Antibiotic‐Impregnated Calcium Sulfate Beads for Local Therapy of Severe Skull Base Osteomyelitis

ABSTRACT

We report on a patient with severe progressive osteomyelitis of the lateral skull base, despite targeted long‐term antibiotic therapy. Successful treatment and recovery of the facial nerve palsy were achieved through additional surgical debridement and insertion of synthetic calcium sulfate beads as a local antibiotic carrier to the skull base. We describe the characteristics of this novel biodegradable long‐term release matrix and the surgical technique in detail. The patient is free from recurrence 2 years postoperatively.

Key Clinical Message

Mainstay of treatment for skull base osteomyelitis is systemic antibiotic therapy. Surgical intervention may be beneficial in severe cases for draining abscesses as well as reducing necrotic tissue and osteolytic bone. In such cases, implantation of antibiotic‐loaded calcium sulfate in the resection cavity may be a promising adjuvant therapeutic option.

Novel Local Therapy of Severe Skull Base Osteomyelitis.

1. Introduction

Skull base osteomyelitis (SBO) secondary to otitis externa is a life‐threatening condition in a difficult‐to‐reach surgical site. The aggressiveness of this disease is often underestimated due to its subacute course. When Chandler first proposed the term “malignant” otitis externa in 1968 [1], he used it to underline its high mortality rate, which even half a century later has been reported to be 42% in severe cases [2]. The various names for this uncommon clinical entity found in the literature, such as skull base osteomyelitis, malignant, necrotizing, or invasive otitis externa (external otitis), are a reflection of the inconsistency and lack of evidence concerning its diagnosis and therapy. Hence, there is no universally accepted treatment protocol for SBO.

The complex anatomy of the skull base limits surgical resection in severe osteomyelitis cases. In addition, poor tissue perfusion of necrotic or ischemic tissue hampers the complete eradication of the infection through systemic antibiotic administration. Direct drug delivery to the resection margins may bridge this therapeutic gap by achieving sustained high local antibiotic concentrations. This case report describes successful adjuvant therapy with a novel application of synthetic calcium sulfate (CS) beads loaded with gentamicin at the lateral skull base in a patient with severe osteomyelitis.

2. Case History/Examination and Treatment

An 86‐year‐old patient was initially treated for otitis externa in a private Ear Nose Throat (ENT) practice for 3 weeks. Microbiology swab grew Citrobacter koseri , and he received amoxicillin/clavulanate (1 g twice daily, perorally for 1 week) to which it was sensitive. Approximately 4 weeks after temporary improvement of the local findings and the otalgia, facial nerve palsy occurred. The patient was admitted to an ENT department of a secondary hospital for further treatment. Recurrent granulation tissue at the junction of the cartilaginous and osseous portion of the external auditory canal (Figure 1A) was removed multiple times. Severe otalgia was treated with a 4.2 mg fentanyl transdermal patch delivering 25 μg/h, replaced every 3 days. The microbiological examination revealed Pseudomonas aeruginosa . The patient received 8 weeks of intravenous therapy with piperacillin/tazobactam (4.5 g four times daily because of intermediate resistance). Laboratory testing excluded diabetes mellitus (HbA1c 5.7%) and there were no underlying chronic ear disease or symptomatic immunocompromising conditions. The white blood cell count, which was initially slightly elevated (10.5 Gpt/L) normalized 2 days after initiating the antibiotic treatment. The C‐reactive protein stabilized from 83.8 mg/L on admission to 20.6 mg/L. High‐resolution computed tomography (CT) and magnetic resonance imaging (MRI) confirmed the SBO. Since the treatment achieved no more than a temporary improvement in otalgia and local findings, while the facial nerve palsy progressed to grade VI [3] (Figure 2A), a radiological follow‐up examination was performed.

FIGURE 1.

External auditory canal preoperative with granulation tissue protruding from an ulcer of the inferior aspect of the cartilaginous‐osseous junction (A) and with circular scar tissue 7 months after the surgery (B). The tympanic membrane behind was not affected.

FIGURE 2.

Complete facial nerve palsy on the left side preoperative (A). It has recovered 7 months postoperative, allowing the explantation of the eyelid chain (B). In‐ear hearing aid in the patient's hand (C).

CT revealed a pneumatized tympanic cavity and bony erosions of the floor of the external auditory canal and the stylomastoid (Figure 3A,B). MRI showed further expansion of the SBO (Figure 3C,D) and the patient was transferred to our department at a tertiary hospital.

FIGURE 3.

The bone erosions (arrow) on the skull base are demonstrated on axial (A) and sagittal (B) computed tomography planes. The spread of the infection along the soft tissue is demonstrated preoperatively on axial (C) and coronal (D) magnetic resonance imaging. T1‐weighted sequences revealed contrast enhancement (asterisk) in the temporomandibular joint, the prevertebral muscles, the masticator space, the carotid sheath, clivus, and condilus ossis occpitalis as well as secretion of mastoid tip cells on the left side. There were no signs of intracranial invasion or dural enhancement.

On the same day, the patient underwent an extensive surgical procedure under general anesthesia. It included mastoidectomy with resection of the mastoid tip, the vaginal process of the tympanic bone and the styloid process, as well as exposure of the posterior belly of the digastric muscle and decompression of the mastoid segment of the facial nerve. The facial nerve was initially identified above the infection site and subsequently traced within granulation tissue at the stylomastoid foramen, where it lacks a protective endosteum sheath and was difficult to localize (Figure 4A,B). Intraoperative nerve monitoring yielded no response, even with 1 mA stimulation. Furthermore, the external bony auditory canal was circumferentially widened. The dissection was limited by the jugular bulb and the temporomandibular joint capsule. The extent of bone resection is visualized in the 3D reconstruction of postoperative follow‐up CT (Figure 5).

FIGURE 4.

Intraoperative situs after mastoidectomy and resection of the mastoid tip (A) with preservation of the posterior auditory canal wall (pacw). Gray dotted line outlines the external auditory canal with swollen skin after dissection and widening of the bony canal. The facial nerve (fn) was surrounded by granulation tissue (asterisk). After its removal the mastoidal course of the nerve was exposed (white dashed lines). After removal of necrotic tissue between the facial nerve and the jugular bulb abscess cavity (arrow) could be drained (B). Reconstruction of the mastoid tip with conchal cartilage graft (cc) over the gentamicin‐impregnated calcium sulfate beads (C). The antrum (a) was left unobstructed. ss, sigmoid sinus.

FIGURE 5.

The area of the resected bone (A) is visualized by three‐dimensional CT reconstruction. The intact right temporal bone (B) is also shown for comparison. Arrow: Vaginal process of the tympanic bone; white dashed lines: Outline of the resected styloid process; blue dashed lines: Course of the sigmoid sinus (ss) and the jugular bulb (jb); yellow lines: Course of the facial nerve (fn); black dotted lines: Course of the semicircular canals.

The surgical defect was then filled with gentamicin‐impregnated CS beads (Stimulan Rapid Cure, Biocomposites Ltd., Keele, Staffordshire, United Kingdom). Since they are initially hard, they provided temporary support for the conchal cartilage graft during defect reconstruction (Figure 4C). A smooth paste was prepared according to the manufacturer's recommendations (120 mg gentamicin in 3 mL solution and 5 cc CS powder, equal to 12 cc beads) and set to dry in a silicone mold for 10 min (Figure 6). This implanted volume is about eight times smaller than the amount associated with transient hypercalcemia [4]. A flexible platinum eyelid chain was implanted to correct the lagophthalmos. The pain medication was discontinued on the second postoperative day. Deep biopsy excluded malignancy and confirmed P. aeruginosa . Intravenous antibiotic therapy with piperacillin/tazobactam was continued for another 2 weeks (in total, 10 weeks), after which the patient was discharged with ciprofloxacin 750 mg perorally twice daily.

FIGURE 6.

Gentamicin‐impregnated calcium sulfate beads (3 and 4.8 mm) prepared in a flexible mold and ready for implantation.

3. Conclusion and Results

Eight weeks postoperatively, the external auditory canal was completely healed (Figure 1B). Ciprofloxacin therapy was discontinued 3 weeks later once the erythrocyte sedimentation rate normalized (in total, 11 weeks). After 2 years of postoperative follow‐up, the patient remains free of recurrence and the facial palsy has almost completely recovered (grade II [3], Figure 2B).

The infection was suspected to have originated from trauma to the floor of the external auditory canal caused by the patient's in‐ear hearing aid, which had a sharp tip and had possibly been inserted improperly due to osteoarthritis of the hand (Figure 2C). Additionally, the cartilaginous‐osseus junction was vulnerable because of an adjacent wide exostosis. Ototoxicity from local gentamicin therapy was excluded by audiometry and video head impulse test. No side effects were observed. The serum calcium level was monitored on the 4th and 14th postoperative day, as recommended in the literature [5], and remained within the upper normal range. There were no laboratory signs for acute kidney injury.

4. Discussion

This study describes the first use of CS as a vehicle for local long‐term antibiotic release in the treatment of SBO. The first report on the use of CS in ear surgery was published 2 years ago in a patient with chronic mastoiditis [6]. However, the authors impregnated the CS with ceftazidime/avibactam, which is not approved by the manufacturer and its absorption characteristics are not known. Nevertheless, the idea of using a local antibiotic carrier after surgery for SBO is not new. In 1968, Chandler recommended leaving the wound open and packing it with nonadherent gauze impregnated with gentamicin ointment [1]. In 1991, Ostfeld et al. [7] reported on the use of gentamicin‐incorporated beads of polymethyl‐methacrylate (PMMA) as an antimicrobial release system in the mastoid cavity in cases with malignant otitis externa. As in our case, they used an antibiotic‐loaded material, which was already well established in the treatment of arthroplasty infections [8].

Interestingly, PMMA has not gained wide international acceptance as a therapeutic modality for SBO and is not even mentioned in a recent systematic review [9] and current management update [10]. This may be due to several disadvantages of this antibiotic carrier. Based on our own experience, PMMA beads, which are threaded on a multistranded stainless steel wire, are unsuitable for filling the defect in resection cavities at the lateral skull base. While CS is biodegradable and releases the entire antibiotic, PMMA beads serve as a biofilm surface [11] after releasing only 5%–18% of the antibiotic [12], and need to be explanted from the mastoid in a second surgery. Furthermore, the gradual absorption of CS enables sustained release of antibiotic above the minimum inhibitory concentration over 40 days, which is more than three times longer than PMMA [11].

Another adjuvant therapeutic option is the hyperbaric oxygen therapy. Because of the high cost and the lack of evidence [13] it is no longer part of current therapy recommendations [10]. Although most authors agree that surgery can be beneficial in severe cases [2], its role in eradicating SBO is unclear [14]. While the consensus in the literature is that systemic antibiotic therapy is the mainstay of treatment, in our case it was insufficient as monotherapy. However, because of the concurring effect of the surgical intervention and the long‐term ciprofloxacin therapy, the value of the antibiotic‐impregnated CS cannot be definitively determined from this single case. Therefore, no recommendation for surgery with the only objective to implant antibiotic‐impregnated calcium sulfate can be derived from this case.

Our experience confirms previous observations of other authors that on the skull base the granulation tissue can merge into an abscess formation [15, 16]. In this case it formed in the area of the eroded styloid process and the jugular bulb and was not distinguishable on the imaging scans. Intraoperatively, a small quantity of blue–green pus could be drained. Because of this typical color, the bacterium known today as P. aeruginosa was previously named Bacillus pyocyaneus [17]. Although it is the most common causative agent of SBO, other pathogens are also mentioned in the literature. The initial pathogen Citrobacter koseri was probably a predisposing flora. In a mouse model, infection with Streptococcus anhaemolyticus only became invasive after inoculation with P. aeruginosa [18], which is not part of the normal flora of the ear canal.

Even if the inflammatory tissue cannot be completely removed in severe cases, there are good arguments for surgery. These include reducing the infectious burden in necrotic tissue and osteolytic bone, draining abscesses, confirming the causative microorganism, excluding malignancy, detecting antibiotic‐resistant strains or underlying fungal infection via deep tissue biopsy and irrigating with antiseptic solution. Future studies will show whether additional surgery and implantation of local antibiotic carrier could reduce the duration of long‐term antibiotic therapy as in cases with acute spondylodiscitis [19]. Shorter treatment could lower the risk of adverse effects such as nephrotoxicity and gastrointestinal complications, as well as reduce the overall cost of treatment, which requires inpatient intravenous antibiotic therapy for weeks or even months. Most authors recommend antibiotic therapy for at least 6 weeks [20], however, there are reports of an average treatment duration of 29 weeks [21].

The reason for this wide variation and the lack of consensus on the optimum duration of therapy is that there is no reliable clinical, laboratory or radiological sign of complete eradication of the infection. Since bone and soft tissue changes may persist for a longer duration even after disease resolution, CT and MRI are not suitable for identifying treatment end point [22]. Furthermore, the ability of traditional nuclear medicine studies like osteoblast scintigraphy with Technetium‐99 and leukocyte scintigraphy with Gallium‐67 to assess the treatment response is unproven [23]. Additional arguments against their routine use for monitoring of SBO are high radiation exposure, costs, long scan duration and delayed images. Hybrid modality such as Gallium‐68 positron emission tomography (PET)/CT can overcome these disadvantages and could provide reasonably accurate information regarding the disease resolution in a recent study [24]. However, it is not widely available in contrast to F‐18 FDG PET/CT, which is routinely used as a tracer for malignancies but has a significant drawback in the diagnosis of SBO because of its physiological uptake in the brain.

A plausible explanation for the need of long‐term systemic antibiotic therapy is that its effect is limited due to necrotizing vasculitis, caused by lytic enzymes of the mucoid layer in the biofilm of P. aeruginosa [25]. Although the implantation of an antibiotic carrier at the skull base cannot replace systemic therapy, it may support its effect by preventing reinfection of devitalised tissues as the retrocondylar fat pad, which liquefies [26] and the vulnerable almost acellular, poorly vascularized collagen layer of the ear canal cartilage, which is common in SBO patients [27].

Cranial nerve involvement in SBO is widely recognized as a marker of severe infection and increased mortality [28]. Due to its proximity, the facial nerve is typically the first one involved. Since most affected patients have diabetes mellitus, microangiopathy and neuropathy further compromise the vascular supply to the nerve. In a series of six patients with SBO and facial palsy, Mani et al. reported that none of them achieved complete recovery of nerve function (four remained static and two showed some improvement) despite high‐dose intravenous antibiotic therapy with third‐generation cephalosporin and ciprofloxacin [29]. One patient underwent facial nerve decompression without any functional improvement. It remains unclear whether that patient had diabetes. Future clinical experience should validate our observation and determine whether combining locally applied gentamicin‐impregnated CS with facial nerve decompression can successfully improve nerve function in this subset of patients.

In conclusion, in recalcitrant cases with severe osteomyelitis of the lateral skull base and facial nerve palsy abscess drainage and debridement with facial decompression may support the long‐term systemic antibiotic therapy. The efficacy of the surgical intervention may be further enhanced through implantation of antibiotic‐impregnated CS beads in the resection cavity.

Author Contributions

Stefan Lyutenski: conceptualization, investigation, methodology, resources, validation, visualization, writing – original draft, writing – review and editing. Aviva Henze: resources, writing – review and editing. Paul James: investigation, writing – review and editing. Marc Bloching: supervision, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

All data regarding the above case are presented within this manuscript. Further enquiries can be directed to the corresponding author.