Malignant (necrotizing) external otitis

INTRODUCTION — Malignant (necrotizing) external otitis (also termed malignant otitis externa) is an invasive infection of the external auditory canal and skull base, which typically occurs in older adult patients with diabetes mellitus. Increasing reports of malignant external otitis in patients infected with the human immunodeficiency virus (HIV) implicate a compromised immune system as a predisposing factor in this disease.

Pseudomonas aeruginosa is nearly always the responsible organism. The widespread use of oral and topical fluoroquinolones for the treatment of otitis may make the isolation of P. aeruginosa more difficult and has contributed to the emergence of P. aeruginosa resistant to ciprofloxacin [1,2].

The epidemiology, pathogenesis, clinical features, and management of malignant external otitis will be reviewed here. The spectrum of ear and eye infections due to P. aeruginosa and other clinical syndromes caused by this pathogen are discussed separately. (See "Pseudomonas aeruginosa infections of the eye, ear, urinary tract, gastrointestinal tract, and central nervous system", section on 'Ear infections' and "Pseudomonas aeruginosa infections of the eye, ear, urinary tract, gastrointestinal tract, and central nervous system", section on 'Eye infections' and "Pseudomonas aeruginosa skin and soft tissue infections" and "Pseudomonas aeruginosa bacteremia and endocarditis" and "Pseudomonas aeruginosa pneumonia".)

An overview of external otitis is also presented separately. (See "External otitis: Pathogenesis, clinical features, and diagnosis".)

EPIDEMIOLOGY — Older adults diabetic patients are overwhelmingly the population at risk for malignant external otitis. More than 90 percent of adults with this disease were found to have some form of glucose intolerance in one review [1]. A number of hypotheses have been advanced to explain this predisposition in diabetics including:

●Microangiopathy in the ear canal, which might also occur more commonly in older adult individuals [3,4]

●Increased pH in diabetic cerumen [5,6]

However, susceptibility to malignant external otitis has not been correlated with the level of glucose intolerance [3].

By contrast, malignant external otitis is a rare disease in children with fewer than 20 cases reported in the literature. Affected children are more likely to be immunocompromised (eg, malignancy or malnutrition). Children tend to develop fever and leukocytosis in association with this infection and are more likely than adults to have a concomitant P. aeruginosa bacteremia [3].

There are several reports of malignant external otitis in patients infected with HIV [7-14]. In seven such cases, none of the patients were diabetic and were adults younger than classic patients with this infection.

Recent ear surgery and hearing aid irritation may be risk factors for malignant otitis externa [15].

MICROBIOLOGY — Malignant external otitis is caused by P. aeruginosa in more than 95 percent of cases. When more than one organism is recovered, isolates accompanying P. aeruginosa tend to be normal skin flora. Occasional reports of cases caused by other organisms have included Aspergillus species [14,16-21], Staphylococcus aureus [22], Proteus mirabilis [23], Klebsiella oxytoca [24], Burkholderia cepacia [25], and Candida parapsilosis [26]. Infection with these other organisms characteristically occurs in immunocompromised hosts, such as those with acquired immunodeficiency syndrome (AIDS) or cancer. Among seven cases reported in HIV-infected patients, for example, Aspergillus fumigatus was isolated in three. While most cases of fungal malignant external otitis are due to Aspergillus, other fungi have also been reported, including Scedosporium apiospermum, Pseudallescheria boydii, Candida ciferrii, Candida orthopsilosis [27], and Malassezia sympodialis [28,29].

PATHOGENESIS — P. aeruginosa is a ubiquitous gram-negative bacterium that is capable of growing in distilled water [30,31]. Since it is not a normal component of ear canal flora even in diabetic patients, its recovery indicates the presence of a pathogen [32-34]. (See "Epidemiology, microbiology, and pathogenesis of Pseudomonas aeruginosa infection".)

Contamination of water with Pseudomonas has been directly linked to simple external otitis [32,35]. We previously reported a case-control study designed to test the hypothesis that aural water exposure contributed to the development of malignant external otitis. In this study, patients with the disease had a statistically more frequent antecedent history of ear irrigation (generally for the purposes of removing cerumen) compared with matched controls [36]. Many reports have subsequently confirmed this association between aural water exposure and malignant external otitis [4,37-41].

CLINICAL MANIFESTATIONS — Patients with malignant external otitis classically present with exquisite otalgia and otorrhea, which are not responsive to topical measures used to treat simple external otitis. The pain is generally more severe than that found in simple external otitis, although the two may be difficult to distinguish in their early stages. The pain in malignant external otitis tends to be nocturnal and extend into the temporomandibular joint, resulting in pain with chewing.

On physical examination, granulation tissue is frequently visible in the inferior portion of the external auditory canal at the bone-cartilage junction (at the site of Santorini's fissures). However, this finding may be absent in atypical patients (eg, immunocompromised individuals and children).

As the infection advances, osteomyelitis of the base of the skull and temporomandibular joint osteomyelitis can develop [3,6,42,43]. Progression of the osteomyelitis can be associated with cranial nerve palsies. In one series of 23 adult diabetic patients with malignant external otitis, 10 patients had cranial nerve involvement, six had only facial nerve involvement, and four had a combination of nerves involved (VI, VII, IX, X, XI, XII) [44]. Children with malignant external otitis have a higher incidence of facial palsy due to their relatively undeveloped mastoid process and the more medial location of the fissures of Santorini, which places the facial nerve in closer proximity to the ear canal [45]. The glossopharyngeal, vagal, and spinal accessory nerves can be afflicted at the jugular foramen, and the hypoglossal nerve can be affected as it exits the hypoglossal canal. The trigeminal and abducens nerves are rarely affected at the petrous apex, and there is a single report of optic nerve involvement in a patient with malignant external otitis [46]. The olfactory, oculomotor, and trochlear nerves appear to be unaffected by this disease.

Other central nervous system complications are rare but can be fatal when they occur. These include meningitis, brain abscess, dural sinus thrombosis, or pseudoaneurysm of the intrapetrous internal carotid artery [38,47]. (See "Health care-associated meningitis and ventriculitis in adults: Clinical features and diagnosis" and "Pathogenesis, clinical manifestations, and diagnosis of brain abscess" and "Septic dural sinus thrombosis".)

DIAGNOSIS — The diagnosis is often overlooked, leading to delay in effective therapy [3,15]. In the absence of a single pathognomonic criterion, the diagnosis of malignant external otitis is based upon a constellation of clinical, laboratory, and radiographic findings. A retrospective review of 73 cases at a tertiary care center suggested that patients who present with most of the classic clinical and radiographic criteria and/or who fail to respond to the initial course of intensive therapy have worse outcomes [48]. Individuals noted to have "severe" disease at presentation as manifest by cranial nerve palsy, positive fungal culture, relapse, and invasion on imaging have a worse treatment outcome [49].

General laboratory findings — Laboratory parameters are generally normal in malignant external otitis, with the exception of an elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP). Although nonspecific, a strikingly elevated ESR or CRP is the most characteristic laboratory abnormality and is a useful way of monitoring disease activity [3].

Microbiology studies — Cultures of ear canal drainage, or granulations, should be performed and sent for Gram stain and culture for bacteria. Stains (eg, calcofluor) and cultures for fungi should also be sent.

Although bacteremia is rare in necrotizing otitis externa in adults, it is reasonable to send blood cultures prior to starting antibiotics. Immunocompromised patients and children in particular may be bacteremic without overt signs of toxicity.

Imaging — The utility of nuclear imaging studies is controversial, whereas anatomic localizing procedures such as computed tomography (CT) and magnetic resonance imaging (MRI) can be useful for both diagnosis and follow-up.

Computed tomography and magnetic resonance imaging — Anatomic imaging modalities allow for both anatomic localization of disease as well as the assessment of disease resolution. CT scanning is ideal for the assessment of bone erosion. In a prospective study, we determined that the presence of bone erosion and/or soft tissue abnormalities in the subtemporal region was helpful in making the diagnosis of malignant external otitis [50]. Although bone did not remineralize, resolution of the soft tissue component did correlate with disease activity. While some studies indicate that CT findings predict clinical outcome [51], others have reported that the CT findings do not correlate with the clinical course [52]. Analysis of CT and MRI in 18 patients with malignant external otitis confirmed that these radiographic modalities provide complementary information [53].

To compare CT with MRI, we performed a long-term prospective study in seven patients with malignant external otitis [54]. MRI was slightly better at demonstrating medial skull base disease due to its ability to delineate changes in the fat content of the marrow. Better results with MRI have also been noted by others [55]. Anterior extension into the retrocondylar fat on MRI may indicate the earliest change in malignant external otitis, with extension in more than one direction (eg, anterior, medial, midline, intracranial, extracranial) being associated with worse prognosis [56]. Since bone erosion distinguishes malignant external otitis from external otitis, CT is the better test for initial diagnosis of bone erosion, although this may be absent in very early presentations of malignant external otitis. MRI is better for establishing extent of disease and monitoring response to therapy. MRI may also identify very early cases prior to appearance of bony erosion on CT. MRI can also be used to distinguish skull base osteomyelitis secondary to malignant external otitis from nasopharyngeal carcinoma [57]. One group has proposed a radiologic stratification for malignant external otitis ranging from phase I (inflammation limited to the external auditory canal without bony erosion) to phase V (inflammation extending to the contralateral ear/skull base) [58].

Gallium scan — Gallium citrate (Ga-67) scanning appears to be more specific than bone scanning since the radioisotope is incorporated into granulocytes and bacteria. Although several studies have reported that gallium scanning can be used to follow disease activity, others have noted that normal scans can be found in patients with recurrent disease [59-65]. The combination of Ga-67 with single photon emission computerized tomography (SPECT) scanning may be useful in the diagnosis and follow-up examination [15,63-65]. However, it has not been compared with CT plus MRI. (See 'Computed tomography and magnetic resonance imaging' above.)

Bone scan — Bone scanning with technetium (Tc 99m), where the radionuclide tracer accumulates at sites of osteoblastic activity, is very sensitive in making the diagnosis. However, it is not a specific study since there are reports of positive bone scans in simple external otitis [66], and bone scans are not suitable for following response to treatment since they do not normalize. Quantitative bone scanning may be able to distinguish simple from malignant external otitis and demonstrate disease resolution [67,68]. Use of the mouse monoclonal antibody linked to technetium (Tc 99m sulesomab), which is approved for osteomyelitis imaging, was reported in two cases of malignant external otitis where imaging results appeared to accurately reflect disease activity and response to treatment [69].

Biopsy — Squamous cell carcinoma of the temporal bone can also present as a painful draining ear canal. Since radiographic studies cannot differentiate tumor from necrotizing infection, biopsy is the only definitive method to distinguish between these two entities. A positive culture for P. aeruginosa and elevation of the ESR and/or CRP are more commonly associated with infection. There are only two reports of simultaneous presentation of temporal bone cancer and malignant external otitis [70,71].

The other mimic of malignant external otitis caused by P. aeruginosa is malignant external otitis caused by Aspergillus spp or, very rarely, other pathogens. Since malignant external otitis caused by P. aeruginosa is far more common than either carcinoma of the temporal bone or malignant external otitis caused by Aspergillus spp, we generally reserve biopsy for patients who have not responded to therapy for P. aeruginosa infection.

TREATMENT

Systemic antimicrobial therapy — Antipseudomonal antimicrobials are the mainstay of therapy for malignant external otitis. The optimal approach to initial empiric regimen selection is uncertain. Our approach to treatment depends on the severity of disease. The local rate of fluoroquinolone resistance in Pseudomonas may also be a consideration.

●For immunocompetent patients with uncomplicated malignant otitis externa, we suggest ciprofloxacin monotherapy.

We usually initiate treatment with intravenous (IV) ciprofloxacin (in adults: 400 mg IV every eight hours; in children: 20 to 30 mg/kg per day IV divided every 12 hours, max 800 mg/day) until we observe a subjective clinical response and/or a decrease in erythrocyte sedimentation rate or C-reactive protein. At that point, the patient can be transitioned to oral ciprofloxacin (in adults: 750 mg orally every 12 hours; in children: 20 to 30 mg/kg per day orally divided every 12 hours, max 1500 mg/day). Patients taking ciprofloxacin along with medications that may interfere with absorption (eg, iron or calcium supplements) should space these appropriately to prevent interference with absorption. Levofloxacin is also likely to be effective since it has activity against P. aeruginosa, but clinical experience with levofloxacin has not been reported.

●For patients with advanced malignant otitis externa (eg, significant bony erosion, multiple cranial neuropathies) or immunocompromising conditions or when the local rate of fluoroquinolone resistance in Pseudomonas is very high, we suggest initial combination therapy with ciprofloxacin plus an antipseudomonal beta-lactam (see below for dosing). Once there has been clinical improvement, patients can be switched to ciprofloxacin alone.

The objective of combination therapy is to increase the likelihood of using an active agent in a patient for whom ineffective antibiotic therapy could lead to progressive disease with high morbidity. However, no studies have compared initial empiric combination therapy versus monotherapy with ciprofloxacin in severe cases of malignant otitis externa. (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Role of combination antimicrobial therapy'.)

With the introduction and widespread use of both oral and topical fluoroquinolones, less severe clinical presentations of malignant external otitis and the emergence of ciprofloxacin resistance have been increasing [1,72-74]. Patients who have failed to improve on a fluoroquinolone (eg, persistent symptoms or persistently elevated inflammatory markers) warrant biopsy for culture and susceptibility testing.

If cultures yield fluoroquinolone-resistant P. aeruginosa, they should be treated with an antipseudomonal antibiotic. If piperacillin is available, we prefer it to piperacillin-tazobactam, but piperacillin-tazobactam or an antipseudomonal cephalosporin may be used if piperacillin is not available (it is not available in the United States). We do not recommend combination therapy with an aminoglycoside since ototoxicity with vestibular disturbances has occurred despite assiduous monitoring of aminoglycoside serum concentrations.

The dosing of antipseudomonal beta-lactams is as follows:

●Piperacillin – In adults: 3 g IV every four hours or 4 g IV every six hours; in children: 50 to 75 mg/kg IV every four to six hours (not to exceed 4 g per dose or 24 g per day).

●Piperacillin-tazobactam – In adults, 4.5 g IV every six hours; in children ≤40 kg, 300 mg/kg of the piperacillin component per day IV divided every eight hours (not to exceed 16 g per day of the piperacillin component); in children >40 kg, 3 g every six hours or 4 g every six to eight hours.

●Ceftazidime – In adults: 2 g IV every eight hours; in children: 100 to 150 mg/kg per day IV divided every eight hours (not to exceed 6 g per day).

●Cefepime – In adults: 2 g IV every 12 hours is the standard dose (some clinicians use 2 g IV every eight hours initially for severe P. aeruginosa infections); in children: 50 mg/kg IV every eight hours (not to exceed 2 g per dose).

●Meropenem – In adults: 2 g IV every eight hours; in children: 60 mg/kg per day IV divided every eight hours (not to exceed 3 g per day). If intracranial extension is a concern, 120 mg/kg per day IV divided every eight hours (not to exceed 6 g per day) should be employed.

Whether a fluoroquinolone or antipseudomonal beta-lactam is used, prolonged treatment of malignant otitis externa for six to eight weeks is generally recommended, as indicated for osteomyelitis.

If Aspergillus species are the causative organisms, prolonged treatment (>12 weeks) with voriconazole may be the therapy of choice [75,76]. Alternative therapy is with liposomal amphotericin B, which decreases the nephrotoxicity of amphotericin B deoxycholate. Voriconazole was superior to amphotericin in a randomized controlled trial of patients with other types of invasive Aspergillus infections (primarily pulmonary) [77]. Isavuconazole, a new triazole shown to be noninferior to voriconazole in treating invasive Aspergillus infections [78], may be another option for treating Aspergillus malignant otitis externa, but no such cases have been described. Success has also been reported with a short course of amphotericin B and long-term oral itraconazole in a single case report [79]. (See "Pharmacology of amphotericin B" and "Treatment and prevention of invasive aspergillosis".)

Most of the supportive evidence for antipseudomonal antibiotics for the treatment of malignant external otitis is observational. Cases are rare, and thus randomized controlled comparisons of therapy are not feasible. Prior to the development of systemic agents, recurrences of malignant external otitis were frequent, and mortality was approximately 50 percent [4]. The introduction of parenteral semisynthetic penicillins reduced the mortality to 20 percent [80], and a further reduction in mortality to 5 to 10 percent has occurred since the introduction of ciprofloxacin and antipseudomonal cephalosporins, such as ceftazidime and cefepime. Studies from 1988 to 1991 showed that prolonged therapy with ciprofloxacin alone was effective in treating most cases of malignant otitis externa [81-87], although, as above, resistance to fluoroquinolones has been increasing.

There have been reports of tendon inflammation and/or rupture with fluoroquinolones in all age groups; risk may be increased with concurrent glucocorticoids, in solid organ transplant recipients, and in patients >60 years of age. In some studies in children, an increased incidence of reversible adverse events involving joints or surrounding tissues has been observed, but no compelling published evidence supports the occurrence of sustained injury to developing bones or joints in children treated with available fluoroquinolones [88-92]. The risks and benefits should be considered if a fluoroquinolone is prescribed in a child younger than 18 years of age. (See "Fluoroquinolones", section on 'Children' and "Fluoroquinolones", section on 'Tendinopathy'.)

Furthermore, fluoroquinolones have been associated with numerous other adverse effects, including hypoglycemia, central nervous system dysfunction, neuropathy, and aortic aneurysm and dissection. Fluoroquinolones may also predispose to arrhythmias due to QTc prolongation, and a baseline electrocardiogram (EKG) before and after initiating fluoroquinolones is appropriate. The US Food and Drug Administration (FDA) has issued several black box warnings and special alerts about fluoroquinolones. Specific risk factors for developing these side effects have not been identified in many cases (See "Fluoroquinolones", section on 'Adverse effects'.)

Interventions with limited role — There is no role for topical antibiotics in malignant external otitis therapy. Instillation of antipseudomonal topical agents may only increase the difficulty in isolating the organism from the ear canal. Surgical excision also plays no role in the current treatment of this disease, although this modality was used prior to the availability of systemic antipseudomonal antibiotics. Debridement and/or biopsy to rule out cancer are the only indicated surgical procedures.

Hyperbaric oxygen has been used on occasion with mixed results and may be considered as an adjuvant treatment for refractory cases [42,93-96]. However, a Cochrane review found no randomized controlled trials comparing hyperbaric oxygen therapy to treatment with antibiotics and/or surgery and concluded that there was no clear evidence to demonstrate the efficacy of hyperbaric oxygen treatment [97].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute otitis media, otitis media with effusion, and external otitis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient education: Outer ear infection (The Basics)")

●Beyond the Basics topic (see "Patient education: External otitis (including swimmer's ear) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition − Malignant (necrotizing) external otitis (also termed malignant otitis externa) is an invasive infection of the external auditory canal and skull base, which typically occurs in older adult patients with diabetes mellitus. (See 'Introduction' above.)

●Microbiology − Malignant external otitis is caused by Pseudomonas aeruginosa in more than 95 percent of cases. Since P. aeruginosa is not a normal component of ear canal flora even in diabetic patients, its recovery indicates the presence of a pathogen. Occasional reports of cases caused by other organisms have included Aspergillus species, Staphylococcus aureus, Proteus mirabilis, Klebsiella oxytoca, Burkholderia cepacia, and Candida parapsilosis. Infection with these other organisms characteristically occurs in immunocompromised hosts, such as those with AIDS or cancer. (See 'Microbiology' above.)

●Clinical presentation − Patients with malignant external otitis classically present with exquisite otalgia and otorrhea, which are not responsive to topical measures used to treat simple external otitis. The pain is generally more severe than that found in simple external otitis, although the two may be difficult to distinguish in their early stages. (See 'Clinical manifestations' above.)

●Complications − As the infection advances, osteomyelitis of the base of the skull and temporomandibular joint osteomyelitis can develop. Progression of the osteomyelitis can be associated with cranial nerve palsies. Other central nervous system complications are rare but can be fatal when they occur. These include meningitis, brain abscess, and dural sinus thrombosis. (See 'Clinical manifestations' above.)

●Diagnosis − The diagnosis of malignant external otitis is based upon a constellation of clinical, laboratory, and radiographic findings. (See 'Diagnosis' above.)

●Imaging − Anatomic localizing procedures, such as computed tomography (CT) and magnetic resonance imaging (MRI) scans, can be useful for both diagnosis and follow-up. CT is the better test for identifying bony erosion, while MRI is better for establishing extent of disease and monitoring response to therapy. MRI may also identify very early cases prior to appearance of bony erosion on CT. (See 'Imaging' above.)

●Antibiotic selection − For empiric therapy of immunocompetent patients with uncomplicated malignant external otitis, we suggest ciprofloxacin (Grade 2C). Initial combination therapy with ciprofloxacin plus an antipseudomonal beta-lactam is appropriate for patients with advanced infection or severe immunocompromising conditions; they can be transitioned to ciprofloxacin following clinical improvement. (See 'Systemic antimicrobial therapy' above.)

●Duration of therapy − The duration of antibiotic treatment is generally six to eight weeks, as indicated for osteomyelitis. Patients with treatment failure should undergo biopsy for culture and susceptibility testing. (See 'Systemic antimicrobial therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Victor L Yu, MD, who contributed to an earlier version of this topic review.