Discussion

The aim of this systematic review was to summarise antimicrobial regimens used to manage necrotising otitis externa reported in published literature, and to identify most effective and safe antimicrobial regimens and strategies. Due to insufficient and heterogeneous variable reporting, the most efficacious and safe regimens could not be determined, and an accepted process for treatment cessation could not be identified.

Complete antimicrobial therapy details could not be identified due to underreporting of drug combinations, doses used and the reasons for these. Nevertheless, this review identified that fluoroquinolones were the most prescribed antimicrobial (68 per cent), with ciprofloxacin being most used. Most patients received dual therapy first line (57 per cent), and monotherapy second line (23 per cent).

Prior to the introduction of ciprofloxacin, patients with necrotising otitis externa traditionally were treated with in-patient intravenous dual therapy, consisting of an aminoglycoside and semisynthetic penicillin.^{Reference Berenholz, Katzenell and Harell16} Since the introduction of ciprofloxacin in the 1980s, patients have been treated largely with ciprofloxacin as a first-line choice.^{Reference Lang, Goshen, Kitzes-Cohen and Sadé43,Reference Sadé, Lang, Goshen and Kitzes-Cohen44} Increasingly, dual therapy with both ciprofloxacin and an additional antibiotic to cover ciprofloxacin-resistant strains of pseudomonas is chosen as a first-line treatment.^{Reference Berenholz, Katzenell and Harell16} Notably, Pulcini et al. reported better prognosis with dual therapy, in comparison to monotherapy.^{Reference Pulcini, Mahdyoun, Cua, Gahide, Castillo and Guevara48}

The incidence of ciprofloxacin-resistant strains of pseudomonas in aural swabs has remained stable at 7–20 per cent over the past two decades.^{Reference Linton and Stapleton6}

Regarding delivery method, most patients received intravenous (82 per cent) therapy first line, and oral (31 per cent) therapy second line. Treatment tended to be initiated in the in-patient setting (95 per cent) and continued in the out-patient setting (50 per cent). Since the introduction of ciprofloxacin, which has good oral bioavailability, increasing numbers of patients are managed in the out-patient setting.^{Reference Lang, Goshen, Kitzes-Cohen and Sadé43,Reference Sadé, Lang, Goshen and Kitzes-Cohen44} However, evidence to support decisions regarding intravenous versus oral treatment, or switch between the two, is lacking. There are no studies that directly compare the efficacy of oral and intravenous antibiotic treatment. Nevertheless, early studies report that in comparison to intravenous ciprofloxacin, oral ciprofloxacin is associated with fewer side effects.^{Reference Sadé, Lang, Goshen and Kitzes-Cohen44} Moreover, studies suggest that intravenous monotherapy produces comparable outcomes to co-administration of antipseudomonal penicillin and aminoglycoside antibiotics.^{Reference Sadé, Lang, Goshen and Kitzes-Cohen44,Reference Meyers, Mendelson, Parisier and Hirschman49} Future research could usefully focus on comparing monotherapy, dual therapy, and oral and intravenous antibiotic treatment through double-blind prospective clinical trials.

Necrotising otitis externa patients tend to be frail, immunosuppressed, and have medical co-morbidities.^{Reference Bisbinas and Stapleton1} Necrotising otitis externa patients also tend to receive prolonged parenteral antimicrobial treatment. It is therefore unsurprising that 95 per cent of studies in this review involved delivery of at least initial courses of treatment in an in-patient setting. Non-in-patient settings identified in this review were variable. In 45 per cent of studies, in-patient treatment was followed by treatment in the out-patient setting, and in one study (5 per cent), treatment was solely delivered in the out-patient setting.^{Reference Durojaiye, Slucka and Kritsotakis22} The latter assessed home-administered intravenous treatment, which was proposed as an alternative to in-patient treatment in resource-poor settings.

Out-patient antibiotic therapy studies for necrotising otitis externa are surprisingly limited, especially since this is a commonplace practice. Out-patient antibiotic therapy has been shown to be highly effective in the management of other infections.^{Reference Durojaiye, Bell, Andrews, Ntziora and Cartwright50} Failure of out-patient antibiotic therapy in necrotising otitis externa has been associated with extensive disease on imaging, facial-nerve involvement, and medical co-morbidities.^{Reference Durojaiye, Slucka and Kritsotakis22} Although the delivery of out-patient antibiotic therapy and home-based treatment could be limited by the need for training and education, they remain cost-effective options for the management of necrotising otitis externa.^{Reference Durojaiye, Bell, Andrews, Ntziora and Cartwright50}

Most included studies (50 per cent) initiated treatment on an empirical basis, and amended treatment based on microbiological culture results. Although this is the most popular approach, reporting of outcomes was not sufficiently robust to identify whether this approach was more efficacious or safe than other strategies. Notably, microbiological sampling techniques varied between studies and are discussed in several studies. Culture-negative cases of clinically and radiologically diagnosed necrotising otitis externa are well recognised,^{Reference Chaabouni, Achour, Yousfi, Thabet, Trigui and Kallel20} and may be explained by prior antibiotic use, fungal necrotising otitis externa or inadequate sampling technique.^{Reference Gruber, Roitman, Doweck, Uri, Shaked-Mishan and Kolop-Feldman51} In culture-negative and non-resolving cases, deep tissue sampling is increasingly being used^{Reference Rosenfeld, Schwartz, Cannon, Roland, Simon and Kumar52} to optimise antimicrobial therapy choices and strategies.

Mean antimicrobial treatment duration identified in this review was approximately nine weeks. A median could not be calculated due to limited and variable reporting of treatment duration between studies, reflecting the lack of consensus on optimal duration. Although some studies documented treatment duration, they did not provide explanations for treatment durations, or variations between these within their own patient cohort.

It would be ideal to identify optimal treatment duration, or criteria for treatment cessation, because extended courses of antimicrobials such as fluoroquinolones can be associated with complications. For example, prolonged use is associated with side effects such as tendon rupture and clostridium difficile infection,^{Reference Durojaiye, Slucka and Kritsotakis22} and may contribute to increased pseudomonal resistance.^{Reference Berenholz, Katzenell and Harell16,Reference Durojaiye, Slucka and Kritsotakis22} This is concerning because pseudomonas has intracellular efflux mechanisms that reduce antibiotic penetration, rendering it a challenge to eradicate.^{Reference Berenholz, Katzenell and Harell16} Although challenging to attribute specific antimicrobial regimens due to heterogeneous reporting, it is clear from this review that the side effects of antimicrobial therapy are common and can be serious.^{Reference Ijaz, Williams, Cole and Watson23}

Criteria for cessation of treatment were provided by 10 studies. These included variable combinations of disease resolution based on clinical symptoms and examination, imaging and inflammatory markers. Inflammatory markers must be used with caution in immunocompromised populations because they can be unreliable.^{Reference Pizzo53–Reference Moallemi, Niroomand, Tadayon, Forouzanfar and Fatemi55} Due to insufficient and heterogeneous variable reporting, an accepted process for treatment cessation could not be identified.

All-cause mortality was reported by 71 per cent of included studies, with a mean of 19 per cent, although follow-up periods varied. Disease-specific mortality was estimated as being five per cent across studies. These figures may be unreliable for several reasons, including inadequate reporting across studies, variability in patient follow-up duration and disease-specific mortality identification in a frail patient population with multiple co-morbidities.

Outcomes such as disease progression, relapse and readmission were reported variably between studies, rendering it impossible to compare outcomes or to pair outcomes with treatment strategies, either within or between studies. Furthermore, these terms were variably defined between studies, if indeed they were defined at all. One study reported that relapse is not associated with antibiotic treatment duration, but rather, complex disease.^{Reference Hodgson, Sinclair, Arwyn-Jones, Oh, Nucken and Perenyei24} Some studies reported that fungal infections and/or antibiotic-resistant organisms can contribute to advanced disease.^{Reference Le Clerc, Verillaud, Duet, Guichard, Herman and Kania9,Reference Hobson, Moy, Byers, Raz, Hirsch and McCall56} Other studies report no association between pathogens and outcomes.^{Reference Loh and Loh15,Reference Hobson, Moy, Byers, Raz, Hirsch and McCall56}