describe the microbiological spectrum in 28 patients diagnosed with otogenic SBO and treated in an academic tertiary hospital over 21 years, highlights the management challenges of SBO, and identify deterioration risk factors of SBO patients observed in our cohort.
MATERIALS AND METHODS
Study design, settings, and population
The authors performed a single-center retrospective observational study from 1999 through 2019 at King Fahad Hospital of the University (KFHU), an academic tertiary care center with 502 beds in Al-Khobar city, Eastern Province, Saudi Arabia. They reviewed the medical files and electronic medical records for all patients admitted with a diagnosis of SBO or MOE; only adult patients with available relevant medical information and radiologically confirmed SBO diagnosis were included.
Data collection
A data collection sheet was customized to fill in relevant patient information from medical files and electronic medical records. The demographic part includes the patient’s age at diagnosis, gender, and nationality (Saudi, non-Saudi).
The clinical data was divided into five parts: first, the clinical presentation and related information, including the otogenic source of infection and the confirmed diagnosis of SBO or MOE (according to Cohen and Friedman criteria) [16]. Second, radiology includes descriptions of computed tomography (CT) scans, magnetic resonance imaging (MRI), and bone scan findings, if available. Third, the laboratory diagnostics, including the results of ear swab cultures, identify the possible causative microbes. Fourth, management includes surgical interventions and systemic and topical microbiological therapy. Fifth, the patient outcome part (cure, improvement, refractory disease, or death).
Ear swabs were collected using an aseptic technique. In patients with otitis externa, the swab is obtained by rotating the lesions of interest 5 to 10 times, whereas the swabs of SBO with otitis media are obtained mainly by collecting fluid on a flexible shaft swab if the tympanic membrane was ruptured or during the surgical interventions. After Gram staining, the samples were plated for aerobic culture.
Ethical Considerations
This study was conducted according to the Declaration of Helsinki of the World Medical Association on ethical principles of medical research and approved by the Institutional Review Board (IRB) of Imam Abdulrahman bin Faisal University (IRB-2019-01-272). All personal patient information has been secured and used for research purposes only.
Statistical analysis
Data was analyzed using SPSS 27.0 (IBM SPSS, New York). We took great care in presenting continuous variables as mean values with standard deviations, and categorical variables as frequencies and percentages, ensuring a comprehensive understanding of the data. Statistical significance was tested using the chi-square test when the dependent and independent variables were categorical and the t-test if a dependent continuous variable and an independent categorical variable were compared. A calculated P-value ≤ .05 was considered significant.
RESULTS
A total of 44 patients with suspected SBO secondary to otological infection were admitted between 1999 and 2019 to KFHU; 15 of them were diagnosed with MOE only without SBO, and one patient had missed relevant medical data; 28 patients with confirmed SBO by CT scans were included (Figure 1). Demographic characteristics, comorbidities, main clinical manifestations, and complications of the SBO study cohort were presented in Table 1. Of seven patients who developed cranial nerve deficits, the VII nerve was affected in six and the VI nerve in three (two patients had VI and VII nerve deficits).
Figure 1 - Otogenic SBO study flow chart.
Table 1 - Demographics, clinical manifestations, and comorbidities of the SBO study cohort.
Concerning isolated microbes, the most used microbiological tests were ear swab cultures; 23 patients (82.1%) had positive cultures with 41 isolates identified, and five patients had no culture or negative culture (Figure 2). SBO infection was only bacterial in 8 patients (34.8%), fungal in 9 patients (39.1%), and mixed in 6 patients (26.1%). The more frequent isolated Gram-negative bacterium was Pseudomonas aeruginosa (P. aeruginosa), anaerobic culture from one patient showed Anaerococcus vaginalis. In addition, the cultures showed an increased involvement of fungal agents in developing SBO; Candida and Aspergillus species constituted 24.4% and 17.1% of all microbe isolates, respectively (Table 2). Furthermore, one isolate belonging to Trichophyton spp. was identified.
Figure 2 - Distribution of SBO causative microbes.
Table 2 - Frequency and percentages of isolated microbes from SBO patients.
In relation to the imaging modalities used for establishing SBO diagnosis and follow-up, all SBO patients underwent CT, six patients had MRI, and six had bone scans. The authors have classified the severity of SBO, depending on the findings of non-enhanced and contrast-enhanced high-resolution CT scan of the temporal bone (HRCT-TB), 0.6 mm thickness, coronal, axial, and sagittal, as mild, moderate, or severe.
Regarding the management of SBO, all patients had received at least one systemic antibiotic (intravenous or oral), 26 patients (92.8%) had received ≥2 consecutive antibiotic monotherapy courses, and 16 (57.1%) received systemic ABs combination.
Different systemic antibiotics were used, including penicillins (amoxicillin/ clavulanic acid, piperacillin/tazobactam), cephalosporins (cefuroxime, ceftazidime, cefepime), carbapenems (meropenem, imipenem/cilastatin), fluoroquinolones (ciprofloxacin, levofloxacin), aminoglycosides (gentamicin, amikacin), metronidazole, clindamycin, linezolid, and azithromycin. Beta-lactam ABs plus an aminoglycoside or fluoroquinolone were the cornerstone of systemic combination ABs therapy. In addition to systemic ABs, topical ABs were applied for prolonged periods; ofloxacin, gentamicin, neomycin, polymyxin, or fusidic acid were frequently used as topical ABs. On the other hand, systemic antifungals (fluconazole, voriconazole, caspofungin, anidulafungin) and topical antifungals (miconazole, itraconazole) were less frequently used despite increased fungi involvement (Table 3). The mean duration of patients’ hospitalizations was more than seven weeks; 32.1% had ≥2 hospitalizations. Concerning the therapy outcomes, 23 surviving patients were followed for around 30 months on average, and five patients lost documented follow-up. 56.5% of followed patients were cured or improved. Furthermore, nine patients (39.1%) died, two of them as a result of SBO complications and seven due to other co-morbidities.
Table 3 - Therapeutic interventions and outcomes of patients with SBO.
The risk factors for developing SBO observed in the current study are male gender, uncontrolled DM, history of hypertension, late presentation due to misdiagnosis of MOE, or chronic otitis media. However, the risk factors for deterioration, as illustrated in Table 4, are particularly noteworthy. Advanced age (>70 years) and heart failure, both of which can be significantly associated with patient deterioration. Additionally, systemic AB monotherapy was associated with patient cure or improvement.
Table 4 - Risk factors of deterioration in patients with SBO.
DISCUSSION
SBO is a rare clinical entity that typically presents as complications of otogenic, paranasal sinuses, or nasal infections in elderly diabetic or immunocompromised patients [6, 17]. Establishing the confirmed diagnosis of SBO is frequently challenged by subtle clinical presentations, non-specific laboratory findings, negative or misleading microbiological investigations, and uncertainty of interpretation of imaging studies that fail to identify the disease extension or differentiate between SBO and other pathological entities.
The current study sheds light on the microbial spectrum of a relatively large cohort of SBO patients, reviews the management challenges, identifies some risk factors for patient deterioration, and highlights new microbiological findings and practical management suggestions.
Surprisingly, the fungal isolates constitute 44% of all isolated microbes, which indicates that fungal agents’ involvement markedly increases in SBO compared with the previous studies [12, 18, 19]. In addition, Candida spp. were isolated more frequently than Aspergillus spp. (24.4% vs 17.1 of all isolated microbes), which was again in contrast with previous study findings [18-20]. This discrepancy might be related to the ecological differences of SBO study cohorts, reflect the dynamic trend of SBO causative microbes, or be due to misleading late swap culture after starting topical therapy (82.1% of the patients received topical ABs). Furthermore, the commonly used ear swab to identify SBO might become positive due to contamination or colonization. No published data compare the sensitivity or specificity of ear swab cultures vs. tissue cultures in SBO; however, tissue cultures seem more accurate and have higher sensitivity and specificity than swab cultures, as demonstrated in previous studies on skin and soft tissue deep infections [21, 22].
The bacterial spectrum of SBO, as demonstrated in the current data, showed a predominance of Pseudomonas aeruginosa strains (45.8% of all isolated bacteria), which is in line with previously published studies [7, 8, 19]. However, the involvement of other bacteria increased along with the increase of fungal agents. In addition, Anaerococcus vaginalis, an obligate anaerobic bacterium, was isolated from one patient. Anaerococcus spp. are usually part of the human microbiota and are occasionally isolated from soft tissue infections, chronic sinusitis, and female genital infections [23]. Moreover, it was not reported previously as a causative agent of SBO. Furthermore, Trichophyton spp. was also grown from another patient. It belongs to dermatophyte fungi reported before as an opportunistic agent of invasive infections, such as deep skin and soft tissue infections and pneumonia, but not described as SBO causative fungous [24, 25]. Nevertheless, confirmation of the involvement of both organisms needs more accurate diagnostic tests such as tissue culture. The involvement of more than one microbe in developing SBO, including opportunistic agents, was presented in 32.1% of the current study; such findings were also reported previously [9, 26].
The main clinical presentations of SBO were earache, headache, and otorrhea, which were reported by 82.6%, 91.3%, and 78.3% of the study cohort, respectively. The uncertainty in confirming an otogenic SBO diagnosis started from elusive non-specific clinical findings of SBO and delayed diagnosis due to late presentation, usually after receiving multiple courses of ABs.
Cranial nerve deficits are alarming signs, the reported incidence ranging between 29.6% and 78% with a higher incidence in otogenic SBO [8, 10, 20]. In the current study, the incidence of cranial nerve deficits was 34.9%, affecting mainly the VII nerve, followed by the VI nerve, which was in line with previous studies [27-29]. However, the deficits in most cranial nerves were reported: Draf et al. describe multiple cranial nerve involvement, including III to IIX nerves, whereas Damiani et al. reported involvement of all cranial nerves except the I and VI nerves [29, 30]. Atypical presentations are described more frequently with central SBO; the course of such cases can mimic malignancy progression [11].
Cerebral venous thrombosis is another serious complication of SBO, with a reported incidence of 43% [20]. Thrombosis development in jugular veins and cerebral venous sinuses was described, making the management of SBO more challenging [31-33]. In the current study, cerebral venous thrombosis incidence was 21.4%. Unilateral or bilateral internal jugular vein thrombosis, sigmoid sinus thrombosis, and cavernous thrombosis were documented.
Imaging studies are essential in establishing the diagnosis of SBO; HRCT-TB scan with and without contrast, MRI, and nuclear imaging were usually used to detect bone abnormalities [11, 17]. In the current study, all patients underwent HRCT-TB scan; the authors stratified the MOE/SBO according to HRCT-TB scan findings into mild, moderate, or severe to identify the disease extensions (Figure 3). However, all imaging modalities demonstrate diagnostic limitations; early performed HRCT-TB might fail to detect early bone erosions or even bone destruction [11, 34]. MRI can demonstrate the involvement of soft tissue and other anatomical structures surrounding the affected bones; however, MRI findings related to osteomyelitis are highly sensitive but less specific [35]. Several nuclear imaging modalities are used to detect SBO in the early stage, identify the disease extension, and predict management outcomes [10, 36, 37]. The main two groups of nuclear imaging are the gamma tracers’ group (includes Technetium-99m methylene diphosphonate bone scan and Single Photon Emission Computed Tomography with a Computed Tomography [SPECT/CT] scan) and β-emitting tracers’ group (includes fluorodeoxyglucose and sodium fluoride) [17]. SPECT/CT demonstrated 100% sensitivity and 89% specificity in detecting infection foci and was superior to high-resolution CT scan or SPECT alone in identifying the disease extensions [38, 39]. 18-Fluoro-deoxyglucose positron emission tomography (FDG-PET) is another promising nuclear imaging modality in combination with CT or MRI with higher sensitivity and specificity [40, 41]. However, nuclear imaging has drawbacks of high radiation exposure, prolonged image acquisition, poor anatomical resolution, and limited availability. Moreover, in rare cases, CT scans, MRI, or nuclear imaging may not confirm the underlying pathologies, whether SBO, granulomatosis, or malignancy [27]. In such cases, histopathological studies are still needed to establish the final diagnosis.
Figure 3 - High-resolution CT scans of the temporal bone (bone window) without contrast.
Patient 1. (A&B): Evidence of complete opacification of the left mastoid air cells with bony erosion of the mastoid cortex, carotid canal, jugular foramen, and fullness of the nasopharynx. Patient 2. (C&D): Complete obliteration of the R. mastoid air cells, multiple areas of bone destruction of the mastoid, sphenoidal, and occipital bones with significant bone involvement of the right temporomandibular joint in the form of cortical irregularity
The therapeutic approach of patients with SBO is still challenging, and there are no evidence-based guidelines or consensus regarding the optimal management [40]. The vital role of surgical interventions in avoiding complicated co-morbidities, decreasing mortality rates, and improving patient outcomes has been proven previously [1, 9, 20, 42]. In the current study, nine patients (32.1%) underwent surgical interventions for debridement and tissue biopsies. The reported percentage of patients who underwent surgical interventions varied according to the study settings and involved cohort characteristics, ranging between 22.2% and 80% [9, 10, 20, 42].
Antimicrobial therapy is the backbone of SBO management; early and prolonged parenteral antibiotic therapy is vital to avoid SBO complications and improve patient outcomes [1, 8, 43]. Traditionally, antipseudomonal ABs was applied empirically, and the antimicrobial therapy was tailored later according to the microbiological results. All involved patients in the current study received empirical antibiotics. Different systemic antibiotics were used. Most patients (92.8%) received ≥2 systemic antibiotics in addition to the topical AB therapy, which was in line with previous studies [1, 6]. There is no consensus regarding the preferred empirical antimicrobial regimen, antimicrobial monotherapy or combination use, or therapy duration [44]. Considering the synergistic effect of some semi-synthetic penicillins and aminoglycosides against P. aeruginosa, some researchers support such a combination, while others prefer to combine Ceftazidime with fluoroquinolones [19, 44-48]. Sixteen of our SBO patients (57.1%) received systemic AB combination; the most used empirical combination in the current study cohort was ciprofloxacin with either ceftazidime or meropenem. The rationales behind the antimicrobial combinations were brooding the spectrum of empirical antimicrobial therapy, negative culture results, and increased P. aeruginosa resistance to fluoroquinolones and other ABs [19, 44, 48]. However, our study findings indicate the trend to use combination antimicrobial therapy in more complicated cases with poor outcomes and did not show superiority compared with antimicrobial monotherapy.
Moreover, assuming that P. aeruginosa is the causative agent of most cases of SBO and tailoring the empirical antimicrobial regimen to cover foremost such organism should be revised; the current data showed that P. aeruginosa constitutes only 26.8% of all isolated microbes, 39.1% of SBO were fungal infections, and 26.1% were mixed (bacterial and fungal) infections. This microbiological trend and the increased rate of the involved fungal agents, which were also reported previously, make SBO management more challenging [19, 49].
In line with the antimicrobial therapy duration reported in previous studies (6 -10 weeks), the mean duration of systemic antimicrobial therapy in this study was 8.3 and 6.5 weeks for bacterial and fungal SBO, respectively [44, 46, 48, 50, 51]. However, a longer duration of 21 weeks was also reported, reflecting heterogeneity regarding antimicrobial therapy duration [42]. Longer duration was linked to severe or central SBO, uncontrolled diabetes mellitus, end-stage renal disease, and fungal infection [42, 52, 53]. The therapy duration for each SBO case should be decided independently according to the clinical, laboratory, and imaging improvements achieved [54].
In addition to systemic antimicrobial therapy, topical therapy was intensively applied with a mean duration of 6.1 and 2.7 weeks for antibiotic and fungal agents, respectively. The culture of ear swabs is not ideal for identifying the causative microbes; positive cultures due to contamination or colonization are possible and rarely discussed. Peled et al. recommended deep tissue biopsy instead of ear swab cultures [55]. Furthermore, topical antimicrobials will most likely affect the results of subsequent swab cultures. The increasing isolation of Candida spp. reported recently, as well as in our study, may reflect the intensive use of topical ABs [56].
Despite the marked improvement in diagnostics and therapy options, managing SBO is still challenging. 56.5% of followed patients were cured or improved, comparable with the previously reported treatment’s satisfactory response [56]. The mortality attributed to SBO in our cohort was 7.14%; however, overall mortality reached 39.1%, indicating that multiple underlying risk factors directly affect the patient outcome. On the other hand, the reported mortality rate of SBO patients in the previous studies ranged between 9.5% and 61%, depending on study settings, date, and follow-up period [7, 10, 30, 42, 44, 57]. In addition, SBO mortality and complications such as cranial nerve involvement were linked to the disease severity, delay of diagnosis due to late presentation, and inappropriate treatment [28, 42, 58].
Regarding the predisposing factors of SBO, our data shows that age, diabetes mellitus, MOE, hypertension, and male gender were prevalent characteristics of SBO patients. The male-to-female ratio was 4.7:1, which was in line with the reported ratio by Lee et al. and a recently published review by Krishnakumar et al. [10, 56]. However, the reasons behind the gender difference are not well recognized.
In relation to the variables associated with patient deterioration, a significant association was found with advanced age (>70 years), ICU admission, concomitant cardiac failure, and use of AB combination therapy (Table 4). However, the history of ICU admission and use of AB combination reflects the severity of the disease rather than the risk of deterioration. Other variables, including gender, length of hospitalization, history of MOE, other co-morbidities, level of Hgb A1c, causative microbes, surgical interventions, and options or duration of systemic or topical antimicrobial therapy, were not significantly associated with patient deterioration. Reviewing of the literature indicates that the extent of SBO identified by CT, MRI, or SPECT, involvement of cranial nerves, uncontrolled diabetes mellitus, Charlson comorbidity index, immunocompromised status, fungal infections, infection relapse, and performing surgery were prognostic factors of MOE/SBO deterioration [10, 28, 53, 59, 60]. In contrast, Loh et al. found that cranial nerve involvement, diabetes control, and even diagnosis delay will not predict the disease prognosis [44]. Das et al. report that otogenic central SBO is associated with a long history of diabetes, chronic kidney disease, and more involvement of cranial nerves compared to non-otogenic central SBO [20].
Finally, this study had notable limitations. First, it is a retrospective observational study of a relatively rare disease that covered SBO patients for an extended period with the possibility of information bias regarding some variables. Second, the high overall mortality in elderly patients with SBO is multifactorial and does not directly reflect the disease outcome. Third, all included patients presented late diagnosis and had diabetes except one; other patients with immunocompromised status, malignancies, or post-surgery patients developing SBO were not represented. Fourth, the data regarding the resistance of causative agents were unavailable, and in the absence of an institutional guideline, heterogeneous antimicrobial regimens were applied empirically.
However, the findings provide valuable information regarding the microbiological spectrum, diagnostic and therapeutic challenges, and deterioration risk factors.
CONCLUSIONS
The current study highlights the microbiological spectrum and trend of SBO causative agents over an extended period of more than two decades, presents the clinical and radiological diagnostic challenges, identifies the advanced age and concomitant heart failure as deterioration risk factors, and suggests tissue biopsies as the golden standard for accurate identification of causative microbes. Further studies that concentrate on early detection of otogenic SBO, proper microbiological diagnosis, and systematic approach are needed.
There are no conflicts of competing interest to be disclosed regarding this paper.
Source of funding
None to be mentioned.
Data availability
The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
Authors’ contribution
Salma S. AlSharhan (SS), Marwan J. Alwazzeh (MJ), Mona K. AlRammah (MK), Wasan F. AlMarzouq (WF), Aishah A. AlGhuneem (AA), Afnan J. Alshrefy (AJ), Nada A. Albahrani (NA), Lena S. Telmesani (LS), Amal A. AlGhamdi (AL), Laila M. Telmesani (LM).
SS and MJ designed the study and wrote and revised the manuscript; AA, AJ, and NA collected the data and wrote the study proposal; MK, WF, and LS reviewed the literature and participated in writing the manuscript; AL participated in the study design, compiled, and analyzed the data; LM supervised the work and revised the manuscript. All authors read and approved the final manuscript.
REFERENCES
[1] Khan MA, Quadri SAQ, Kazmi AS, et al. A comprehensive review of skull base osteomyelitis: diagnostic and therapeutic challenges among various presentations. Asian J Neurosurg. 2018; 13(4): 959-970.
[2] Toulmouche MA. Observations on cerebral otorrhea: latest considerations. Gaz Med Paris. 1838; 6: 422-426.
[3] Meltzer PE, Kelemen G. Pyocyaneous osteomyelitis of the temporal bone, mandible and zygoma. The Laryngoscope. 1959; 69(10): 1300-1316.
[4] Schreiber A, Ravanelli M, Rampinelli V, et al. Skull base osteomyelitis: clinical and radiologic analysis of a rare and multifaceted pathological entity. Neurosurg Rev. 2021 Feb; 44(1): 555-569.
[5] Takata J, Hopkins M, Alexander V, et al. Systematic review of the diagnosis and management of necrotising otitis externa: Highlighting the need for high-quality research. Clin Otolaryngol. 2023 May; 48(3): 381-394.
[6] Sokołowski J, Lachowska M, Karchier E, Bartoszewicz R, Niemczyk K. Skull base osteomyelitis: factors implicating clinical outcome. Acta Neurol Belg. 2019; 119(3): 431-437.
[7] Spielmann PM, Yu R, Neeff M. Skull base osteomyelitis: current microbiology and management. J Laryngol Otol. 2013; 127(S1): S8-S12.
[8] Blyth CC, Gomes L, Sorrell TC, da Cruz M, Sud A, Chen SCA. Skull-base osteomyelitis: fungal vs. bacterial infection. Clin Microbiol Infect. 2011; 17(2): 306-311.
[9] Ridder GJ, Breunig C, Kaminsky J, Pfeiffer J. Central skull base osteomyelitis: new insights and implications for diagnosis and treatment. Eur Arch Otorhinolaryngol. 2015; 272(5): 1269-1276.
[10] Lee S, Hooper R, Fuller A, Turlakow A, Cousins V, Nouraei R. Otogenic cranial base osteomyelitis: a proposed prognosis-based system for disease classification. Otol Neurotol. 2008; 29(5): 666-672.
[11] Muranjan SN, Khadilkar SV, Wagle SC, Jaggi ST. Central Skull Base Osteomyelitis: Diagnostic Dilemmas and Management Issues. Indian J Otolaryngol Head Neck Surg. 2016; 68(2): 149-156.
[12] Johnson AK, Batra PS. Central skull base osteomyelitis: an emerging clinical entity. Laryngoscope. 2014; 124(5): 1083-1087.
[13] Singh A, Al Khabori M, Hyder MJ. Skull base osteomyelitis: diagnostic and therapeutic challenges in atypical presentation. Otolaryngol Head Neck Surg. 2005; 133(1): 121-125.
[14] Cavel O, Fliss DM, Segev Y, Zik D, Khafif A, Landsberg R. The role of the otorhinolaryngologist in the management of central skull base osteomyelitis. Am J Rhinol. 2007; 21(3): 281-285.
[15] Rothholtz VS, Lee AD, Shamloo B, Bazargan M, Pan D, Djalilian HR. Skull base osteomyelitis: the effect of comorbid disease on hospitalization. Laryngoscope. 2008; 118(11): 1917-1924.
[16] Cohen D, Friedman P. The diagnostic criteria of malignant external otitis. J Laryngol Otol. 1987; 101(3): 216-221.
[17] Álvarez Jáñez F, Barriga LQ, Iñigo TR, Roldán Lora F. Diagnosis of Skull Base Osteomyelitis. Radiographics. 2021; 41(1): 156-174.
[18] Stephen S, Subashini B, Thomas R, Philip A, Sundaresan R. Skull Base Osteomyelitis Caused by an elegant fungus. J Assoc Physicians India. 2016; 64(2): 70-71.
[19] Le Clerc N, Verillaud B, Duet M, Guichard JP, Herman P, Kania R. Skull base osteomyelitis: incidence of resistance, morbidity, and treatment strategy. Laryngoscope. 2014; 124(9): 2013-2016.
[20] Das S, Iyadurai R, Gunasekaran K, et al. Clinical characteristics and complications of skull base osteomyelitis: A 12-year study in a teaching hospital in South India. J Family Med Prim Care. 2019; 8(3): 834-839.
[21] Aggarwal VK, Higuera C, Deirmengian G, Parvizi J, Austin MS. Swab cultures are not as effective as tissue cultures for diagnosis of periprosthetic joint infection. Clin Orthop Relat Res. 2013; 471(10): 3196-3203.
[22] Tedeschi S, Negosanti L, Sgarzani R, et al. Superficial swab versus deep-tissue biopsy for the microbiological diagnosis of local infection in advanced-stage pressure ulcers of spinal-cord-injured patients: a prospective study. Clin Microbiol Infect. 2017; 23(12): 943-947.
[23] Cobo F. Infections caused by anaerobic microorganisms. encyclopedia of infection and immunity [Internet]. Elsevier; 2022, p. 614-627. Available at https://linkinghub.elsevier.com/retrieve/pii/B9780128187319000653 [accessed 12 April 2024].
[24] Nir-Paz R, Elinav H, Pierard GE, et al. Deep Infection by Trichophyton rubrum in an Immunocompromised Patient. J Clin Microbiol. 2003; v41(11): 5298-5301.
[25] Vu LT, Duc NM, Tra My TT, Bang LV, Luu DT, Thong PM. The first case of Trichophyton spp. pneumonia reported in Vietnam. Respir Med Case Rep. 2021; 32: 101371.
[26] Akhtar F, Iftikhar J, Azhar M, Raza A, Sultan F. Skull Base Osteomyelitis: A Single-Center Experience. Cureus. 2021; 13(12): e20162.
[27] Ganhewa AD, Kuthubutheen J. A diagnostic dilemma of central skull base osteomyelitis mimicking neoplasia in a diabetic patient. BMJ Case Rep. 2013; 2013: bcr2012007183.
[28] Chen CN, Chen YS, Yeh TH, Hsu CJ, Tseng FY. Outcomes of malignant external otitis: survival vs mortality. Acta Otolaryngol. 2010; 130(1): 89-94.
[29] Draf W, Regli F. To the differential diagnosis of cranial nerve lesions: the progressive necrotising external otitis. J Neurol. 1975; 210(3): 219-226.
[30] Damiani JM, Damiani KK, Kinney SE. Malignant external otitis with multiple cranial nerve involvement. Am J Otol. 1979; 1(2): 115-120.
[31] Singh A, Al Khabori M, Hyder MJ. Skull base osteomyelitis: diagnostic and therapeutic challenges in atypical presentation. Otolaryngol Head Neck Surg. 2005; 133(1): 121-12 5.
[32] Lee SJ, Weon YC, Cha HJ, et al. A case of atypical skull base osteomyelitis with septic pulmonary embolism. J Korean Med Sci. 2011 Jul; 26(7): 962-965.
[33] Nadol JB. Histopathology of Pseudomonas osteomyelitis of the temporal bone starting as malignant external otitis. Am J Otolaryngol. 1980 Nov; 1(5): 359-371.
[34] Rowlands RG, Lekakis GK, Hinton AE. Masked pseudomonal skull base osteomyelitis presenting with a bilateral Xth cranial nerve palsy. J Laryngol Otol. 2002; 116(7): 556-558.
[35] Erdman WA, Tamburro F, Jayson HT, Weatherall PT, Ferry KB, Peshock RM. Osteomyelitis: characteristics and pitfalls of diagnosis with MR imaging. Radiology. 1991; 180(2): 533-539.
[36] Chandler JR, Grobman L, Quencer R, Serafini A. Osteomyelitis of the base of the skull. Laryngoscope. 1986; 96(3): 245-251.
[37] Gold S, Som PM, Lucente FE, Lawson W, Mendelson M, Parisier SC. Radiographic findings in progressive necrotizing “malignant” external otitis. Laryngoscope. 1984; 94(3): 363-366.
[38] Filippi L, Schillaci O. Usefulness of hybrid SPECT/CT in 99mTc-HMPAO-labeled leukocyte scintigraphy for bone and joint infections. J Nucl Med. 2006; 47(12): 1908-1913.
[39] Balakrishnan R, Dalakoti P, Nayak DR, Pujary K, Singh R, Kumar R. Efficacy of HRCT Imaging vs SPECT/CT Scans in the Staging of Malignant External Otitis. Otolaryngol Head Neck Surg. 2019; 161(2): 336-342.
[40] Auinger AB, Arnoldner C. Current management of skull base osteomyelitis. Curr Opin Otolaryngol Head Neck Surg. 2021; 29(5): 342-348.
[41] Sturm JJ, Stern Shavit S, Lalwani AK. What is the Best Test for Diagnosis and Monitoring Treatment Response in Malignant Otitis Externa? The Laryngoscope. 2020; 130(11): 2516-2517.
[42] Johnson AK, Batra PS. Central skull base osteomyelitis: an emerging clinical entity. Laryngoscope. 2014; 124(5): 1083-1087.
[43] Ueki Y, Matsuyama H, Morita Y, Takahashi K, Yamamoto Y, Takahashi S. Clinical Study of Skull Base Osteomyelitis. Nihon Jibiinkoka Gakkai Kaiho. 2015; 118(1): 40-45.
[44] Loh S, Loh WS. Malignant otitis externa: an Asian perspective on treatment outcomes and prognostic factors. Otolaryngol Head Neck Surg. 2013; 148(6): 991-996.
[45] Thy M, Timsit JF, De Montmollin E. Aminoglycosides for the treatment of severe infection due to resistant Gram-negative pathogens. Antibiotics. 2023; 12(5): 860.
[46] Babiatzki A, Sadé J. Malignant external otitis. J Laryngol Otol. 1987; 101(3): 205-210.
[47] Conde-Díaz C, Llenas-García J, Parra Grande M, Terol Esclapez G, Masiá M, Gutiérrez F. Severe skull base osteomyelitis caused by Pseudomonas aeruginosa with successful outcome after prolonged outpatient therapy with continuous infusion of ceftazidime and oral ciprofloxacin: a case report. J Med Case Rep. 2017; 11(1): 48.
[48] Djalilian HR, Shamloo B, Thakkar KH, Najme-Rahim M. Treatment of culture-negative skull base osteomyelitis. Otol Neurotol. 2006; 27(2): 250-255.
[49] Glikson E, Sagiv D, Wolf M, Shapira Y. Necrotizing otitis externa: diagnosis, treatment, and outcome in a case series. Diagn Microbiol Infect Dis. 2017; 87(1): 74-78.
[50] Visosky AMB, Isaacson B, Oghalai JS. Circumferential petrosectomy for petrous apicitis and cranial base osteomyelitis. Otol Neurotol. 2006; 27(7): 1003-1013.
[51] Muranjan SN, Khadilkar SV, Wagle SC, Jaggi ST. Central Skull Base Osteomyelitis: diagnostic dilemmas and management issues. Indian J Otolaryngol Head Neck Surg. 2016; 68(2): 149-156.
[52] Treviño González JL, Reyes Suárez LL, Hernández De León JE. Malignant otitis externa: An updated review. Am J Otolaryngol. 2021; 42(2): 102894.
[53] Stevens SM, Lambert PR, Baker AB, Meyer TA. Malignant Otitis Externa: a novel stratification protocol for predicting treatment outcomes. Otol Neurotol. 2015; 36(9): 1492-1498.
[54] Benecke JE. Management of osteomyelitis of the skull base. Laryngoscope. 1989; 99(12): 1220-1223.
[55] Peled C, Kraus M, Kaplan D. Diagnosis and treatment of necrotising otitis externa and diabetic foot osteomyelitis - similarities and differences. J Laryngol Otol. 2018; 132(9): 775-779.
[56] Krishnakumar L, Vinayakumar V, Suchit Roy BR, Gopalan M, Venugopal M. Skull Base Osteomyelitis- Marauders of the Skull. Indian J Otolaryngol Head Neck Surg. 2024; 76(2): 1770-1774.
[57] Glikson E, Sagiv D, Wolf M, Shapira Y. Necrotizing otitis externa: diagnosis, treatment, and outcome in a case series. Diagn Microbiol Infect Dis. 2017; 87(1): 74-78.
[58] Murray ME, Britton J. Osteomyelitis of the skull base: the role of high resolution CT in diagnosis. Clin Radiol. 1994; 49(6): 408-411.
[59] Lee SK, Lee SA, Seon SW, et al. Analysis of prognostic factors in malignant external otitis. Clin Exp Otorhinolaryngol. 2017; 10(3): 228-235.
[60] Sandner A, Henze D, Neumann K, Kösling S. Value of hyperbaric oxygen in the treatment of advanced skull base osteomyelitis. Laryngorhinootologie. 2009 Oct; 88(10): 641-646.