A Fatal Case of Meningitis Complicating Chronic Otitis Media and Base of Skull Osteomyelitis due to Carbapenemase (OXA-48)-Producing Klebsiella pneumoniae

Osteomyelitis of the base of the skull is a rare but life-threatening disease. Although Klebsiella pneumoniae is not a pathogen that is frequently associated with this infection, the clinical course can rapidly progress to meningitis. Here, we describe a case of chronic otitis media, secondary to OXA-48K. pneumoniae, which was complicated by osteomyelitis of the base of the skull and fatal meningitis.


Introduction
Osteomyelitis of the base of the skull (SBO) was first described in 1775 by Percival Pott as a collection of pus under the pericranium in a patient with forehead trauma and extradural hemorrhage [1]. Malignant otitis externa, paranasal acute and chronic sinusitis and postoperative craniotomy infections are the main risk factors for cranial osteomyelitis [2][3][4][5][6]. Otitis media is not a common cause for SBO [5,7].
Despite being a rare disease in the era of antibiotics, SBO is a life-threating infection that is difficult to treat, with a 40% mortality rate or long-term neurological sequalae [2,9,10,16,17].
Here, we describe a fatal case of rapidly progressive SBO secondary to multidrug-resistant Klebsiella pneumoniae (OXA-48).

The Case
This was a 65-year-old male patient, known to have liver cirrhosis secondary to hepatitis C infection (Child-Pugh Score B) with a history of spontaneous bacterial peritonitis 1 3 and portal hypertension. His background history was also significant for ischemic heart disease with previous coronary artery bypass surgery (CABG). He was admitted to hospital electively for trans-jugular intrahepatic portosystemic shunt (TIPS) for the treatment of refractory ascites.
On admission, he gave a history of discharge from the left ear for 4 weeks; this was associated with gait unsteadiness and episodic tinnitus. He denied any history of fever or headache. He used to treat the ear discharge with local antibiotics; this led to a partial reduction in the discharge.
The otolaryngology physician evaluated him 1 day after admission and reported a profuse discharge from the left ear, a normal external auditory canal, no tragus, and no mastoid tenderness. He was started on ofloxacin ear drops and a sample of ear discharge was obtained for culture.
His temporal bone imaging, performed after admission, indicated soft tissue in the left auditory canal, middle ear cavity and inner ear, as well as opacification of the left mastoid ear cell with erosive changes of the tegmen tympani and mastoid air cell; these findings were suggestive of chronic otitis media and osteomyelitis.
Gram staining of the ear discharge showed gram-negative bacilli. He was empirically started on piperacillin/tazobactam by the primary team. The ear discharge persisted while on piperacillin/tazobactam. The ear culture grew K. pneumoniae and the OXA-48 gene was detected by an Xpert Carba-R Assay, performed on the GeneXpert Instrument System. This assay is a qualitative in vitro diagnostic test designed for the detection and differentiation of the bla KPC, bla NDM, bla VIM, bla VIM, bla OXA-48 and bla IMP gene sequences associated with carbapenem non-susceptibility. This test is carried out by automated real-time polymerase chain reaction (PCR).
The organism was resistant to all third-generation cephalosporins, piperacillin/tazobactam, trimethoprim/sulfamethoxazole, and meropenem, while imipenem was reported as 'intermediate' and gentamicin was 'susceptible'. The organism was resistant to both tigecycline and colistin. At this time, imipenem and gentamicin. Ceftazidime/avibactam was not available.
The ear discharge continued and the patient began to experience fever, progressive headache, increasing weakness, fatigability, and slight confusion. A non-contrast brain MRI was performed (due to worsening kidney function); the results were highly suggestive of ventriculitis. Ceftazidime/ avibactam became available and was started within 5 days of admission. Meropenem was later added for synergistic effect. Lumbar puncture was performed and was suggestive of bacterial meningitis with elevated WBC and low glucose (Table 1). Cerebrospinal fluid (CSF) grew the same OXA-48-producing K. pneumoniae. On day 10 after admission, the patient had a seizure and developed a lower level of consciousness, thus requiring intensive care unit (ICU) admission and intubation. An external ventricular drain was inserted. His clinical condition did not improve; the deteriorated further and died.

Discussion
Here, we describe the clinical presentation and rapid progression to fatal meningitis in an immunocompromised patient with SBO, secondary to chronic otitis media. The rapid progression and fatal outcome probably resulted from the nature of the organism isolated (OXA-48K. pneumoniae) and the delay in administrating ceftazidime/avibactam. This clinical scenario should alert physicians that SBO due to OXA-48K. pneumoniae can be the hallmark of fulminant infection with a devastating outcome.
Skull base osteomyelitis (SBO) is the term applied to infections of the temporal, sphenoid, or occipital bones. This condition can be divided into two main groups based on the precipitating etiology: sinorhino-otogenic origin and other origins. The other origins include iatrogenic, post-traumatic, hematologic, and other etiologies. In developed countries, cranial osteomyelitis occurs mostly as postoperative craniotomy-related infections, along with paranasal sinusitis and ear infections (mainly otitis externa); however, direct head injuries are the most frequent cause of cranial osteomyelitis in developing countries.
Otitis media is not a common adult disease, with a reported incidence of 2.7 per 1000 person-years in those above the age of 65 years [18,19]. Meningitis complicating otitis media is also not frequently encountered in adults. One study estimated the rate at 0.42 per 100,000 per year [20]. In another study, only 3 of 2475 patients with acute otitis media developed meningitis [21]. Cranial involvement of the base of the skull in otitis media occurs through ascending infection from the middle ear, involving the lateral temporal bone and the petrous apex and clivus [16,22,23].
Depending on the predisposing site of infection, patients with cranial osteomyelitis may present with aural symptoms, such as otorrhea, otalgia, hearing impairment, headache, and facial pain. Due to the spread of infection, the cranial nerves in the base of the skull, including the oculomotor, trigeminal, abducens, facial, vestibulocochlear, glossopharyngeal, vagus, accessory, and hypoglossal nerves, may be affected to variable degrees. The clinical course may also be complicated by multiple cerebral infarctions, secondary to sinovenous thrombosis or carotid artery involvement.
The emergence of carbapenemase-producing K. pneumoniae as a cause of both community-and healthcare-related life-threating infections implicates this organism in ear infections and SBO in immunocompromised hosts; thus, the incidence of this condition will likely increase [38][39][40].
Effective antibiotic therapy is the gold standard of therapeutic interventions for SBO. Antibiotics should be cultureguided when possible. However, broad-spectrum antibiotics are often used because samples for culture are difficult to acquire. Good bone penetration is essential in choosing the correct antibiotic. The emergence of multidrug-resistant (MDR) strains, especially carbapenemase-producing bacteria, may make the therapeutic choices more challenging for both cranial bone osteomyelitis and its complications. The novel cephalosporin/β-lactamase inhibitor combination ceftazidime/avibactam may be the only available therapy for MDR K. pneumoniae infection. However, there are still insufficient data available regarding the CSF penetration of ceftazidime/avibactam [41][42][43][44][45][46][47][48]. In an animal model of meningitis, ceftazidime and avibactam both exhibited a 38%  [41] with a reduction of bacterial loads to a mean of 5.66 log 10 colony-forming units (CFU) over 8 h.
In a human case of carbapenemase-producing K. pneumoniae meningitis, it took 3 days (11 doses) of standard dosing to reach a therapeutic CSF level [42,49]. In clinical practice, ceftazidime and avibactam are frequently used in combination with other drugs, such as colistin, aminoglycosides and carbapenems [43,[46][47][48]. In our case, and despite the apparent synergism between ceftazidime/avibactam and meropenem, the outcome was not favorable.
Evidence regarding the use of ceftazidime and avibactam for SBO is also very limited. The drug had a curation rate of 78% for the treatment of bone and joint infections in a previous cohort of 15 patients; however, none of these patients had SBO [50]. A few sporadic cases of cervical osteomyelitis have been successfully treated with ceftazidime/avibactam [51].
The duration of antibiotic therapy for SBO is not known, although the early initiation of antibiotics and treatment for at least 3 months is known to reduce post-infection complications [22,52]. Early surgical debridement may be necessary depending on the extent of the disease for bacterial SBO, but it is more frequently required in cases due to a fungal infection [53,54]. Other forms of adjuvant therapy, such as hypobaric oxygen have been attempted [22,55]. Furthermore, meningitis due to SBO also requires prolonged therapy [43][44][45][46][47][48]56]. The course of our patient was complicated because of the lack of effective antibiotic therapy (ceftazidime/avibactam) early in the treatment course.

Conclusion
SBO complicated by OXA-48K. pneumoniae infection, originating from otitis media, can progress quickly to fatal meningitis, especially in immunocompromised patients. Early appropriate antibiotic therapy is crucial.
Author Contributions WB developed the idea, designed the method and wrote the manuscript. JS reviewed and revised the manuscript and updated the references. LL wrote and revised the manuscript.
Funding This study did not receive any specific form of funding.

Conflict of Interest
The authors declare no competing interest.
Ethical Approval and Consent to Participate Patient consent is not applicable because this is a retrospective case. No particular private information beyond the clinical case is revealed.

Consent for Publication
The authors have consented to publication.
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