ABSTRACT

Abstract: Necrotizing otitis externa (NOE) is a severe inflammatory process of the external ear and temporal bone. Although there are dozens of publications dealing with this serious condition, there are still fundamental issues not fully understood in the diagnosis and treatment of NOE. The aim of this review is to describe the current approach to the management of NOE and emphasize the main issues which lack data and need to be further evaluated.

Materials & methods: We used Pub Med/MEDLINE to search for review articles in English using keywords “necrotizing otitis externa”, “malignant otitis externa”, “necrosis”, “otitis externa”.

Conclusion: With increasing, antibiotic resistance rates, isolating the pathogen and gaining an antibiotic profile are of the utmost importance. Non-Pseudomonas A. NOE and mycotic NOE pose special treatment dilemma, and further data is required for establishing appropriate guidelines. The role of surgery is still unclear but seems to have a place in refractory and/or culture negative cases. Follow up for patients with NOE may be performed with the help of periodic nuclear imaging or with periodic measurements of inflammatory markers.

INTRODUCTION

Necrotizing otitis externa (NOE), also known as malignant otitis externa is an inflammatory disorder involving the external ear and temporal bone. Left untreated, this severe inflammatory process may have grave consequences. NOE was first described by Chandler in 1968 [1] and although there have been dozens of reports on the subject since there are still fundamental issues not fully understood in its diagnosis and treatment. The aim of this review is to describe the current approach to the management of NOE and emphasize the main issues which lack data and need to be further evaluated.

Presenting symptoms

NOE is a continuum of otitis externa, and as such, it represents a wide array of clinical conditions. As a result, there is no true consensus regarding the distinction between severe otitis externa and NOE, nor are there clear diagnostic criteria for NOE.Chandler¹ first described NOE as a severe inflammation of the external ear invading soft tissue, cartilage and bone occurring among elderly diabetic patients. Cohen and Friedman [2] suggested a diagnostic criterion for NOE, classifying the presenting symptoms as obligatory (pain, edema, exudate, granulations, microabscess, positive bone scan or failure of local treatment >1 week and pseudomonas in culture) and occasional (diabetes, cranial nerve involvement, positive radiograph, debilitating condition and old age). Hollis et al [3], a generation later, based the diagnosis of NOE on clinical findings (granulation tissue arising from the external auditory canal) raised serum inflammatory markers and radiographic evidence of soft tissue (with or without bone erosion) in the external auditory canal and infratemporal fossa. Other parameters used for the diagnosis of NOE include age [4] and necrosis showed in histopathology [5].

Several differences in the presentation of NOE among patients with different underlying conditions have been described. HIV patients with NOE were reported to be younger, and in some cases did not present the classic aural polyps or granulation tissue [6]. Additionally, Fungal NOE has been reported to be more common among HIV patients [7]. NOE in children has a more acute onset compared to adults, with more pronounced systemic effects such as fever, malaise, and leukocytosis [8]. Some NOE patients may present with facial nerve palsy or other cranial nerve involvement. Although these may relate to extensive bone involvement- a progressive form of the disease, it doesn't necessarily indicate a worse prognosis [9].

Bacteriology

Pseudomonas Aeruginosa (PSA) is the most common causative agents for the development of NOE [3, 10, 11]. PSA is a gram-negative facultative anaerobe coccobacillus bacterium. It may be found in the soil or water and it thrives on moist surfaces. PSA is rarely a member of the normal flora of the external ear [10, 12]. The bacteria usually colonize the external ear following exposure to the moist environment and penetrate the skin after local trauma. Virulent factors include lytic enzymes such as collagenase, elastase, and others which cause local vasculitis and endarteritis further assisting in the penetration of the surrounding soft tissue. The resistance of PSA to antibiotics arises from mutations in target enzymes and formation of biofilm [13]. The prevalence of PSA NOE has been reported to decline in recent years and, at the same time, reports of culture-negative NOE has been inclining [11]. Since most of the patients with NOE received local and/or systemic anti PSA antibiotics prior to hospitalization, these shifts raise concern regarding bacterial resistance. Several other organisms such as Staphylococcus aureus [14], Klebsiella species [15], Streptococcus epidermidis [16] and others were reported to cause NOE. These cases are rare and it is unclear whether they represent true pathogens [3].

Fungal pathogens have also been known to cause NOE. Among them, Aspergillus species have been reported to be the most common pathogen [3] followed by Candida species [17]. Although less common than PSA, these pathogens should be considered in refractory cases, especially in cases where initial improvement under antibiotic treatment is seen followed by clinical deterioration, as well as in non-diabetic patients. A positive fungal culture taken from the external ear canal poses a dilemma for the treating physician. Since many patients are treated with steroids containing local ear drops prior to hospitalization it is unclear whether the isolated fungi are the true offending agent or a secondary infection due to the local steroid treatment. For this reason, the decision of initiating anti-fungal treatment is, in many cases, delayed. Gruber et al [18] reported the use of polymerase chain reaction (PCR)in deep tissue biopsies in three culture negative refractory cases. In all patients’ fungal pathogens were isolated, which may indicate a higher rate of fungal NOE than previously reported. It appears that deep tissue cultures may have a role in the evaluation and treatment of NOE patients. The exact indications and timing, however, are still no clear.

Diagnostic Imaging

Current imaging studies used in the diagnosis of NOE include computed tomography (CT), magnetic resonance imaging (MRI) and nuclear imaging.

CT is the most common initial imaging modality. With the use of high-resolution CT of the temporal bone (TB-HRCT), bone changes may be seen in the temporomandibular joint (TMJ), temporal bone and skull base (figure-1). It is important to emphasize that these changes are evident only when demineralization of bone reaches at least 30%. Furthermore, other conditions may cause cortical erosions of the temporal bone such as tumors, middle ear cholesteatoma, and keratosis obturans, thus CT lacks the sensitivity and specificity for the diagnosis and follows up of NOE. On the other hand, the involvement of the middle ear, mastoid, and nasopharynx on initial CT have been shown to carry a worse prognosis among NOE patients [19, 20]. Regardless, the high availability of CT scan helps the physician in assessing disease extent during the initial evaluation and for excluding other pathologies such as cholesteatoma, foreign body with soft tissue reaction and malignancy.

MRI is superior to CT in the evaluation of soft tissue, in particular, the parotid, meninges, cranial nerves and medullary bone spaces [21]. Changes in medullary bone and soft tissue are seen on MRI as late as 12 months after initiation of treatment, limiting MRI's suitability to assess disease progression [22].

Nuclear imaging used in the diagnosis of NOE includes technetium-99, gallium-67 and indium-111. Technicium-99 accumulates in bone and reflects osteoblastic activity. It is relatively inexpensive and has a high sensitivity in the evaluation of bone involvement. Since these bone changes continue also after the inflammatory process has ended, it is not suitable for assessment of disease resolution.

Gallium-67, an isotope absorbed by macrophages and reticular endothelial cells, is a sensitive tool for the evaluation of inflammatory processes (figure-2). It accumulates in any area of active inflammation (soft tissue and bone), thus for the diagnosis of osteomyelitis both Technetium-99 and Gallium-67 measurements are required. The main disadvantage of Gallium-67 scan is poor anatomical localization, requiring SPECT/CT imaging to increase anatomical accuracy [21]. Gallium– 67 absorption rapidly resolves after the inflammatory process has ended and as a result, it is considered by many to be the most sensitive tool for the evaluation of disease progression and treatment response. Although sensitive, there have been reports of false negative results in cases where planar Gallium-67 imaging was used [23], as well as in cases of recurrent NOE [24]. Indium-111 labeled white blood cell scan has also been used in the diagnosis of NOE. As part of the ongoing inflammatory process, white blood cell migration occurs, causing accumulation of the labeled cells in the inflamed areas. Although considered as sensitive as Gallium-67 scan in the setting of acute inflammation, its sensitivity decreases in longstanding-chronic infections (due to decreased white blood cell migration).

Treatment

The most common first-line systemic antibiotics given for PSA NOE include quinolones and ceftazidime (reported susceptibility rates in the USA of 68% and 80%, respectively [25]). Other regimens include the addition of rifampin, aminoglycosides, and others. Since NOE is considered as osteomyelitis, the recommended treatment duration is 6 weeks although larger variations exist in the literature (from 12 days to 15 weeks). Local treatment includes aminoglycosides or quinolone-based ear drops (similar to the treatment for acute otitis externa), however, their exact role in the treatment of NOE is not clear.

Cases of ciprofloxacin resistant PSA have increased in recent years [26] with a reported incidence ranging between 31%-37.5% among NOE patients [27-29]. One reason for this might be due to prolonged and improper use of local quinolone-based ear drops at the initial stage by the primary care physician. It is of vital importance that high-risk patients (mostly elderly with DM and immune compromised patients) will be closely monitored and referred to an otolaryngologist if improvement is not evident within days.

The initial treatment of culture-negative NOE is empirical. Lohet al [29] has reported no significant difference among treatment outcome between culture-specific therapy and culture negative patients who received ceftazidime and oral fluorquinolone. Rubin et al [10] have proposed a combination of rifampicine and ciprofloxacine in the treatment of culture-negative NOE. Regardless of the regimen, it appears that dual treatment should be considered in cases of culture-negative NOE. Since NOE patients will be subjected to prolonged antibiotic treatment, adverse side effects such as urticaria, neutropenia, hepatotoxicity, and others, might be a concern. Schimanteret al [30] reported a higher incidence of adverse drug reactions among NOE patients treated with β-lactamase inhibitors compared with ciprofloxacin. Patients should be monitored periodically during treatment for adverse reaction.

Treatment for mycotic NEO includes amphotericin B, voriconazol, itraconazole and others. Serious adverse reactions to anti-mycotic medications include renal and hepatic failure, hematological abnormalities, arrhythmias and more and patients should be closely monitored. In recent year’s liposomal amphotericin B has been indicated for the treatment of invasive fungal infections. Although expensive, it is associated with reduced risk of nephrotoxicity and drug infusion reactions as opposed to normal amphotericin formulation [31] and should be considered for the treatment of mycotic NOE.

Surgery

Prior to the introduction of anti-pseudomonal antibiotics, the radical surgical intervention was advocated for all patients with NOE. The procedures included extensive removal of all necrotic tissue, including soft tissue, cartilage and bone, mastoidectomy (of different types), and when involved in facial nerve decompression. With the introduction of anti-pseudomonal antibiotics in the 1980’s, the need for early radical intervention has decreased substantially. In the last three decades, surgical intervention has been indicated for: 1) Debridement of necrotic tissue 2) Obtaining deep tissue biopsies 3) Surgical exploration in refractory cases 4) Facial nerve decompression. There is no data in regards to the advantages of surgery in the current treatment modalities of NOE nor is there a clear guideline regarding the timing or extent of the surgery.

Hyperbaric treatment

Hyperbaric oxygen therapy (HBOT) has been used in cases of NOE. HBOT increases phagocytic killing, increases angiogenesis and has an additive effect to antibiotic treatment [32]. Jefferson et al [33] reported a case series including 16 refractory cases, not responding to adequate antipseudomonal therapy. All patients responded well to 30 days of HBOT treatment combined with antibiotic treatment and no recurrence was reported. Although promising, a Cochrane review published in 2013 concluded that there is insufficient data to demonstrate the efficacy of HBOT compared to antibiotic and/or surgery for the treatment of NOE [34].

Duration of treatment and follow up

A major question regarding the treatment of NOE is the duration of treatment. Several tests and imaging modalities may assist the physician while considering treatment duration. Gallium-67 has been advocated as the imaging modality for the assessment of treatment duration. Since Gallium-67 accumulate in soft tissue as well, technetium-99 is also required for the diagnosis of bone involvement. Okpalaet al [21] suggested an investigation protocol in which patients completing treatment should undergo a Tc-99 measurement. Only in the presence of a positive Tc-99 measurement should Gallium-67 scan be performed. Inflammatory markers such as leukocyte count, sedimentation rate and C-reactive protein combined with periodic physical examination may also provide a tool for the assessment of disease progression. Loh et al [29] reported a reduction of 21.7% in the ESR (as compared to initial levels) among patients with resolved NOE, as compared to patients with persistent disease. The same trend was also observed in CRP rates. Currently, there is no data indicating the superiority of one method over the other and patient evaluation is performed based on the physician experience and availability of nuclear imaging.

Prognosis

Prognosis of NOE has changed dramatically since Chandler’s first description of NOE. Interestingly, despite the lack of consensus regarding the optimal treatment, the cure is reported in 87%-100% of cases [11]. Recurrence is reported to occur with a mean rate of 9.6% [11]. There are no known trends regarding the timing of recurrence.

Comments

Although known for several decades there are still fundamental issues left unanswered regarding the diagnosis and treatment of NOE. With increasing, antibiotic resistance rates, isolating the pathogen and gaining an antibiotic profile are of the utmost importance. Non-PSA NOE and mycotic NOE pose special treatment dilemma, and further data is required for establishing appropriate guidelines. We do, however, believe that cases of NOE not responding to treatment for more than several weeks is highly suspicious for a mycotic NOE and antifungal treatment should be considered.

The role of surgery is still unclear but seems to have a place in refractory and/or culture negative cases. Whether or not surgery should affect treatment duration is unclear. As mentioned above, treatment duration for NOE is similar to the advised treatment duration of osteomyelitis of other bones. Interestingly, a fundamental difference is seen in management, as surgery is commonly performed in osteomyelitis of other bones.

Follow up for patients with NOE may be performed with the help of periodic nuclear imaging or with periodic measurements of inflammatory markers. Regardless of the approach used, close evaluation of the affected ear is crucial.

Conflict of interest

The authors have no conflict of interest

REFERENCES

1. Chandler JR, Malignant external otitis. Laryngoscope, 1968. 78(8): p. 1257-1294.
2. Cohen D, Friedman P, The diagnostic criteria of malignant external otitis. J Laryngol Otol, 1987. 101: p. 216–21.
3. Hollis S, Evans K, Management of malignant (necrotizing) otitis externa. The Journal of Laryngology & Otology, 2011.125: p. 1212–1217.
4. Soudry E, Joshua BZ, Sulkes J, et al; Characteristics and prognosis of malignant external otitis with facial paralysis. Arch Otolaryngol Head Neck Surg, 2007.133: p. 1002-1004.
5. Rubin J, Yu VL, Malignant external otitis: insights into pathogenesis, clinical manifestations, diagnosis and therapy. Am J Med, 1988. 85: p. 391–398.
6. Ress BD, Luntz M, Telischi FF, et al; Necrotizing otitis externa in patients with AIDS. Laryngoscope, 1997.107: p. 456-460.
7. Yao M, Messner AH, Fungal malignant otitis externa due to Scedosporiumapiospemum. Ann Oto Laryngol, 2001.110: p. 377-380.
8. Carfrea MJ, Kesser BW, Malignant otitis externa. Otolaryngol Clin N Am, 2008. 41: p. 537-549.
9. Soudry E, Joshua BZ, Sulkes J, et al; Characteristics and prognosis of malignant external otitis with facial paralysis. Arch Otolaryngol Head Neck Surg, 2007. 133: p. 1002-1004.
10. Rubin J, Yu VL, Malignant external otitis: insights into pathogenesis, clinical manifestations, diagnosis and therapy. Am J Med, 1988. 85: p. 391–398.
11. Mahdyoun P, Pulcini C, Gahide I, et al; Necrotizing otitis externa: a systematic review. Otology &Neurotology, 2013. 34: p. 620-629.
12. Barrow HN, Levenson MJ, Necrotising “malignant” external otitis caused by Staphylococcal epidermidis. Arch Otolaryngol Head Neck Surg, 1992. 118: p. 94–96.
13. Bernstein J, Holland N, Porter G, et al; Resistance of pseudomonas to ciprofloxacin: implications for the treatment of malignant otitis externa. J Laryngol Otol2007. 121: p. 118-123.
14. Bayardelle P, Granger M, Larochelle D. Staphylococcal malignant external otitis. Can Med Assoc J 1982; 126:155-156.
15. Garcia Rodriguez JA, Montes Martinez I, Gómez González JL, et al. A case of malignant external otitis involving Klebsiellaoxytoca. Eur J ClinMicrobiol Infect Dis 1992; 11:75–77.
16. Barrow HN, Levenson MJ. Necrotising “malignant” external otitis caused by Staphylococcal epidermidis. Arch Otolaryngol Head Neck Surg 1992;118:94–96.
17. Bae W, Lee K, Park J, et-al. A case of malignant otitis externa caused by Candida glabrata in a patient receiving haemodialysis. Scand J Infect Dis;39:370-372.
18. Gruber M, Roitman A, Doweck I, et al. Clinical utility of a polymerase chain reaction assay in culture-negative necrotizing otitis externa. OtolNeurotol2015;36:733-736.
19. Peleg U, Perez R, Raveh D, et al. Startification for malignant otitis externa. Otolaryngol Head Neck Surg 2007; 137:301-305.
20. Joshua BZ, Sulkes J, Raveh E, Bishara J, Nageris BI. Predicting outcome of malignant external otitis. Otol Neurotol, 2008. 29: p. 339-343.
21. Okpala NC, Siraj QH, Nilssen E, Pringle M. Radiological and radionuclide investigation of malignant otitis externa. J Laryngol Otol, 2005. 119: p. 71-75.
22. Al-Noury K, Lotfy A, Computed tomography and magnetic resonance imaging before and after treatment of patients with malignant external otitis. Eur Arch Otorhinolaryngol, 2011. 268: p. 1727–1734.
23. Chen YH, Hsieh HJ, Single photon emission computed tomography/computed tomography for malignant otitis externa: lesion not shown on planar image. Am J Otolaryngol, 2013. 34: p. 169-171.
24. Grandis JR, Branstetter BF, Yu VL, The changing face of malignant (necrotizing) external otitis: clinical, radiological, and anatomic correlations. Lancet Infect Dis, 2004. 4: p. 34-39.
25. Karlowsky A, Jones M, Thornsberry C, et al; Stable antimicrobial susceptibility rates for clinical isolates of pseudomonas aeruginosa from the 2001– 2003 tracking resistance in the United States today surveillance studies. Clin Infect Dis, 2005. 40: p. 89–98.
26. Berenholz L, Katzenell U, Harell M. Evolving resistant pseudomonas to ciprofloxacin in malignant otitis externa. Laryngoscope, 2002. 112: p. 1619-1622.
27. Jones ME, Karlowsky JA, Draghi DC, et al; Antibiotic susceptibility of bacteria most commonly isolated from bone related infections: the role of cephalosporins in antimicrobial therapy. Int J Antimicrob Agents, 2004. 23: p. 240-246.
28. Jang CH, Park SY, Emergence of ciprofloxacin-resistant Pseudomonas in chronic suppurative otitis media. Clin Otolaryngol Allied Sci, 2004. 29: p. 321-323.
29. Loh S, Loh WS, Malignant Otitis Externa: An Asian Perspective on Treatment Outcomes and Prognostic Factors. Otolaryngol Head Neck Surg, 2012. 148: p. 991–996.
30. Shichmanter R, Miller EB, Landau Z, Adverse drug reaction due to prolonged antibiotic therapy for malignant external otitis. Eur J Intern Med, 2004. 15: p. 441-445.
31. Moen MD, Lyseng-Williamson KA, Scott LJ, Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections. Drugs, 2009. 69: p. 361-392.
32. Knighton DR, Halliday B, Hunt TK, Oxygen as an antibiotic. A comparison of the effects of inspired oxygen concentration and antibiotic administration on in vivo bacterial clearance. Arch Surg, 1986. 121: p. 191-195.
33. Jefferson CD, Gates AG, Lerner C, Adjuvant Hyperbaric Oxygen in Malignant External Otitis. Arch Otolaryngol Head Neck Surg, 1992. 118: p. 89-93.
34. Phillips JS, Jones SEM, Hyperbaric oxygen as an adjuvant treatment for malignant otitis externa (Review). Cochrane Database Syst Rev 2013. 5: CD004617.

1. Chandler JR, Malignant external otitis. Laryngoscope, 1968. 78(8): p. 1257-1294.
2. Cohen D, Friedman P, The diagnostic criteria of malignant external otitis. J Laryngol Otol, 1987. 101: p. 216–21.
3. Hollis S, Evans K, Management of malignant (necrotizing) otitis externa. The Journal of Laryngology & Otology, 2011.125: p. 1212–1217.
4. Soudry E, Joshua BZ, Sulkes J, et al; Characteristics and prognosis of malignant external otitis with facial paralysis. Arch Otolaryngol Head Neck Surg, 2007.133: p. 1002-1004.
5. Rubin J, Yu VL, Malignant external otitis: insights into pathogenesis, clinical manifestations, diagnosis and therapy. Am J Med, 1988. 85: p. 391–398.
6. Ress BD, Luntz M, Telischi FF, et al; Necrotizing otitis externa in patients with AIDS. Laryngoscope, 1997.107: p. 456-460.
7. Yao M, Messner AH, Fungal malignant otitis externa due to Scedosporiumapiospemum. Ann Oto Laryngol, 2001.110: p. 377-380.
8. Carfrea MJ, Kesser BW, Malignant otitis externa. Otolaryngol Clin N Am, 2008. 41: p. 537-549.
9. Soudry E, Joshua BZ, Sulkes J, et al; Characteristics and prognosis of malignant external otitis with facial paralysis. Arch Otolaryngol Head Neck Surg, 2007. 133: p. 1002-1004.
10. Rubin J, Yu VL, Malignant external otitis: insights into pathogenesis, clinical manifestations, diagnosis and therapy. Am J Med, 1988. 85: p. 391–398.
11. Mahdyoun P, Pulcini C, Gahide I, et al; Necrotizing otitis externa: a systematic review. Otology &Neurotology, 2013. 34: p. 620-629.
12. Barrow HN, Levenson MJ, Necrotising “malignant” external otitis caused by Staphylococcal epidermidis. Arch Otolaryngol Head Neck Surg, 1992. 118: p. 94–96.
13. Bernstein J, Holland N, Porter G, et al; Resistance of pseudomonas to ciprofloxacin: implications for the treatment of malignant otitis externa. J Laryngol Otol2007. 121: p. 118-123.
14. Bayardelle P, Granger M, Larochelle D. Staphylococcal malignant external otitis. Can Med Assoc J 1982; 126:155-156.
15. Garcia Rodriguez JA, Montes Martinez I, Gómez González JL, et al. A case of malignant external otitis involving Klebsiellaoxytoca. Eur J ClinMicrobiol Infect Dis 1992; 11:75–77.
16. Barrow HN, Levenson MJ. Necrotising “malignant” external otitis caused by Staphylococcal epidermidis. Arch Otolaryngol Head Neck Surg 1992;118:94–96.
17. Bae W, Lee K, Park J, et-al. A case of malignant otitis externa caused by Candida glabrata in a patient receiving haemodialysis. Scand J Infect Dis;39:370-372.
18. Gruber M, Roitman A, Doweck I, et al. Clinical utility of a polymerase chain reaction assay in culture-negative necrotizing otitis externa. OtolNeurotol2015;36:733-736.
19. Peleg U, Perez R, Raveh D, et al. Startification for malignant otitis externa. Otolaryngol Head Neck Surg 2007; 137:301-305.
20. Joshua BZ, Sulkes J, Raveh E, Bishara J, Nageris BI. Predicting outcome of malignant external otitis. Otol Neurotol, 2008. 29: p. 339-343.
21. Okpala NC, Siraj QH, Nilssen E, Pringle M. Radiological and radionuclide investigation of malignant otitis externa. J Laryngol Otol, 2005. 119: p. 71-75.
22. Al-Noury K, Lotfy A, Computed tomography and magnetic resonance imaging before and after treatment of patients with malignant external otitis. Eur Arch Otorhinolaryngol, 2011. 268: p. 1727–1734.
23. Chen YH, Hsieh HJ, Single photon emission computed tomography/computed tomography for malignant otitis externa: lesion not shown on planar image. Am J Otolaryngol, 2013. 34: p. 169-171.
24. Grandis JR, Branstetter BF, Yu VL, The changing face of malignant (necrotizing) external otitis: clinical, radiological, and anatomic correlations. Lancet Infect Dis, 2004. 4: p. 34-39.
25. Karlowsky A, Jones M, Thornsberry C, et al; Stable antimicrobial susceptibility rates for clinical isolates of pseudomonas aeruginosa from the 2001– 2003 tracking resistance in the United States today surveillance studies. Clin Infect Dis, 2005. 40: p. 89–98.
26. Berenholz L, Katzenell U, Harell M. Evolving resistant pseudomonas to ciprofloxacin in malignant otitis externa. Laryngoscope, 2002. 112: p. 1619-1622.
27. Jones ME, Karlowsky JA, Draghi DC, et al; Antibiotic susceptibility of bacteria most commonly isolated from bone related infections: the role of cephalosporins in antimicrobial therapy. Int J Antimicrob Agents, 2004. 23: p. 240-246.
28. Jang CH, Park SY, Emergence of ciprofloxacin-resistant Pseudomonas in chronic suppurative otitis media. Clin Otolaryngol Allied Sci, 2004. 29: p. 321-323.
29. Loh S, Loh WS, Malignant Otitis Externa: An Asian Perspective on Treatment Outcomes and Prognostic Factors. Otolaryngol Head Neck Surg, 2012. 148: p. 991–996.
30. Shichmanter R, Miller EB, Landau Z, Adverse drug reaction due to prolonged antibiotic therapy for malignant external otitis. Eur J Intern Med, 2004. 15: p. 441-445.
31. Moen MD, Lyseng-Williamson KA, Scott LJ, Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections. Drugs, 2009. 69: p. 361-392.
32. Knighton DR, Halliday B, Hunt TK, Oxygen as an antibiotic. A comparison of the effects of inspired oxygen concentration and antibiotic administration on in vivo bacterial clearance. Arch Surg, 1986. 121: p. 191-195.
33. Jefferson CD, Gates AG, Lerner C, Adjuvant Hyperbaric Oxygen in Malignant External Otitis. Arch Otolaryngol Head Neck Surg, 1992. 118: p. 89-93.
34. Phillips JS, Jones SEM, Hyperbaric oxygen as an adjuvant treatment for malignant otitis externa (Review). Cochrane Database Syst Rev 2013. 5: CD004617.