Topical azole treatments for otomycosis

Abstract

Background

Otomycosis is a fungal infection of the outer ear, which may be treated with topical antifungal medications. There are many types, with compounds belonging to the azole group ('azoles') being among the most widely used.

Objectives

To evaluate the benefits and harms of topical azole treatments for otomycosis.

Search methods

The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The search date was 11 November 2020.

Selection criteria

We included randomised controlled trials (RCTs) in adults and children with otomycosis comparing any topical azole antifungal with: placebo, no treatment, another type of topical azole or the same type of azole but applied in different forms. A minimum follow‐up of two weeks was required.

Data collection and analysis

We used standard Cochrane methods. Our primary outcomes were: 1) clinical resolution as measured by the proportion of participants with complete resolution at between two and four weeks after treatment (however defined by the authors of the studies) and 2) significant adverse events. Secondary outcomes were 3) mycological resolution and 4) other less serious adverse effects. We used GRADE to assess the certainty of evidence for each outcome.

Main results

We included four studies with 559 participants from Spain, Mexico and India. Three studies included children and adults; one included only adults. The duration of symptoms was not always explicitly stated. Mycological resolution results were only reported in one study. The studies assessed two comparisons: one type of topical azole versus another and the same azole but administered in different forms (cream versus solution).

A. Topical azoles versus placebo

None of the studies assessed this comparison.

B. Topical azoles versus no treatment

None of the studies assessed this comparison.

C. One type of topical azole versus another type of topical azole

i) Clotrimazole versus other types of azoles (eberconazole, fluconazole, miconazole)

Three studies examined clotrimazole versus other types of azoles. The evidence is very uncertain about the difference between clotrimazole and other types of azole in achieving complete clinical resolution at four weeks (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.59 to 1.07; 3 studies; 439 participants; very low‐certainty evidence). The anticipated absolute effects are 668 per 1000 for clotrimazole versus 835 per 1000 for other azoles.

One study planned a safety analysis and reported no significant adverse events in either group. The evidence is therefore very uncertain about any differences between clotrimazole and other types of azole (no events in either group; 1 study; 174 participants; very low‐certainty evidence).

Clotrimazole may result in little or no difference in mycological resolution at two weeks follow‐up (RR 1.01, 95% CI 0.96 to 1.06; 1 study; 174 participants; low‐certainty evidence) or in other (less serious) adverse events at two weeks follow‐up (36 per 1000, compared to 45 per 1000, RR 0.79, 95% CI 0.18 to 3.41; 1 study; 174 participants; very low‐certainty evidence).

ii) Bifonazole cream versus bifonazole solution

One study compared bifonazole 1% cream with solution. Bifonazole cream may have little or no effect on clinical resolution at two weeks follow‐up when compared to solution, but the evidence is very uncertain (RR 1.07, 95% CI 0.73 to 1.57; 1 study; 40 ears; very low‐certainty evidence). Bifonazole cream may achieve less mycological resolution compared to solution at two weeks after the end of therapy, but the evidence for this is also very uncertain (RR 0.53, 95% CI 0.29 to 0.96; 1 study; 40 ears; very low‐certainty evidence). Five out of 35 patients sustained severe itching and burning from the bifonazole solution but none with the bifonazole cream (very low‐certainty evidence).

Authors' conclusions

We found no studies that evaluated topical azoles compared to placebo or no treatment. The evidence is very uncertain about the effect of clotrimazole on clinical resolution of otomycosis, on significant adverse events or other (non‐serious) adverse events when compared with other topical azoles (eberconazole, fluconazole, miconazole). There may be little or no difference between clotrimazole and other azoles in terms of mycological resolution. It may be difficult to generalise these results because the range of ethnic backgrounds of the participants in the studies is limited.

Plain language summary

Do azole medicines taken as a cream or drops work for treating otomycosis (a fungal ear infection)?

Key messages

Due to weak evidence, we do not know if:

‐ azoles taken as a cream or drops are better than no treatment or a placebo (dummy) treatment;

‐ some azoles are better at ending infections than others.

There is a need for well‐conducted studies that investigate the risks and benefits of these treatments for otomycosis.

What is otomycosis?

Otomycosis is an ear infection caused by micro‐organisms called fungi (related to yeast and mushrooms). It mostly affects people who live in warm or tropical areas. Otomycosis typically causes an itchy ear, and can also cause ear pain, hearing loss and a fluid (discharge) that comes out of the ear.

Otomycosis can be treated with many different creams or drops that fight fungi and are applied to the ears (topical treatments). The most widely used of these come from a group of medicines called azoles.

What did we want to find out?

We wanted to find out about the risks and benefits of using topical azoles to treat otomycosis.

What did we do?

We searched for studies that compared topical azole treatment against:

‐ a placebo (dummy) treatment;

‐ no treatment; or

‐ other azole treatments.

We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found four studies that involved 559 people from Spain, Mexico and India. Three studies included children and adults, and one included only adults.

The studies compared:

‐ the topical azole 'clotrimazole' against a different topical azole (eberconazole, fluconazole or miconazole; three studies); and

‐ the topical azole 'bifonazole' as a cream against bifonazole drops (one study).

No studies compared topical azoles against a placebo or no treatment.

Clotrimazole compared against other topical azoles

The evidence suggests that, 24 days after the start of the treatment, there may be little to no difference between clotrimazole and other topical azoles in:

‐ the number of people whose ears were no longer infected with fungi;

‐ the number of severe adverse (unwanted) effects, such as severe allergic reactions;

‐ the number of non‐severe unwanted effects.

The evidence is not robust enough for us to determine if clotrimazole:

‐ is better than other topical azoles for ending otomycosis.

Bifonazole cream compared against bifonazole drops

The evidence is not robust enough for us to compare the benefits and risks of bifonazole cream against bifonazole drops.

What are the limitations of the evidence?

The main limitations of the evidence are that it relies on few studies that:

‐ sometimes have conflicting results;

‐ are conducted in a few countries only; and

‐ are conducted in ways that may have introduced errors into their results.

How up to date is this evidence?

The evidence is up to date to November 2020.

Summary of findings

Summary of findings 1. Clotrimazole compared to another azole for otomycosis.

Clotrimazole compared to another azole for otomycosis
Patient or population: patients with otomycosis Setting: ENT clinics Intervention: clotrimazole Comparison: another azole
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with another azole	Risk with clotrimazole
Complete clinical resolution Follow‐up: range 2 to 4 weeks	Study population		RR 0.80 (0.59 to 1.07)	439 (3 RCTs)	⊕⊝⊝⊝ very low1	It is very uncertain whether there is a difference between clotrimazole and other azoles at achieving complete clinical resolution at 4 weeks.
	835 per 1000	668 per 1000 (492 per 1000 to 893 per 1000)
Significant adverse events Follow‐up: 24 days	The only study that mentioned significant adverse events reported that there were no events in either group.			174 (1 RCT)	⊕⊝⊝⊝ very low2	Due to the lack of events and low number of participants it is very uncertain whether there is a difference between the groups.
Mycological resolution Follow‐up: 24 days	Study population		RR 1.01 (0.96 to 1.06)	174 (1 RCT)	⊕⊕⊝⊝ low3	Clotrimazole may result in little or no difference in mycological outcomes at 24‐day follow‐up.
	966 per 1000	976 per 1000 (928 to 1000)
Other adverse events Follow‐up: 24 days	Study population		RR 0.79 (0.18 to 3.41)	174 (1 RCT)	⊕⊝⊝⊝ verylow4	It is very uncertain whether there is a difference between clotrimazole and other azoles in non‐significant adverse events at 24 days follow‐up.
	45 per 1000	36 per 1000 (8 to 153)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

¹Downgraded to very low‐certainty evidence: downgraded by one level due to study limitations (risk of bias) because there was unclear allocation concealment, attrition bias and selective reporting bias. Downgraded by one level for inconsistency (heterogeneity of results; I² = 86%). Downgraded by one level for imprecision (confidence interval includes the possibility of both no difference and a substantial reduction in clinical resolution with clotrimazole).

²Downgraded to low‐certainty evidence. Downgraded by one level for indirectness (participants under 18 years old were excluded). Downgraded by two levels for imprecision (small sample size and no events reported, therefore unable to calculate an effect size).

³Downgraded to low‐certainty evidence. Downgraded by one level for indirectness (participants under 18 years old were excluded). Downgraded by one level for imprecision (small sample size).

⁴Downgraded to very low‐certainty evidence. Downgraded by one level for indirectness (participants under 18 years old were excluded). Downgraded by two levels for imprecision (low number of events, small sample size and very wide confidence intervals that include the possibility of either substantial benefit or substantial harm).

Background

Description of the condition

Otomycosis is a term used to describe a superficial fungal infection of the external ear canal. It has a reported worldwide incidence of between 5% and 80% (Gharaghani 2015; Munguia 2008). It is common in tropical countries and patients typically present with localised pruritis (itchiness) of the ear canal. Ear pain, hearing loss and discharge can also occur. Symptoms can be exacerbated if the ear canal skin is manipulated. Otomycosis is often seen in patients who have been treated for bacterial otitis externa with multiple course of topical antibiotic ear drops.

The prevalence of otomycosis amongst those with pre‐existing inflammatory conditions of the ear, such as eczema and psoriasis, ranges from 9% to 30.4% (Ho 2006; Kurnatowski 2001). It is seen in all age groups and amongst those who participate in aquatic sports. It is known to increase during the summer months (Rowlands 2001). More importantly, this disease has been linked to the extensive use of topical antibiotics for the treatment of otitis media and otitis externa (infection of the outer ear) (Munguia 2008). In a Nepalese cross‐sectional study the prevalence of otomycosis was reported to be 23%. Of the 440 patients studied with otorrhoea (ear discharge), otalgia (ear pain) and canal pruritis (itchiness of the ear canal), 100 showed positive fungal cultures (Pradhan 2003). Children with nutritional deficiency may be more susceptible to otomycosis (Enweani 1998).

Diagnosis of otomycosis is based on clinical grounds and should be suspected in patients with pruritic and/or discharging ear canals and fungal elements seen on otomicroscopy. However, while there are similarities in clinical presentation between otomycosis and acute otitis externa their treatments are different (Kaushik 2010). The prolonged usage of topical antibiotics alters the local flora of the ear canal leading to fungal proliferation and otomycosis. Patients with otomycosis often seek the advice of ENT specialists when their condition becomes unrelenting despite multiple courses of topical antibiotics. The role of the ENT specialist is to establish the correct diagnosis and prescribe the most appropriate treatment. This may include topical antifungals as well as suction clearance and dry mopping of debris. The recurrence rates of this disease vary according to the presence of the risk factors listed above.

Both environmental and host factors may predispose people to otomycosis (Kaushik 2010; Munguia 2008). Environmental factors include moisture (leading to skin maceration, elevation of ear canal pH and diminution of cerumen, which protects the ear canal), trauma to the ear canal and high ambient temperatures. Host factors include open and wet mastoid cavities, the presence of excessive cerumen, an immunocompromised state, pregnancy, hearing aids with an occlusive mould, secondary bacterial otitis externa, increased use of topical antibiotics and swimming in pools.

Many species of fungi have been identified as the cause of otomycosis. The two most common species are Aspergillus niger and Candida albicans. Controversy exists regarding the importance of identifying the causal agent(s) prior to treatment. While some clinicians believe it is good practice to use the appropriate treatment based on swab results to establish the sensitivity to antifungal agents (Bassiouny 1986), others advocate empirical treatment without testing for sensitivity (Blyth 2007).

In patients who are immunocompromised, an invasive and life‐threatening form of fungal infection may develop, known as skull base osteomyelitis or malignant otitis externa (Blyth 2011). This results in destruction of the underlying bone of the external ear canal and spreads along the skull base to involve the lower cranial nerves. Symptoms may include intense ear pain, persistent discharge, facial palsy, deafness, hoarseness and dysphagia. This condition should be distinguished from otomycosis and is not the focus of this review.

Description of the intervention

There are at least six main classes of drugs for the treatment of fungal infections: azoles, polyenes, nucleoside analogues, echinocandins, antiseptics and hydroxyquinolines (Table 2). In this review we focus on topical azoles due to their wide availability, low risk of ototoxicity and low rates of antifungal drug resistance. Examples include bifonazole, clotrimazole, eberconazole, fluconazole and miconazole. Clotrimazole is the most widely used topical azole. It can be dispensed as a 1% lotion or a topical cream, with the duration of treatment ranging from a few days to four weeks. Side effects are often localised and limited to skin redness and burning. Clotrimazole has a reported rate of effectiveness in otomycosis that ranges from 50% to 100% (Jackman 2005; Jadhav 2003). Topical azoles can also be used in cases of perforated ear drums (Vennewald 2010).

1. Classes of agents used to treat fungal infections.

Class of antifungals	Examples	Mechanism of action
Azoles	Bifonazole, clotrimazole, eberconazole, fluconazole, miconazole	Inhibits the synthesis of ergosterol
Polyenes	Nystatin, amphotericin B	Interacts with fungal membrane sterols
Nucleoside analogues	Flucytosine	Inhibits macromolecular synthesis
Echinocandins	Caspofungin, micafungin, anidulafungin	Inhibits fungal cell wall synthesis
Antiseptics	Boric acid, gentian violet	Variable
Hydroxyquinolines	Clioquinol (in Locacorten‐Vioform)	Inhibits fungal cell wall synthesis

From Munguia 2008.

During treatment for otomycosis it is also common practice to remove the debris from the ear canal. This is known as aural toileting and it is administered with microsuction or dry mopping just prior to application of the topical remedy. It is considered to be standard therapy in most ENT outpatient clinics and an important adjunctive treatment (Mofatteh 2018). In this review we planned to explore the effects of aural toileting in subgroup analysis.

How the intervention might work

Azole antifungal drugs (with the exception of abafungin) inhibit the enzyme lanosterol 14 α‐demethylase, which is the enzyme necessary to convert lanosterol to ergosterol. Depletion of ergosterol in the fungal membrane disrupts the structure and many of its functions leading to inhibition of fungal growth (Sheehan 1999). It has been shown to have a potent in vitro broad‐spectrum fungicidal activity including against Aspergillus and Candida species, which are common agents in otomycosis (Stern 1988).

Although there is no general consensus as to the duration of topical azole therapy, two weeks appears to be common (Khan 2013).

Why it is important to do this review

Otomycosis is a common condition with a significant health and financial burden. An intervention found to be effective based on good evidence could have an impact globally. Although many treatment options are available clinicians continue to struggle with the most appropriate treatment option (Munguia 2008). Evidence from Denmark has shown that there is wide variation in how this condition is treated by ENT consultants (Arndal 2016). Many cohort studies have been published that investigate the usage of clotrimazole in otomycosis, the majority of which have found it to be safe and effective (Hamza 2011; Khan 2013).

A Cochrane Review has examined a number of interventions for otitis externa but its focus was on bacterial infections of the ear canal and not otomycosis specifically (Kaushik 2010). A set of guidelines published by the Infectious Disease Society of America has examined the treatment of aspergillosis, but this is a condition that is prevalent amongst the immunocompromised population and is most often disseminated with a high risk of morbidity and mortality, which is vastly different to otomycosis (Walsh 2008). A recent systematic review compared the efficacy of clotrimazole versus flumethasone pivalate 0.02% and clioquinol 1% (Locacorten‐Vioform) for otomycosis and concluded that there was insufficient evidence to support either therapy (Herasym 2016).

It is important that an effective treatment is found for otomycosis due to its worldwide prevalence and the accompanying disease burden. A few randomised controlled trials have been conducted, however performing a meta‐analysis may be difficult because the interventions assessed vary in each study. We are aware of studies that have compared clotrimazole with 3% boric acid, with an experimental compound known as G328 and with eberconazole (Cota 2018; de la Paz Cota 2018; NCT01547221).

Topical azoles are widely available on prescription in many countries and they are thought to be well tolerated with few side effects (Bassiouny 1986). A systematic review of the current evidence to assess their effects in the treatment of otomycosis is therefore warranted.

Objectives

To evaluate the benefits and harms of topical azole treatments for otomycosis.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) with a minimum follow‐up duration of two weeks from the start of treatment.

We excluded the following study designs:

• Cross‐over studies (because uncomplicated otomycosis is a self‐limiting condition). Furthermore, it is anticipated that the carry‐over effect of clotrimazole treatment may be prolonged as this drug is typically administered for over two weeks.

Types of participants

We included participants of all ages with a diagnosis of otomycosis.

We included studies that diagnosed otomycosis based on presentation, with symptoms including: ear pain, itchiness, discharge, fullness or hearing impairment with findings of ear discharge. Studies should describe the mycological criteria for confirmation using either direct microscopy or culture showing fungal spores or hyphae.

We excluded studies that focused primarily on otitis externa and those with skull base osteomyelitis (also known as malignant otitis externa). For studies with a mixed group of participants (consisting of otitis externa and otomycosis), we planned to analyse them providing that they had more than 80% of patients with otomycosis.

Types of interventions

Intervention

Topical azole antifungals. We did not set a limit on the dose, duration or frequency of administration.

Control

Placebo, no intervention or another type of topical azole.

Adjunctive treatment

Aural toileting is considered routine in the treatment of discharging ears in an outpatient clinic. It may consist of dry mopping, syringing or microsuction (hoovering).

We planned the following main comparisons:

• topical azoles versus placebo;

• topical azoles versus no treatment;

• one type of topical azole versus another type of topical azole.

We planned to include studies using aural toileting if this adjunctive treatment was administered equally in both the intervention and comparator groups.

We excluded other agents used for treating otomycosis as a comparison as we expected that the majority of these studies would have used a heterogeneous mixture of agents and concentrations. Pooling of data under these circumstances would be problematic.

We recorded details of the interventions including treatment concentration, mode of administration (cream, drops, powder), dose (mg, mL or other) and number of administrations per day.

Types of outcome measures

We analysed the following outcomes, but did not use them as a basis for including or excluding studies.

Primary outcomes

• Clinical resolution as measured by the proportion of participants with complete resolution at between two and four weeks after treatment (however defined by the authors of the studies).

• Significant adverse events (e.g. severe topical allergic reaction).

Secondary outcomes

• Mycological resolution: eradication of pathogenic ear canal fungi as determined by mycological means (e.g. potassium hydroxide smear or fungal culture).

• Other adverse events: local irritation, hearing loss, mild allergic reaction.

For all outcomes other than clinical resolution, the time point for assessment was final follow‐up, as defined by the study authors.

Search methods for identification of studies

The Cochrane ENT Information Specialist conducted systematic searches for randomised controlled trials and controlled clinical trials. There were no language, publication year or publication status restrictions. The date of the search was 11 November 2020.

Electronic searches

The Information Specialist searched for published, unpublished and ongoing studies in the following databases from their inception:

• the Cochrane ENT Register (searched via CRS Web 11 November 2020);

• the Cochrane Central Register of Controlled Trials (CENTRAL) (searched via the Cochrane Register of Studies 11 November 2020);

• Ovid MEDLINE(R) Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) (1946 to 11 November 2020);

• Ovid EMBASE (1974 to 11 November 2020);

• LILACS (Latin American and Caribbean Health Science Information database), lilacs.bversusalud.org (searched 11 November 2020);

• Web of Science (1945 to 11 November 2020);

• CNKI (searched via Google Scholar 1999 to 11 November 2020);

• ClinicalTrials.gov (searched via the Cochrane Register of Studies and www.clinicaltrials.gov (searched 11 November 2020);

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), www.who.int/ictrp (searched 11 November 2020).

The Information Specialist modelled subject strategies for databases on the search strategy designed for CENTRAL. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Handbook 2011). Search strategies for major databases including CENTRAL are provided in Appendix 1.

Searching other resources

We scanned the reference lists of identified publications for additional trials and contacted trial authors where necessary. In addition, the Information Specialist searched Ovid MEDLINE to retrieve existing systematic reviews relevant to this systematic review, so that we could scan their reference lists for additional trials. The Information Specialist also ran non‐systematic searches of Google Scholar to retrieve grey literature and other sources of potential trials.

We did not perform a separate search for adverse effects. We only considered those adverse effects described in the included studies.

We attempted to contact original authors for clarification and further data if trial reports were unclear and we arranged translation of papers when needed.

Data collection and analysis

Selection of studies

Two independent review authors (AL and JT) assessed all titles and abstracts from the search and eliminated studies that clearly did not satisfy the inclusion criteria. For studies that appear to meet the inclusion criteria we obtained the full‐text reports to confirm eligibility. We resolved any differences by discussion and consensus, with the involvement of the third author for clinical and methodological input when necessary. We listed the reasons for exclusion in the Characteristics of excluded studies table. A study flow diagram (PRISMA) was provided to illustrate the process for selection of studies (Handbook 2011).

Data extraction and management

AL and JT independently extracted data from each study report using specifically designed data extraction forms. We checked any discrepancies in the data extracted against the original reports and resolve any differences by consensus. We contacted the original study authors for clarification or missing data whenever possible.

We recorded the following data from each of the included studies: general characteristics (type of study, year of study, citation data, number of patients included and their baseline characteristics and risk factors), potential sources of bias, fungal types, procedures (type of randomisation, inclusion criteria, protocol for follow‐up and assessment, protocol for therapy and control, and number of patients who dropped out of the study), outcome data (definitions, clinical signs and symptoms, adverse events, microbiological data) and authors' conclusions. If information or data were missing, we attempted to contact the study authors.

Where possible we extracted data to allow an intention‐to‐treat analysis (i.e. the analysis should include all the participants in the groups to which they were randomly assigned irrespective of compliance or whether patients had received the treatment as planned).

For clinical resolution we reported the results between two and four weeks after completion of the interventions. For all other outcomes the time point of assessment was final follow‐up as defined by the study authors.

In addition to extracting pre‐specified information about study characteristics and aspects of methodology relevant to risk of bias, we extracted the following summary statistics for each trial and each outcome:

• For binary data: the number of participants experiencing an event and the number of patients assessed at the time point.

• For ordinal scale data: we planned to analyse data which appeared to be approximately normally distributed as continuous data or if the analysis that the investigators performed suggests parametric tests were appropriate. However, none of the included studies recorded any outcomes as continuous data.

As regards extraction of data for adverse events, there were variations in how studies had reported these. For instance, one study made a distinction between 'otalgia' and 'ear discomfort' whilst another reported 'itching' and 'burning' as a combined outcome. Prior to the start of data extraction we had agreed to divide adverse events into significant ones including severe topical allergic reactions from 'others' such as local irritation, hearing loss or mild allergic reactions. We extracted data for significant complications as a composite outcome. If a study reported more than one complication and we could not distinguish whether these occurred in one or more participants we extracted data with the highest incidence to ensure that we did not provide an unduly conservative estimate of the complication rate.

Assessment of risk of bias in included studies

AL and TJ independently undertook assessment of the risk of bias of the included trials as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011) for the following domains:

• sequence generation;

• allocation concealment;

• blinding of participants and personnel;

• blinding of outcome assessment;

• incomplete outcome data;

• selective outcome reporting; and

• other sources of bias.

We used the Cochrane 'Risk of bias' tool in RevMan 5.4 (RevMan 2014), which involves describing each of these domains as reported in the trial and then assigning a judgement about the adequacy of each entry: low, high or unclear risk of bias. We provided evidence to support our assessments in 'Risk of bias' tables.

Measures of treatment effect

We summarised the effects of dichotomous outcomes (e.g. proportion of patients with clinical or mycological resolution) as risk ratios (RR) with confidence intervals (CIs). For each of the key outcomes that we presented in the 'Summary of findings' table, we also expressed the results as corresponding risk based on the pooled results and compared to the assumed risk as risk ratios with CIs. The assumed baseline risk was the average mean risk of the control groups in the included studies used as the 'study population' (Handbook 2011).

Unit of analysis issues

The unit of randomisation was the individual participant. However, there was one included study that compared two different modes of azole application as opposed to two different formulations. In that study the unit of randomisation was the ear (35 participants, 40 ears). We were unable to identify the specific response for individuals with bilateral disease, therefore we could not estimate the correlation in response between ears. However, as the number of participants with bilateral disease was relatively low, we presented the results as if there were no correlation between ears of the same individual. This will result in narrower confidence intervals than would be the case if appropriate adjustment for correlation could be accounted. In the study concerned, five out of 35 patients had bilateral disease of which two of the patients received the same treatment in both ears whereas the remainder were treated with an azole solution in one side and an azole cream on the other side. We did not include the data in our meta‐analysis.

We analysed multiple‐intervention studies according to the guidance in the Cochrane Handbook for Systematic Reviews of Interventions, including all relevant groups and avoiding double‐counting of participants (Handbook 2011).

Dealing with missing data

We attempted to contact study authors via email whenever the outcome of interest was not reported, or if the methods of the study suggested that the outcome had been measured. We had planned to impute missing standard deviations from 95% CIs, but this was not necessary as none of our included studies reported any continuous outcomes.

Assessment of heterogeneity

We assessed statistical heterogeneity by visually inspecting the forest plots in conjunction with the Chi² test, using a 5% level of statistical significance, and the I² statistic. The I² statistic describes the percentage of variability in effect estimates that is due to heterogeneity rather than sampling error (chance). A value greater than 50% usually suggests substantial heterogeneity (Handbook 2011).

Assessment of reporting biases

We intended to create funnel plots if we were able to include sufficient studies (more than 10) for an outcome. In the event that asymmetry was observed, we would have conducted a more formal investigation. However, we included too few studies to construct a funnel plot.

Data synthesis

AL entered data into Review Manager 5.3 (RevMan 2014).

If we found sufficient studies, we planned to undertake a quantitative analysis and present the data in forest plots. We planned to pool studies in a meta‐analysis using a fixed‐effect model if possible, or a random‐effects model if we found substantial clinical or methodological heterogeneity in the included studies or identified substantial statistical heterogeneity (Handbook 2011).

We anticipated that trialists would usually have determined their outcome measures on more than one occasion. In general, these assessment visits would fall into the following categories: early (e.g. half‐way through treatment), end‐of‐therapy (a day or so after the cessation of treatment), test‐of‐cure (around a week after treatment) or test‐of‐recurrence (a few weeks after treatment has finished). Trialists may vary in the number and timing of visits they choose. In order to make a fair comparison between trials it is important to compare outcome measures taken at similar times. We had therefore decided a priori that we would only perform pooling of data from different studies (meta‐analysis) for outcome measures taken at similar times.

We carried out all analyses using Review Manager 5.3 (RevMan 2014). For dichotomous data, we analysed treatment differences as risk ratio (RR) calculated using the Mantel‐Haenszel method. We planned to analyse time‐to‐event data using the generic inverse variance method, but this was not required as we had no data of this type. For continuous outcomes, if all the data were from the same scale, we would have pooled mean values obtained at follow‐up with change outcomes and reported this as a mean difference. However, if the standardised mean difference had to be used as an effect measurement, we did not plan to pool change and endpoint data. In the event, we did not undertake any meta‐analysis of continuous outcomes as none of the selected studies reported this type of outcome.

Subgroup analysis and investigation of heterogeneity

We had planned to explore the effects of aural toileting as an adjunctive treatment in subgroup analysis. However, this was not possible due to the low number of studies. We were also unable to distinguish participants based on the frequency of aural toileting as they all received this manoeuvre only once prior to the commencement of their study.

We did not intend to perform subgroup analyses based on dosage because azole antifungals are topical medications applied over a very small surface area with similar mechanisms of action. Hence, we do not believe that this variation is clinically important. We also planned to consider the methodology and frequency of aural toileting (dry mopping) if there was remaining unexplained heterogeneity despite conducting the other subgroup analyses.

Sensitivity analysis

We planned to carry out sensitivity analysis for the follow factors to determine whether the findings were robust to the decisions made in the course of identifying, screening and analysing the trials:

• risk of bias of included studies: excluding studies with high risk of bias, defined as a high risk of allocation concealment bias and a high risk of attrition bias (overall loss to follow‐up of over 20%);

• how outcomes were measured: we planned to investigate the impact of including data when the validity of the measurement was unclear. Unfortunately, none of the included studies appeared to use valid measurement tools, so we were not able to carry out this sensitivity analysis.

If any of these investigations found a difference in the size of the effect or heterogeneity, we would have mentioned this in the Effects of interventions section.

Summary of findings and assessment of the certainty of the evidence

Using the GRADE approach, two review authors (AL and JT) independently rated the overall certainty of evidence using the Guideline Development Tool (GDT) (www.guidelinedevelopment.org). We had planned to do this for the following comparisons:

• topical azoles versus placebo;

• topical azoles versus no treatment;

• one type of topical azole versus another type of topical azole.

In the event, we only had data to present a 'Summary of findings' table for the comparison of clotrimazole versus another type of azole.

The certainty of evidence reflects the extent to which we are confident that an estimate of effect is correct and we applied this in the interpretation of results. There were four possible ratings: high, moderate, low and very low (Handbook 2011). A rating of high certainty of evidence implies that we are confident in our estimate of effect and that further research is very unlikely to change our confidence in the estimate of effect. A rating of very low certainty implies that any estimate of effect obtained is very uncertain.

The GRADE approach rates evidence from RCTs that do not have serious limitations as high certainty. However, several factors can lead to the downgrading of the evidence to moderate, low or very low. The degree of downgrading is determined by the seriousness of these factors:

• study limitations (risk of bias);

• inconsistency;

• indirectness of evidence;

• imprecision; and

• publication bias.

The outcomes selected for GRADE assessment were: clinical resolution as measured by the proportion of participants with complete resolution, significant adverse events (severe topical allergic reaction), mycological resolution and other adverse effects (local irritation, hearing loss, mild allergic reaction).

Results

Description of studies

Results of the search

The search retrieved a total of 913 references. This number was reduced to 609 after removal of duplicates. We screened the titles and abstracts and subsequently removed 574 references. We assessed 35 full texts for eligibility of which 21 records (20 studies) were discarded with reasons recorded in the review (Excluded studies). There are four studies awaiting assessment, as we were unable to obtain the full text (Characteristics of studies awaiting classification). We identified four ongoing studies (five references).

A flowchart of study retrieval and selection is provided in Figure 1.

1.

Process for sifting search results and selecting studies for inclusion.

We also ran another search to identify any new systematic reviews and guidelines relating to our topic so their reference lists could be scanned for additional trials and referenced in this review, however this search came back empty.

Included studies

We included four studies (del Palacio 1993; de la Paz Cota 2018; Navaneethan 2014; Prabhakaran 2018). The Characteristics of included studies table provides their further details.

Study design

Three studies were randomised, parallel‐group, two‐arm trials (del Palacio 1993; de la Paz Cota 2018; Prabhakaran 2018). One study was a randomised, parallel‐group, three‐arm trial (Navaneethan 2014).

Unit of randomisation

There were no cluster‐randomised trials. del Palacio 1993 randomised participants by ear. However, it was explicitly stated that two of the patients with bilateral otomycosis were treated with bifonazole cream in both ears and the other three patients with bifonazole solution in one side and cream in the other. For the reasons stated in the Methods section we did not include this study in our meta‐analysis but a narrative report is provided.

Sample size

A total of 559 participants were recruited in the four studies. The breakdown is as follows: del Palacio 1993 (35); de la Paz Cota 2018 (190); Navaneethan 2014 (214); Prabhakaran 2018 (120).

Location

Two studies were conducted in India (Navaneethan 2014; Prabhakaran 2018). One study was conducted in Mexico (de la Paz Cota 2018) and the remaining study in Spain (del Palacio 1993).

Setting

All studies were conducted in the ENT departments of hospitals. However, it is not clear if they were done in secondary or tertiary care centres. One study was conducted across nine centres (de la Paz Cota 2018).

Population

Age and sex

The ages of participants are reported in the Characteristics of included studies table. One study excluded participants less than 18 years old (de la Paz Cota 2018). No study showed evidence of randomisation by age. All four studies included both males and females and the percentages of females ranged from 50% to 66%.

Diagnosis

Otomycosis was the main diagnosis in all studies. This was diagnosed clinically with or without mycological confirmation.

Interventions

Details of the interventions and treatment durations together with any adjuvant treatment for each of the included studies are summarised in the Characteristics of included studies table. The treatment duration lasted between 7 and 21 days. One study did not explicitly state the duration of treatment for some of their interventional drugs but it appeared that treatment did not extend beyond two weeks (Navaneethan 2014).

Comparisons

The included studies all presented data for one comparison: one type of topical azole versus another type of topical azole. One study used the same azole in different formulations (del Palacio 1993), and the other three studies compared clotrimazole against various types of azoles (de la Paz Cota 2018; Navaneethan 2014; Prabhakaran 2018).

Outcomes

Clinical resolution

All four studies reported clinical resolution as an outcome although there are significant variations in their definitions, methods of determination and timing of assessments.

Significant adverse events

One study reported this outcome, in a qualitative manner (del Palacio 1993).

Mycological resolution

Two studies reported this outcome although the definitions and the timing of performing myological cultures differed (de la Paz Cota 2018; del Palacio 1993). Two studies performed mycological confirmation at the start of the study but it was not repeated at follow‐up (Navaneethan 2014; Prabhakaran 2018).

Other adverse events (local irritation, hearing loss, mild allergic reaction)

del Palacio 1993 reported this outcome in a qualitative manner. de la Paz Cota 2018 recorded their adverse events according to the preferred term and system organ class of the Medical Dictionary for Regulatory Activities (version 17.1) (MedDRA). None of the adverse events recorded in their study was significant.

Funding

One paper was funded by a grant from a pharmaceutical company: de la Paz Cota 2018 had their research supported by Laboratorios Salvat A.S.

The other three studies did not provide information regarding funding. del Palacio 1993 acknowledged Bayer A.G. for supplying the medication for their study.

Excluded studies

We excluded 20 studies after further review. We asked translators fluent in Russian and Mandarin, affiliated with Cochrane, to assist in the translation of studies that were published in their respective languages. Further details for the reasons for exclusion can be found in the Characteristics of excluded studies table. Their main reasons for exclusion were as follows (some studies have more than one reason to account for their exclusion):

• Not RCTs: Albano 1966; Carrat 2001; Cojocaru 1970; Khamaganova 2010; Pal'chun 2012; Wei 2018.

• Comparisons were non‐azoles: Beck 1969; Berjis 2012; Boncalon 2009; del Palacio 2002; Diaz‐Pavon 2018; Gordana 2007; Jimenez‐Garcia 2019; Joiemon 2006; Malik 2012; Mofatteh 2017; Nunez Navarrete 2000; Pal'chun 2012; Romsaithong 2016; Zhang 2010.

• Unable to procure full texts for review: Bambule 1978; Ben Rejeb 1984; Hu 2007; Ren 2015.

• Intervention was suction clearance and azoles were used in both groups: Rafique 2014.

Ongoing studies

Four studies were ongoing at the time of writing this review. We made multiple attempts to contact some of the study authors to obtain further information, however we did not receive any responses. Some details of these studies can be found in the Characteristics of ongoing studies table.

Risk of bias in included studies

Please refer to Figure 2 for a 'Risk of bias' graph (our judgements about each risk of bias item presented as percentages across all included studies) and Figure 3 for a 'Risk of bias' summary (our judgements about each risk of bias item for each included study).

2.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Random sequence generation

We judged all studies to be of unclear risk of bias (del Palacio 1993; de la Paz Cota 2018; Navaneethan 2014; Prabhakaran 2018). Although all of them mentioned that their studies were randomised none provided clear information about how their random sequences were generated. Navaneethan 2014 used a trained nursing assistant to group the patients randomly and Prabhakaran 2018 used random number tables with the division of patients based on odd versus even number lots. de la Paz Cota 2018 used random permuted blocks with a block size of four without providing details of how the results were applied. None of the studies showed a significant imbalance between the treatment and comparison groups.

Allocation concealment

We judged two studies to be at high risk of allocation concealment bias as neither of these studies described concealment of the allocation sequence (del Palacio 1993; Navaneethan 2014). We assessed Prabhakaran 2018 as being at unclear risk. This study did not describe the methods of allocation concealment. However, the similarity in the consistency and viscosity of the two drugs were likely to facilitate this process in an indirect way.

We judged de la Paz Cota 2018 as being at low risk of allocation concealment bias as the authors explicitly stated that the sponsor, participants, investigators and study personnel were blinded to treatment allocation.

Blinding

Performance bias

We determined one study to be at high risk of performance bias. del Palacio 1993 did not mention blinding and thus it can be assumed to be an open study. In addition, the treatment was given either as bifonazole cream or a solution, which would make blinding difficult to achieve.

We determined two studies to be at unclear risk of bias. Navaneethan 2014 made some effort to blind the participants and investigators and a trained nursing assistant was utilised to ensure blinding was carried out, but the clotrimazole and fluconazole were administered as solutions and miconazole was given as a cream with different consistency. Blinding under these circumstances would not be effective. Prabhakaran 2018 did not provide information on how they kept participants and their assessors blinded from the allocated treatments.

de la Paz Cota 2018 was deemed to be at low risk of bias as it explicitly stated that the sponsor, participants, investigators and study personnel were blinded to treatment allocation.

Detection bias

Similar to performance bias, we assessed one study to be at high risk (del Palacio 1993), two studies to be at unclear risk (Navaneethan 2014; Prabhakaran 2018) and one study to be at low risk of detection bias (de la Paz Cota 2018).

Incomplete outcome data

We deemed one study to be at high risk of attrition bias: Navaneethan 2014 reported that 145 out of 214 enrolled in their study presented for their assessment at the end of the second week. The percentage of loss to follow‐up was 32%.

We assessed the other three studies to be at low risk of attrition bias. Their loss to follow‐up rates were as follows:

• de la Paz Cota 2018: 12%;

• del Palacio 1993: 10%;

• Prabhakaran 2018: 0%.

In particular, de la Paz Cota 2018 stated that patient request was the most common reason for discontinuation in both treatment arms.

Selective reporting

None of the studies had protocols identified through our searches of clinical trial registries.

We assessed two studies to be at high risk of bias. Navaneethan 2014 provided no information on the outcome of the 19 patients who did not return for follow‐up. Furthermore, some rudimentary mycological data were presented for the first follow‐up period even though the protocol did not mention that this was to be presented. Prabhakaran 2018 stated in their protocol that all patients were reviewed weekly for reduction in symptoms and signs. However, no follow‐up data on symptoms (and mycology) were presented. Both studies used assessment scales that were non‐standardised and open to subjective interpretation.

One study was assessed as being at unclear risk of bias. del Palacio 1993 did not provide definition as to what the outcomes constituted or how they were measured. However, all outcomes stated in the methodology section were reported. There were no statistics or P values reported.

We assessed de la Paz Cota 2018 to be at low risk of bias as the outcomes that were presented in their methods sections were well reported in the results section.

Other potential sources of bias

Measurement bias

We assessed all four studies to be at unclear risk of measurement bias as they all used different Likert‐type scales without mentioning whether they had undergone statistical validation for internal consistency and test‐retest reliability. The study by de la Paz Cota 2018 used a four‐point signs and symptoms scale with a global score obtained from the sum of each individual score for pruritis, otalgia, otorrhoea and aural fullness. del Palacio 1993 used a similar scale for a variety of clinical parameters. Navaneethan 2014 employed clinical examination and graded the responses as good, moderate and no response. Prabhakaran 2018 also used clinical examination (the detection of debris on microscopy) as the main factor to determine the response to treatment.

Funding

de la Paz Cota 2018 stated that "this work was supported by Laboratorios Salvat, S.A." The other three studies did not provide information on funding.

Declarations of interest

de la Paz Cota 2018 declared that the authors had no conflicts of interest, whilst the other three studies did not make any statement about interests.

Effects of interventions

See: Table 1

Topical azoles versus placebo

None of the included studies assessed this comparison.

Topical azoles versus no treatment

None of the included studies assessed this comparison.

One type of topical azole versus another type of topical azole

1) Clotrimazole versus other azoles

We included three studies (524 participants) in this comparison. See Table 1.

• de la Paz Cota 2018 compared clotrimazole with eberconazole.

• Navaneethan 2014 compared clotrimazole, miconazole and fluconazole (three‐arm trial).

• Prabhakaran 2018 compared clotrimazole with fluconazole.

Primary outcomes

Complete clinical resolution between two and four weeks after treatment

de la Paz Cota 2018 reported that slightly fewer participants receiving clotrimazole achieved clinical cure compared with eberconazole (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.82 to 1.12).

Navaneethan 2014 reported that fewer patients achieved clinical cure with clotrimazole drops compared to miconazole and fluconazole (RR 0.93, 95% CI 0.79 to 1.09).

Prabhakaran 2018 reported that fewer patients achieved clinical cure with clotrimazole drops compared to fluconazole drops (RR 0.50 95% CI 0.35 to 0.71).

We pooled the results of these studies in a meta‐analysis for this outcome (RR 0.80, 95% CI 0.59 to 1.07; 3 studies; 439 participants; I² = 86%; very low‐certainty evidence). It is very uncertain whether there is a difference between clotrimazole and other azoles at achieving complete clinical resolution at four weeks.

Significant adverse events

de la Paz Cota 2018 (n = 190) reported that there were no serious adverse events in either treatment group. Due to the low number of participants and events it is very uncertain whether there is a difference between the groups (very low‐certainty evidence).

Secondary outcomes

Mycological resolution

de la Paz Cota 2018 (n = 190) reported this outcome. The evidence suggests that clotrimazole results in little to no difference in mycological resolution at 24‐day follow‐up (RR 1.01, 95% CI 0.96 to 1.06; 1 study; 190 participants; low‐certainty evidence).

Other adverse events

de la Paz Cota 2018 (n = 190) reported this outcome. The evidence suggests that clotrimazole results in little to no difference in non‐significant adverse events (RR 0.79, 95% CI 0.18 to 3.41; 1 study; 190 participants; very low‐certainty evidence). The absolute effect was 9 fewer per 1000 (from 37 fewer to 108 more per 1000).

Subgroup analyses

No subgroup analyses were possible for this comparison:

• Aural toileting: all studies included aural toileting as a pre‐treatment.

2) One mode of application versus another mode of application of topical azole

One study compared different formulations of bifonazole as opposed to another type of azole (del Palacio 1993). We did not include this study in our main comparison meta‐analysis for two reasons. First, we feel that comparing different formulations of the same azole is not the same as comparing one type of azole with another. Hence its inclusion would constitute a protocol violation. Secondly, the unit of randomisation in this study was the ear rather than the participant and we were unable to account appropriately for the correlation between ears amongst the participants with bilateral disease. Nevertheless we believe it is appropriate to include this study in our review since it is clinically relevant to compare the clinical efficacy of different formulations of the same drug in treating otomycosis (see Differences between protocol and review).

Primary outcomes

Complete clinical resolution between two to four weeks after treatment

The evidence suggests that bifonazole cream results in little to no difference in clinical resolution at two weeks after the end of therapy: 15/20 bifonazole cream (intervention); 14/20 bifonazole solution (comparator) (RR 1.07, 95% CI 0.73 to 1.57; very low‐certainty evidence).

Significant adverse events

Five out of 35 patients sustained severe itching and burning from the bifonazole solution but none with the bifonazole cream: 5/20 ears in the solution group compared to 0/20 ears in the cream group (very low‐certainty evidence).

Secondary outcomes

Mycological resolution

Bifonazole cream achieved less mycological resolution compared to bifonazole solution at two weeks after the end of therapy: 8/20 bifonazole cream; 15/20 bifonazole solution (RR 0.53, 95% CI 0.29 to 0.96, very low‐certainty evidence).

Other adverse events

Twelve out of 35 patients (34%) sustained moderate itching and burning with bifonazole solution. No participants reported irritation with bifonazole cream on their treated side.

Discussion

Summary of main results

We included four studies in this review (de la Paz Cota 2018; del Palacio 1993; Navaneethan 2014; Prabhakaran 2018). All of these studies included patients with otomycosis as the main diagnosis. Due to the limited number of studies and the incomplete reporting of some outcomes we were unable to accumulate strong evidence for our comparisons. The reporting of adverse events was sub‐optimal, with only de la Paz Cota 2018 using standardised methods in some of their reporting.

Topical azoles versus placebo

None of the included studies assessed this comparison.

Topical azoles versus no treatment

None of the included studies assessed this comparison.

One type of topical azole versus another type of topical azole

1) Clotrimazole versus other azoles

See Table 1.

Three studies compared one type or formulation of topical azole versus another (de la Paz Cota 2018; Navaneethan 2014; Prabhakaran 2018). They compared clotrimazole as one of their study drugs with other types of azoles, namely eberconazole, fluconazole and miconazole. In de la Paz Cota 2018, participants were given either eberconazole or clotrimazole solutions (five drops twice a day) for 14 consecutive days. Navaneethan 2014 compared clotrimazole drops, miconazole cream and fluconazole drops with varying amounts and frequency of administration. More importantly, the duration of treatment was not explicitly stated. Prabhakaran 2018 compared clotrimazole drops with fluconazole (three drops thrice daily) for three weeks. All three studies employed some form of dry mopping as an adjunct treatment.

It is very uncertain whether there is a difference between clotrimazole and other azoles at achieving complete clinical resolution at four weeks (RR 0.80, 95% CI 0.59 to 1.07; 3 studies; 439 participants; I² = 86%). We assessed the evidence to be of very low certainty. In terms of absolute effects the results for achieving clinical resolution at four weeks were: clotrimazole 668 per 1000 and other azoles 835 per 1000.

Only one study recorded significant adverse events but reported none (de la Paz Cota 2018).

With regards to mycological resolution at 24 days follow‐up, the evidence suggests that clotrimazole may result in little or no difference (RR 1.01, 95% CI 0.96 to 1.06). We downgraded the evidence for this outcome to low certainty due to indirectness (exclusion of participants under the age of 18) and imprecision (small sample size). Clotrimazole may result in little or no difference in other (less severe) adverse events at 24 days follow‐up (RR 0.79, 95% CI 0.18 to 3.41). We downgraded this outcome to very low certainty due to indirectness (exclusion of participants under the age of 18) and imprecision (very few events with a small sample size, and wide confidence intervals for the effect estimate).

2) Bifonazole cream versus bifonazole solution

In del Palacio 1993, it was reported that there was no difference in clinical resolution between bifonazole cream and solution at two weeks following the end of therapy. Bifonazole cream may reduce the mycological cure rate compared to the solution formulation (RR 0.53, 95% CI 0.29 to 0.96), but the evidence is very uncertain. Overall, we assessed the evidence from this single study to be of very low certainty due to study limitations (multiple risks of bias: allocation concealment, performance and detection bias), imprecision (small number of events with narrow confidence intervals) and indirectness (single‐centre study from one country limiting external validity). Therefore, it remains very uncertain indeed whether there is a difference between the two drug formulations in terms of these two outcomes.

Overall completeness and applicability of evidence

We identified three studies that compared clotrimazole versus another type of azole and one study that compared two different formulations of application of the same drug, which fulfilled our inclusion criteria. However, this does not represent the entire spectrum of azoles used clinically and it would be difficult to extrapolate our results to those drugs. All of the included studies only recruited participants with otomycosis and most included adults and children. The only exception was de la Paz Cota 2018, which excluded participants below the age of 18 years.

We stated a priori in our protocol that we would examine clinical resolution at two to four weeks follow‐up as one of our primary endpoints. We chose this endpoint as we felt that it is clinically more relevant than partial resolution. One of the studies used a clinical scale comprising data obtained from signs, symptoms and fungal culture (de la Paz Cota 2018). In order for participants to achieve clinical resolution they had to be asymptomatic and have a negative culture. However, Navaneethan 2014 and Prabhakaran 2018 used the amount of debris build‐up as the sole indicator of clinical resolution. We felt this to be less robust, notwithstanding the subjectivity involved in the assessment of clinical responses. None of the papers mentioned that their assessment scales were pre‐tested to ensure good internal validity and test‐retest reliability.

Data for a number of outcomes were missing. In particular, only de la Paz Cota 2018 showed follow‐up fungal culture data at the end of their follow‐up period, defined as day 24. Mycological follow‐up results were not available in Navaneethan 2014 or Prabhakaran 2018. This makes the classification of treatment outcomes problematic.

We considered compliance with treatment and water precautions to be two potentially confounding factors. del Palacio 1993 was the only study that followed the participants daily during treatment whereas the other studies relied on home administration of the interventional drugs. No data were available on compliance with treatment. Swimming is known to be a risk factor in otomycosis (www.healthline.com/health/otomycosis#outlook), however none of the studies reported data on patient compliance with water precautions.

One limitation in our review involves the heterogeneity with which adverse events were reported in two studies (de la Paz Cota 2018; del Palacio 1993). In particular, de la Paz Cota 2018 employed objective and stringent criteria in their safety analysis. Neither of these studies reported significant adverse effects. del Palacio 1993 reported five patients with severe itching and burning with bifonazole solution yet all of these completed the full course of treatment. None of their participants developed adverse events with bifonazole cream and all of their adverse events were seen in patients who received bifonazole solution. Three patients with bilateral otomycosis developed intolerance only on the side treated with bifonazole solution. We considered the risk of double counting of adverse events and the risks of serious systemic toxicities to be low given that only 5 out of 35 patients had bilateral otomycosis and the interventions were all topically based.

The length of follow‐up for three out of four studies was between one and four weeks. del Palacio 1993 was the only study that reported outcomes at two and a half years after treatment. Therefore there remains limited evidence regarding the long‐term effects of topical azoles for the resolution symptoms in patients with otomycosis.

Out of the four studies, only de la Paz Cota 2018 used statistical methods for their intention‐to‐treat population to impute their missing data. We considered the high dropout rate of 32% in one study to be problematic (Navaneethan 2014).

The effect of aural toileting in the treatment of otomycosis remains unknown. It is a manoeuvre widely used in otolaryngology outpatient departments. All four of the studies that we analysed utilised it for all of their participants. We were therefore unable to perform a subgroup analysis. Aural toileting may have an impact on the treatment of chronic ear diseases from other infectious causes. In a recent Cochrane Review on the treatment of chronic suppurative otitis media (chronic infection of the middle ear with pus), the researchers noted in one of their comparisons that fewer patients receiving topical and oral antibiotics had resolution of their ear discharges compared with acetic acid and suction aural toileting (Head 2020). However, in a related Cochrane Review the authors were very uncertain whether aural toileting has any effect in resolving ear discharge in patients with chronic suppurative otitis media (Bhutta 2020). These authors also met with similar challenges to us in their analyses in terms of the paucity of data and the poor quality of evidence. More research into the effects of aural toileting in otomycosis is required.

In certain parts of the world otomycosis is relatively rare. However, it can occur secondary to misuse of ototopical drugs for otitis externa or tympanostomy tube otorrhoea and can be treated with clotrimazole. There is no evidence to show that clotrimazole is ototoxic in experimental models or in clinical practice in children with tympanostomy tubes. Furthermore, a single application after microscopic debridement has been shown to cure fungal tympanostomy tube otorrhoea in most cases (Isaacson 2020).

Quality of the evidence

In this review the overall certainty of the evidence assessed using GRADE for clotrimazole versus other azoles ranged from low to very low, with downgrading in the GRADE domains of study limitations (risk of bias), imprecision, inconsistency and indirectness (Handbook 2011).

Study limitations (risk of bias)

We judged de la Paz Cota 2018 to be the study least affected by biases. We considered the other three studies to be rife with selection and allocation biases as none of them reported methods of random sequence generation and measures to enhance blinding. In particular, Navaneethan 2014 and Prabhakaran 2018 did not rely on fungal cultures as part of their determinants of the patients' response. This may have impacted on the accuracy of the diagnostic outcomes. Navaneethan 2014 lowered the GRADE rating further because of the relatively high dropout rate of 32%. All of the studies faced a common challenge of not having a validated instrument to measure the clinical response of participants.

Imprecision

For an estimate of imprecision we examined the sample size contributions of the included studies in combination with the confidence intervals from Table 1. The included studies were small, with a mean sample size of 140. We were able to pool the results of three studies involving clotrimazole and provide an estimate of clinical resolution. The confidence interval ranges from 0.59 to 1.07. We were only able to draw our confidence intervals for the other outcomes of mycological cure and other adverse effects from one study (de la Paz Cota 2018).

Inconsistency

de la Paz Cota 2018 and Navaneethan 2014 concluded that clotrimazole was not superior to other azoles in their studies. However, Prabhakaran 2018 found that topical fluconazole was superior to clotrimazole. The I² value in our pooled analysis was 86%, indicating significant heterogeneity. We also discovered considerable variation in clinical resolution with clotrimazole across the studies. This varied from 38% at four weeks (Prabhakaran 2018) to 86% at three weeks (de la Paz Cota 2018). The reasons for this variation were not clear but it could be due to differences in the baseline characteristics of the population, compliance with treatment or local levels of fungal resistance. We noted that Prabhakaran 2018 was the only study that specifically included immunocompromised patients but the exact proportion remains unknown. All of these factors add to the difficulty in drawing meaningful conclusions.

Indirectness

We judged de la Paz Cota 2018 to have a lower risk of bias compared to the other studies. However, only participants aged 18 years or older were included. The results from this study may therefore not apply to patients with otomycosis in all age groups. Also, the countries in which these studies originated were restricted to Spain, Mexico and India. This limits the generalisability of the results.

Similarly, the overall certainty of the evidence assessed using GRADE for the bifonazole cream versus bifonazole solution comparison (del Palacio 1993) was very low, with downgrading in the GRADE domains of study limitations (risk of bias), imprecision (small number of events with narrow confidence intervals) and indirectness (single‐centre study from one country limiting external validity) (Handbook 2011).

Potential biases in the review process

In our search we identified several studies that we classified as ongoing, some of which stated that the recruitment process was completed but their full data were not published. We attempted to contact the persons responsible for these studies for clarification but received no responses. This raises a concern that there may be more studies conducted in a similar way yet unpublished or where the results are available but have not been identified through our searches.

Agreements and disagreements with other studies or reviews

There are few previous systematic reviews or guidelines on the treatment of otomycosis. The World Health Organization (WHO) in 2006 suggested that otomycosis can be treated effectively with a single instillation of 1% silver nitrate gel, repeated after a couple of days if needed (WHO 2006). There was no mention of using azoles. Neither the American Academy of Otolaryngology nor the BMJ Best Practice has published guidance on otomycosis.

One published systematic review compared Locacorten‐Vioform and clotrimazole for otomycosis. Although the review found both to be safe and effective, the authors concluded that there is insufficient evidence to support increased efficacy of either drug (Herasym 2016).

Authors' conclusions

Implications for practice.

It is not possible to ascertain whether topical azoles are more effective than placebo or no treatment for otomycosis as no studies have assessed these comparisons. It is also not possible to say whether clotrimazole is more effective than other topical azoles in achieving clinical resolution of otomycosis due to the very low certainty of the evidence. The evidence is very uncertain about the effects of clotrimazole in achieving clinical resolution of otomycosis at four weeks follow‐up, as well as on outcomes including significant adverse events or other (non‐severe) adverse events, when compared to other azoles. The evidence suggests that clotrimazole results in little to no difference in mycological resolution compared to other topical azoles. It is very uncertain if bifonazole cream is more effective in achieving clinical resolution compared to bifonazole solution. Bifonazole cream may reduce the mycological cure rate compared to bifonazole solution but the evidence remains very uncertain.

Implications for research.

The results of this review, current to 11 November 2020, show that there is a paucity of evidence comparing one type of azole versus placebo, no treatment or another type of azole. The very low‐certainty evidence in this review needs to be addressed in future updates of this topic. Potential adverse events were not well reported and the impact of confounding factors such as user compliance and water exposure are also unclear.

Suggestions for future trials

We propose key features of future research into azoles in the treatment of otomycosis as follows:

Design and methods

• Randomised controlled trials should be analysed and reported by person (not by ear).

• In patients with bilateral otomycosis, and for outcomes that can be reported by ear such as clinical resolution, only one finding should be reported per person to avoid double counting.

• Appropriate methods must be reported for randomisation and allocation concealment to avoid selection bias, with adequate statistical power.

• Blinding of participants and assessors is preferable. In cases where blinding of participants/clinicians is not possible, efforts should be made to blind the members of staff responsible for outcome assessment and data analysis.

Population

• Diagnosis of otomycosis should be according to standardised criteria and be otoscopically and mycologically confirmed.

• If patients from 'high‐risk' groups are included they should be accounted for and explored in the design of the study via sensitivity analyses.

Interventions

• Future research should compare azoles versus placebo, no treatment or aural toileting alone.

• It should also allow for subgroup analyses on the various types of formulation, e.g. cream versus solution. Subgroup analyses should also be carried out for aural toileting as there is insufficient evidence in the literature to suggest that aural toileting is beneficial when used either alone or in combination with other treatment modalities, for example in the management of chronic suppurative otitis media (Bhutta 2020).

• There should be clear reporting of the therapies used including frequency and duration, and clear descriptions of adjunctive therapies such as aural toileting.

Outcomes

• There are currently no standardised outcomes and definitions for otomycosis trials, and these are urgently needed. It would allow for ease of analysis and comparison of data across trials.

• Outcome assessment should include follow‐up mycological cultures.

• The assessment of adverse effects should be defined in the protocol and these should be systematically sought during the trials.

• Studies should follow up patients for at least six months or longer to identify the rate of relapse.

• Trials should be registered in a regional or international clinical trials registry and when published adhere to reporting guidelines such as CONSORT (CONSORT 2010).

History

Protocol first published: Issue 9, 2011

Date	Event	Description
22 March 2019	Amended	Protocol revision.

Appendices

Appendix 1. Search strategies

CENTRAL (CRS)	MEDLINE (Ovid)	Embase (Ovid)	CINAHL (EBSCO)
1 MESH DESCRIPTOR Otomycosis EXPLODE ALL AND CENTRAL:TARGET 2 (otomyco*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 3 (singapore NEXT ear):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 4 #1 OR #2 OR #3 AND CENTRAL:TARGET 5 MESH DESCRIPTOR Ear, External EXPLODE ALL AND CENTRAL:TARGET 6 MESH DESCRIPTOR Otitis Externa EXPLODE ALL AND CENTRAL:TARGET 7 ((outer OR extern*) adj3 (ear OR otitis)):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 8 ((pruritis OR itch*) AND ear):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 9 ((external AND auditory AND canal)):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 10 #5 OR #6 OR #7 OR #8 OR #9 AND CENTRAL:TARGET 11 MESH DESCRIPTOR Mycoses EXPLODE ALL AND CENTRAL:TARGET 12 MESH DESCRIPTOR Microbiology EXPLODE ALL AND CENTRAL:TARGET 13 MESH DESCRIPTOR Fungi EXPLODE ALL AND CENTRAL:TARGET 14 (mycos* OR fung* OR Candida or candidias* or aspergill*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 15 MESH DESCRIPTOR Antifungal Agents EXPLODE ALL AND CENTRAL:TARGET 16 MESH DESCRIPTOR azoles EXPLODE ALL AND CENTRAL:TARGET 17 (azole* or triazole* or antifunag*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 18 (Imidazole* OR imidazolidinone OR Aminoimidazole* OR Antazoline OR Biotin OR Carbimazole* OR Cimetidine OR Clotrimazole* OR Creatinine OR Dacarbazine OR Dexmedetomidine OR Econazole* OR Enoximone OR Etimizol OR Etomidate OR Fadrozole* OR Fluspirilene OR Histamine OR Histidinol OR Idazoxan OR Imidazolidine* OR Imidazoline* OR Impromidine OR Levamisole* OR Losartan OR Medetomidine OR Methimazole* OR Miconazole* OR Naphazoline OR Niridazole* OR Nitroimidazole* OR Olmesartan Medoxomil OR Ondansetron OR Oxymetazoline OR Phentolamine OR Tetramisole* OR Trimethaphan OR Urocanic Acid OR Vardenafil Dihydrochloride OR Isoxazole* OR isoxazolepropionic Acid OR Cycloserine OR Ibotenic Acid OR Isocarboxazid OR Paliperidone Palmitate OR Oxazole* OR Aminorex OR Dimethadione OR Fura‐2 OR Muscimol OR Oxadiazole* OR Oxazolidinone* OR Oxazolone* OR Pemoline OR Trimethadione OR Pyrazole* OR Betazole* OR Celecoxib OR Epirizole* OR Indazole* OR Muzolimine OR Oxypurinol OR Pyrazolone* OR Sulfaphenazole* OR Pyrrole* OR Atorvastatin Calcium OR Cromakalim OR Maleimide* OR Porphobilinogen OR Prodigiosin OR Pyrrolnitrin OR Ryanodine OR Tetrapyrrole* OR Tolmetin OR Tetrazole* OR Cefotetan OR Losartan OR Olmesartan Medoxomil OR Tetrazolium Salt* OR Valsartan OR Thiazole* OR Benzothiazole* OR Chlormethiazole* OR Cobicistat OR Dasatinib OR Famotidine OR FANFT OR Febuxostat OR Firefly Luciferin OR Levamisole* OR Lurasidone Hydrochloride OR Niridazole* OR Nizatidine OR Oxythiamine OR Rhodanine OR Ritonavir OR Sulfathiazole* OR Tetramisole* OR Thiabendazole* OR Thiadiazole* OR Thiamine OR Thiazolidinedione* OR Triazole* OR Amitrole* OR Fluconazole* OR Guanazole* OR Itraconazole* OR Sitagliptin Phosphate OR Trapidil OR Voriconazole*):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 19 MESH DESCRIPTOR Ketoconazole EXPLODE ALL AND CENTRAL:TARGET 20 (Klotrimazole* OR Mycelex OR Lotrimin OR Canesten OR Kanesten OR Zonal* OR Béagyne OR Diflucan OR Fluc Hexal OR Flucobeta OR FlucoLich OR Fluconazol* OR Flunazul OR Fungata OR Lavisa OR Loitin OR Neofomiral OR Oxifungol OR Solacap OR Triflucan OR Ketoconazole* OR Nizoral OR Miconasil* OR Monistat OR Brentan OR Dactarin OR Ekonazole* OR GynoPevaril OR (Gyno AND Pevaril) OR (Gyno AND Pervaryl)):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 21 (Castellani OR (otic AND powder)):AB,EH,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET 22 #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #20 OR #19 OR #21 AND CENTRAL:TARGET 23 #10 AND #22 AND CENTRAL:TARGET 24 #23 OR #4 AND CENTRAL:TARGET	1 exp Otomycosis/ 2 (otomyco* or (singapore adj3 ear)).ab,ti. 3 1 or 2 4 exp Ear, External/ 5 exp Otitis Externa/ 6 ((outer or extern*) adj3 ear).ab,ti. 7 "otitis extern*".ab,ti. 8 ((pruritis or itch?) adj3 ear).ab,ti. 9 4 or 5 or 6 or 7 or 8 10 exp Mycoses/ 11 exp Microbiology/ 12 exp Fungi/ 13 (mycos* or fung* or Candida or candidias* or aspergill*).ab,ti. 14 exp Antifungal Agents/ 15 (azole* or triazole* or antifung*).ab,ti. 16 exp Ketoconazole/ 17 (Imidazole? or imidazolidinone or Aminoimidazole? or Antazoline or Biotin or Carbimazole? or Cimetidine or Clotrimazole? or Creatinine or Dacarbazine or Dexmedetomidine or Econazole? or Enoximone or Etimizol or Etomidate or Fadrozole? or Fluspirilene or Histamine or Histidinol or Idazoxan or Imidazolidine? or Imidazoline? or Impromidine or Levamisole? or Losartan or Medetomidine or Methimazole? or Miconazole? or Naphazoline or Niridazole? or Nitroimidazole? or Olmesartan Medoxomil or Ondansetron or Oxymetazoline or Phentolamine or Tetramisole? or Trimethaphan or Urocanic Acid or Vardenafil Dihydrochloride or Isoxazole? or isoxazolepropionic Acid or Cycloserine or Ibotenic Acid or Isocarboxazid or Paliperidone Palmitate or Oxazole? or Aminorex or Dimethadione or Fura‐2 or Muscimol or Oxadiazole? or Oxazolidinone? or Oxazolone? or Pemoline or Trimethadione or Pyrazole? or Betazole? or Celecoxib or Epirizole? or Indazole? or Muzolimine or Oxypurinol or Pyrazolone? or Sulfaphenazole? or Pyrrole? or Atorvastatin Calcium or Cromakalim or Maleimide? or Porphobilinogen or Prodigiosin or Pyrrolnitrin or Ryanodine or Tetrapyrrole? or Tolmetin or Tetrazole? or Cefotetan or Losartan or Olmesartan Medoxomil or Tetrazolium Salt? or Valsartan or Thiazole? or Benzothiazole? or Chlormethiazole? or Cobicistat or Dasatinib or Famotidine or FANFT or Febuxostat or Firefly Luciferin or Levamisole? or Lurasidone Hydrochloride or Niridazole? or Nizatidine or Oxythiamine or Rhodanine or Ritonavir or Sulfathiazole? or Tetramisole? or Thiabendazole? or Thiadiazole? or Thiamine or Thiazolidinedione? or Triazole? or Amitrole? or Fluconazole? or Guanazole? or Itraconazole? or Sitagliptin Phosphate or Trapidil or Voriconazole?).ab,ti. 18 (Klotrimazole? or Mycelex or Lotrimin or Canesten or Kanesten or Zonal? or B#agyne or Diflucan or Fluc Hexal or Flucobeta or FlucoLich or Fluconazol? or Flunazul or Fungata or Lavisa or Loitin or Neofomiral or Oxifungol or Solacap or Triflucan or Ketoconazole? or Nizoral or Miconasil? or Monistat or Brentan or Dactarin or Ekonazole? or GynoPevaril or (Gyno and Pevaril) or (Gyno and Pervaryl)).ab,ti. 19 (Castellani or (otic adj3 powder)).ab,ti. 20 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 21 9 and 20 22 3 or 21 23 randomized controlled trial.pt. 24 controlled clinical trial.pt. 25 randomized.ab. 26 placebo.ab. 27 drug therapy.fs. 28 randomly.ab. 29 trial.ab. 30 groups.ab. 31 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 32 exp animals/ not humans.sh. 33 31 not 32 34 22 and 33	1 exp otomycosis/ 2 (otomyco* or (singapore adj3 ear)).ab,ti. 3 1 or 2 4 exp external ear/ 5 exp external otitis/ 6 ((outer or extern*) adj3 ear).ab,ti. 7 "otitis extern*".ab,ti. 8 ((pruritis or itch?) adj3 ear).ab,ti. 9 4 or 5 or 6 or 7 or 8 10 exp mycosis/ 11 exp microbiology/ 12 exp fungus/ 13 (mycos* or fung* or Candida or candidias* or aspergill*).ab,ti. 14 exp antifungal agent/ 15 (azole* or triazole* or antifung*).ab,ti. 16 exp ketoconazole/ 17 (Imidazole? or imidazolidinone or Aminoimidazole? or Antazoline or Biotin or Carbimazole? or Cimetidine or Clotrimazole? or Creatinine or Dacarbazine or Dexmedetomidine or Econazole? or Enoximone or Etimizol or Etomidate or Fadrozole? or Fluspirilene or Histamine or Histidinol or Idazoxan or Imidazolidine? or Imidazoline? or Impromidine or Levamisole? or Losartan or Medetomidine or Methimazole? or Miconazole? or Naphazoline or Niridazole? or Nitroimidazole? or Olmesartan Medoxomil or Ondansetron or Oxymetazoline or Phentolamine or Tetramisole? or Trimethaphan or Urocanic Acid or Vardenafil Dihydrochloride or Isoxazole? or isoxazolepropionic Acid or Cycloserine or Ibotenic Acid or Isocarboxazid or Paliperidone Palmitate or Oxazole? or Aminorex or Dimethadione or Fura‐2 or Muscimol or Oxadiazole? or Oxazolidinone? or Oxazolone? or Pemoline or Trimethadione or Pyrazole? or Betazole? or Celecoxib or Epirizole? or Indazole? or Muzolimine or Oxypurinol or Pyrazolone? or Sulfaphenazole? or Pyrrole? or Atorvastatin Calcium or Cromakalim or Maleimide? or Porphobilinogen or Prodigiosin or Pyrrolnitrin or Ryanodine or Tetrapyrrole? or Tolmetin or Tetrazole? or Cefotetan or Losartan or Olmesartan Medoxomil or Tetrazolium Salt? or Valsartan or Thiazole? or Benzothiazole? or Chlormethiazole? or Cobicistat or Dasatinib or Famotidine or FANFT or Febuxostat or Firefly Luciferin or Levamisole? or Lurasidone Hydrochloride or Niridazole? or Nizatidine or Oxythiamine or Rhodanine or Ritonavir or Sulfathiazole? or Tetramisole? or Thiabendazole? or Thiadiazole? or Thiamine or Thiazolidinedione? or Triazole? or Amitrole? or Fluconazole? or Guanazole? or Itraconazole? or Sitagliptin Phosphate or Trapidil or Voriconazole?).ab,ti. 18 (Klotrimazole? or Mycelex or Lotrimin or Canesten or Kanesten or Zonal? or B#agyne or Diflucan or Fluc Hexal or Flucobeta or FlucoLich or Fluconazol? or Flunazul or Fungata or Lavisa or Loitin or Neofomiral or Oxifungol or Solacap or Triflucan or Ketoconazole? or Nizoral or Miconasil? or Monistat or Brentan or Dactarin or Ekonazole? or GynoPevaril or (Gyno and Pevaril) or (Gyno and Pervaryl)).ab,ti. 19 (Castellani or (otic adj3 powder)).ab,ti. 20 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 21 9 and 20 22 3 or 21 23 (random* or factorial* or placebo* or assign* or allocat* or crossover*).tw. 24 (control* adj group*).tw. 25 (trial* and (control* or comparative)).tw. 26 ((blind* or mask*) and (single or double or triple or treble)).tw. 27 (treatment adj arm*).tw. 28 (control* adj group*).tw. 29 (phase adj (III or three)).tw. 30 (versus or versus).tw. 31 rct.tw. 32 crossover procedure/ 33 double blind procedure/ 34 single blind procedure/ 35 randomization/ 36 placebo/ 37 exp clinical trial/ 38 parallel design/ 39 Latin square design/ 40 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 41 exp ANIMAL/ or exp NONHUMAN/ or exp ANIMAL EXPERIMENT/ or exp ANIMAL MODEL/ 42 exp human/ 43 41 not 42 44 40 not 43 45 22 and 44	S35 S20 AND S34 S34 S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 S33 TX rct S32 (MH "Placebos") S31 (MH "Quantitative Studies") S30 (MH "Random Assignment") S29 (MH "Clinical Trials+") S28 TX versus or versus S27 TX phase AND TX ( three or III ) S26 TX "control group" S25 TX "treatment arm" S24 TX ( blind* or mask* ) AND TX ( single or double or triple or treble ) S23 TX trial AND TX ( control* or comparative ) S22 TX "cross over" S21 TX random* or factorial* or placebo* or assign* or allocat* or cossover* S20 S1 OR S19 S19 S7 AND S18 S18 S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 S17 TX (Castellani or (otic N3 powder)) S16 TX (Klotrimazole? or Mycelex or Lotrimin or Canesten or Kanesten or Zonal? or B#agyne or Diflucan or Fluc Hexal or Flucobeta or FlucoLich or Fluconazol? or Flunazul or Fungata or Lavisa or Loitin or Neofomiral or Oxifungol or Solacap or Triflucan or Ketoconazole? or Nizoral or Miconasil? or Monistat or Brentan or Dactarin or Ekonazole? or GynoPevaril or (Gyno and Pevaril) or (Gyno and Pervaryl)) S15 TX (midazole? or imidazolidinone or Aminoimidazole? or Antazoline or Biotin or Carbimazole? or Cimetidine or Clotrimazole? or Creatinine or Dacarbazine or Dexmedetomidine or Econazole? or Enoximone or Etimizol or Etomidate or Fadrozole? or Fluspirilene or Histamine or Histidinol or Idazoxan or Imidazolidine? or Imidazoline? or Impromidine or Levamisole? or Losartan or Medetomidine or Methimazole? or Miconazole? or Naphazoline or Niridazole? or Nitroimidazole? or Olmesartan Medoxomil or Ondansetron or Oxymetazoline or Phentolamine or Tetramisole? or Trimethaphan or Urocanic Acid or Vardenafil Dihydrochloride or Isoxazole? or isoxazolepropionic Acid or Cycloserine or Ibotenic Acid or Isocarboxazid or Paliperidone Palmitate or Oxazole? or Aminorex or Dimethadione or Fura‐2 or Muscimol or Oxadiazole? or Oxazolidinone? or Oxazolone? or Pemoline or Trimethadione or Pyrazole? or Betazole? or Celecoxib or Epirizole? or Indazole? or Muzolimine or Oxypurinol or Pyrazolone? or Sulfaphenazole? or Pyrrole? or Atorvastatin Calcium or Cromakalim or Maleimide? or Porphobilinogen or Prodigiosin or Pyrrolnitrin or Ryanodine or Tetrapyrrole? or Tolmetin or Tetrazole? or Cefotetan or Losartan or Olmesartan Medoxomil or Tetrazolium Salt? or Valsartan or Thiazole? or Benzothiazole? or Chlormethiazole? or Cobicistat or Dasatinib or Famotidine or FANFT or Febuxostat or Firefly Luciferin or Levamisole? or Lurasidone Hydrochloride or Niridazole? or Nizatidine or Oxythiamine or Rhodanine or Ritonavir or Sulfathiazole? or Tetramisole? or Thiabendazole? or Thiadiazole? or Thiamine or Thiazolidinedione? or Triazole? or Amitrole? or Fluconazole? or Guanazole? or Itraconazole? or Sitagliptin Phosphate or Trapidil or Voriconazole?) S14 (MH "Ketoconazole") S13 TX (azole* or triazole* or antifung*) S12 (MH "Antifungal Agents+") S11 TX (mycos* or fung* or Candida or candidias* or aspergill*) S10 (MH "Fungi+") S9 (MH "Microbiology+") S8 (MH "Mycoses+") S7 S2 OR S3 OR S4 OR S5 OR S6 S6 TX ((pruritis or itch?) N3 ear) S5 TX "otitis extern*" S4 TX ((outer or extern*) N3 ear) S3 (MH "Otitis Externa+") S2 (MH "Ear, External+") S1 TX otomyco* or (singapore N3 ear)
Web of Science	Trial Registries	LILACS	CNKI (via Google Scholar)
# 14 #13 AND #12 Indexes=SCI‐EXPANDED, CPCI‐S Timespan=1945‐2019 # 13 TOPIC: ((randomised OR randomized OR randomisation OR randomisation OR placebo* OR (random* AND (allocat* OR assign*)) OR (blind* AND (single OR double OR treble OR triple)))) Indexes=SCI‐EXPANDED, CPCI‐S Timespan=1945‐2019 # 12 #11 OR #1 Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years # 11 #10 AND #4 Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years # 10 #9 OR #8 OR #7 OR #6 OR #5 Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years #9 TOPIC: ((Castellani OR (otic NEAR3 powder))) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years #8 TOPIC: ((Klotrimazole* OR Mycelex OR Lotrimin OR Canesten OR Kanesten OR Zonal* OR Diflucan OR Fluc Hexal OR Flucobeta OR FlucoLich OR Fluconazol* OR Flunazul OR Fungata OR Lavisa OR Loitin OR Neofomiral OR Oxifungol OR Solacap OR Triflucan OR Ketoconazole* OR NizORal OR Miconasil* OR Monistat OR Brentan OR Dactarin OR Ekonazole* OR GynoPevaril OR (Gyno AND Pevaril) OR (Gyno AND Pervaryl))) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years #7 TOPIC: (Imidazole* or imidazolidinone or Aminoimidazole* or Antazoline or Biotin or Carbimazole* or Cimetidine or Clotrimazole* or Creatinine or Dacarbazine or Dexmedetomidine or Econazole* or Enoximone or Etimizol or Etomidate or Fadrozole* or Fluspirilene or Histamine or Histidinol or Idazoxan or Imidazolidine* or Imidazoline* or Impromidine or Levamisole* or Losartan or Medetomidine or Methimazole* or Miconazole* or Naphazoline or Niridazole* or Nitroimidazole* or Olmesartan Medoxomil or Ondansetron or Oxymetazoline or Phentolamine or Tetramisole* or Trimethaphan or Urocanic Acid or Vardenafil Dihydrochloride or Isoxazole* or isoxazolepropionic Acid or Cycloserine or Ibotenic Acid or Isocarboxazid or Paliperidone Palmitate or Oxazole* or Aminorex or Dimethadione or Fura‐2 or Muscimol or Oxadiazole* or Oxazolidinone* or Oxazolone* or Pemoline or Trimethadione or Pyrazole* or Betazole* or Celecoxib or Epirizole* or Indazole* or Muzolimine or Oxypurinol or Pyrazolone* or Sulfaphenazole* or Pyrrole* or Atorvastatin Calcium or Cromakalim or Maleimide* or Porphobilinogen or Prodigiosin or Pyrrolnitrin or Ryanodine or Tetrapyrrole* or Tolmetin or Tetrazole* or Cefotetan or Losartan or Olmesartan Medoxomil or Tetrazolium Salt* or Valsartan or Thiazole* or Benzothiazole* or Chlormethiazole* or Cobicistat or Dasatinib or Famotidine or FANFT or Febuxostat or Firefly Luciferin or Levamisole* or Lurasidone Hydrochloride or Niridazole* or Nizatidine or Oxythiamine or Rhodanine or Ritonavir or Sulfathiazole* or Tetramisole* or Thiabendazole* or Thiadiazole* or Thiamine or Thiazolidinedione* or Triazole* or Amitrole* or Fluconazole* or Guanazole* or Itraconazole* or Sitagliptin Phosphate or Trapidil or Voriconazole*) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years #6 TOPIC: ((azole* or triazole* or antifung*)) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years #5 TOPIC: ((mycos* or fung* or Candida or candidias* or aspergill*)) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years #4 #3 OR #2 Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years #3 TOPIC: (((pruritis or itch*) NEAR/3 ear)) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years #2 TOPIC: (((outer or extern*) NEAR/3 ear)) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years #1 TOPIC: ((otomyco* or (singapore NEAR/3 ear))) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years	CT.gov and ICTRP Via the Cochrane Register of Studies 1 otomycosis OR (singapore NEXT ear) AND CENTRAL:TARGET 2 http*:SO AND CENTRAL:TARGET 3 (NCT0* or ACTRN* or ChiCTR* or DRKS* or EUCTR* or eudract* or IRCT* or ISRCTN* or JapicCTI* or JPRN* or NTR0* or NTR1* or NTR2* or NTR3* or NTR4* or NTR5* or NTR6* or NTR7* or NTR8* or NTR9* or SRCTN* or UMIN0*):AU AND CENTRAL:TARGET 4 #2 OR #3 5 #4 AND #1 Clinicaltrials.gov otomycosis OR "singapore ear" ICTRP otomycosis OR singapore ear	TW:otomycosis OR TW:"singapore ear" OR TW:Otomicos	site:en.cnki.com.cn (otomycosis OR "singapore ear") (randomised OR randomized OR randomisation OR randomization OR randomly OR placebo OR blind OR groups)

Data and analyses

Comparison 1. Clotrimazole versus another azole.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Complete clinical resolution at 2 to 4 weeks	3	439	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.59, 1.08]
1.2 Mycological cure	1	174	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.96, 1.06]
1.3 Other adverse events	1	174	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.18, 3.41]

1.1. Analysis.

Comparison 1: Clotrimazole versus another azole, Outcome 1: Complete clinical resolution at 2 to 4 weeks

1.2. Analysis.

Comparison 1: Clotrimazole versus another azole, Outcome 2: Mycological cure

1.3. Analysis.

Comparison 1: Clotrimazole versus another azole, Outcome 3: Other adverse events

Characteristics of studies

Characteristics of included studies [ordered by study ID]

de la Paz Cota 2018.

Study characteristics
Methods	Two‐arm, double‐blind, parallel‐group active controlled phase 3 RCT, with 15 days duration of treatment and 24 days duration of follow‐up
Participants	Location: Mexico, 9 centres Setting of recruitment and treatment: otolaryngology clinics at 9 centres from May 2013 to November 2014 Sample size in the intention‐to‐treat population: Number randomised: 190 (95 in each group) Number completed: 174 (89 in the eberconazole group and 85 in the clotrimazole group) Participant (baseline) characteristics: Age (average): 41.8 years in the eberconazole group and 39.8 years in the clotrimazole group Gender (M/F): 48.3%/51.7% Bilateral disease: 5.6% in the eberconazole group and 10.6% in the clotrimazole group Latino or Hispanic ethnicity: 93.3% in the eberconazole group and 92.9% in the clotrimazole group Positive mycological culture: 79.8% in the eberconazole group; 80.5% in the clotrimazole group Negative mycological culture: 20.2% in the eberconazole group; 19.5% in the clotrimazole group Other important effect modifiers: Number who had a diagnosis of otitis externa: none Number who had a diagnosis of skull base osteomyelitis: not reported Inclusion criteria: Men or women aged 18 years or older with clinical diagnosis of otomycosis requiring topical treatment Symptoms: pruritis, otalgia, otorrhoea, aural fullness Exclusion criteria: Bacterial otitis externa Structural ear abnormalities Perforated tympanic membrane Any recent systemic infection Other concomitant diseases that may affect the interpretation of the study Malignancy in remission prior to study participation Use of concomitant drugs that may interfere with the study evaluations Immunodeficiency
Interventions	Intervention group (n = 95 patients): eberconazole 1%, 5 drops twice a day for 14 consecutive days Comparison group (n = 95 patients): clotrimazole 1%, 5 drops twice a day for 14 consecutive days Additional interventions: cleaning of the auditory canal
Outcomes	Primary outcomes: Proportion of participants with complete response: defined as having a negative fungal culture or presumed eradication AND a signs and symptoms score of 0 at the end of the study Proportion of participants with partial response: defined as a negative culture or presumed eradication AND a global score for signs and symptoms of 1 or 2, both on day 24 Proportion of participants with no response: defined as positive cultures or negative culture/presumed eradication AND a global score for signs and symptoms > 2 on day 24 Secondary outcomes: Proportion of participants with clinical cure at each visit The change in signs and symptoms score at the end of treatment (day 15) and at the end of study (day 24) relative to the baseline Proportion of participants with negative fungal culture or presumed eradication on day 24 Safety analysis: adverse events classified according to the MedDRA preferred term and system organ class as well as by severity, seriousness and causal relationship with study treatment
Funding sources	Supported by Laboratorios Salvat, S.A. as part of the Mexican COFEPRIS approval of the eberconazole 1% otic solution for the treatment of otomycosis
Declarations of interest	"The authors declare no conflict of interest"
Notes	Participants lost to follow‐up (%): 23 (12%) Unit of randomisation: person Methods for including patients with bilateral disease: not stated
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "...using random permuted blocks with a block size of four." Comment: no details about how sequence generation was conducted.
Allocation concealment (selection bias)	Low risk	Quote: "the sponsor, participants, investigators and study personnel were blinded to treatment allocation." Comment: adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "eberconazole 1% and clotrimazole 1% treatments were supplied in indistinguishable bottles containing 10 ml" Comment: both drugs appeared identical and this should be sufficient to mask the treatment options.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The sponsor, subjects, investigators and study personnel were blinded to treatment allocation." Comment: adequate blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "There were 23 withdrawals in the study; 7 in patients receiving eberconazole and 16 in those treated with clotrimazole. Patients' request was the most common reason for discontinuation in both treatment arms, which corresponded to 6 dropouts in the eberconazole group and 11 in the clotrimazole group.....primary and secondary endpoints were primarily evaluated in the ITT population." Comment: unequal withdrawals between groups. Loss to follow‐up rate = 23/190*100 = 12.1%.
Selective reporting (reporting bias)	Low risk	Comment: no trial protocol was identified on clinicaltrials.gov. The outcomes that were presented in the methods sections are well reported in the results section.
Other bias	Unclear risk	Quote: "symptoms were scored using a 4‐point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe) and the global score was obtained from the sum of each individual score for pruritus, otalgia, otorrhea, and aural fullness." Comment: there was no mention of the internal validity or test/retest reliability of this scale.

del Palacio 1993.

Study characteristics
Methods	Two‐arm, non‐blinded, single‐centre, parallel‐group RCT, with 7 days duration of treatment and 2.5 years of follow‐up
Participants	Location: Spain, 1 site Setting of recruitment and treatment: otolaryngology outpatient clinic of Hospital 12 de Octubre, from July to December 1987 Sample size: Number randomised: 35 patients; 40 ears: 20 ears (17 patients) in bifonazole 1% solution as the intervention group, 20 ears (18 patients) in bifonazole 1% cream as the comparison group Number completed treatment: 20 (ears) in bifonazole 1% solution and 20 (ears) in bifonazole 1% cream Participant (baseline) characteristics: Age: mean: 37.2 years in the bifonazole solution group and 39.6 years in the bifonazole cream group Age range: 6 to 57 years in the bifonazole solution group and 15 to 70 years in the bifonazole cream group Gender (M/F): 4/13 in the bifonazole solution group and 8/10 in the bifonazole cream group Duration of symptoms: 23 ears had up to 1 month; 11 ears between 1 to 6 months; 6 ears over 6 months of symptoms Tympanic membrane status: 29 ears intact, 4 ears perforated Mastoid cavities: 7 Eczema, atopia and asthma: 5 ears No predisposing factors: 16 patients Previous topical corticosteroids: 8 patients Previous antifungal therapy: 3 patients Previous antibiotic therapy: 8 patients Symptoms: scaling 95%; weeping 93%; maceration 93%; erythema 80%; itching 68%; pain 50% Other important effect modifiers: Number who had a diagnosis of otitis externa: none Number who had a diagnosis of skull base osteomyelitis: not reported Inclusion criteria: Symptomatic otomycosis confirmed by direct microscopy and culture Exclusion criteria: Patients who had had topical or systemic antifungal or antibacterial therapy within 4 weeks prior to the start of the study Pregnant women
Interventions	Intervention group (n = 20 ears): bifonazole 1% solution, once daily for 7 consecutive days by means of a wick (gauze strip 5 x 1 cm) ribbon gauze impregnated with the solution, which was replaced daily Comparison group (n = 20 ears): bifonazole 1% cream, once daily for 7 consecutive days by means of a wick (gauze strip 5 x 1 cm) ribbon gauze impregnated with the cream, which was replaced daily Additional interventions: dry mopping (suction aspiration) of the ears prior to antifungal therapy or when necessary during the course of treatment
Outcomes	Primary outcomes: Clinical response and fungal culture findings at 3 days, 2 weeks and 2.5 years post therapy. Graded into the following categories: clinical cure with negative fungal culture, clinical cure with positive fungal culture, clinical improvement with either negative or positive fungal culture, therapeutic failure and relapse with positive mycology in patients who had healed or improved after treatment Secondary outcomes: Adverse events during the trial and their severity
Funding sources	No information provided
Declarations of interest	Bayer A.G. (Germany) for provision of the study drugs
Notes	Participants lost to follow‐up (%): 4 ears (2 patients) were lost to follow‐up at 2.5 years (10%) Units of randomisation: ear; 5 patients with bilateral disease: 2 were treated with cream in both ears whereas the other 3 were treated with solution on one side and cream on the other side
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Patients with symptomatic otomycosis confirmed by direct microscopy and culture were randomly assigned to treatment with either bifonazole 1% cream or solution." Comment: there is insufficient information on methods of sequence generation.
Allocation concealment (selection bias)	High risk	Quote: "Patients with symptomatic otomycosis confirmed by direct microscopy and culture were randomly assigned to treatment with either bifonazole 1% cream or solution." Comment: no further information available on allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: it was not possible to blind because the appearance and consistency of a solution and a cream are different.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "The patients were seen daily during treatment and at follow up visits." Comment: one can assume that blinding of outcome assessment was not carried out.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Table 5 showed that all 40 ears were assessed at 2 weeks after the end of therapy. However, 36/40 ears were available for review at 2.5 years. Comment: loss to follow‐up was 10% (4/40) in total. No reasons for this loss are given.
Selective reporting (reporting bias)	Unclear risk	Quote: "the responses were graded in the following categories: clinical cure with negative fungal cultures, clinical cure with positive fungal culture, clinical improvement with either negative or positive culture, therapeutic failure and relapse." Comment: no protocol was available on clinicaltrials.gov. There was no definition as to what the outcome constituted or how it was measured. All outcomes stated in the methodology section were reported. There were no statistics or P values reported in the tables.
Other bias	Unclear risk	Quote: "Parameters of clinical disease activity were assessed by the ENT surgeon with an operating microscope and scored as 1=none; 2=mild; 3=moderate; 4=severe." Comment: there was no mention of the internal validity or test/retest reliability of this scale.

Navaneethan 2014.

Study characteristics
Methods	Triple‐arm, double‐blind, single‐centre RCT, with unknown duration of treatment and 2 weeks duration of follow‐up
Participants	Location: India Setting of recruitment and treatment: single centre in ENT Department in Adhiparasakthi Institute of Medical Sciences and Research, Melmaruvathur, India Sample size: Number randomised: (Group A/Group B/Group C) 72/72/71 Number completed: (Group A/Group B/Group C) 46/50/49 Sample size derived from power calculation: not done Participant (baseline) characteristics: Age (percentage): not provided Gender: Female: 128 (59%) Male: 86 (41%) Main diagnosis: clinical otomycosis with distinctive findings on otoscopic examination Other important effect modifiers: not reported Inclusion criteria: Patients (adults and children) with clinical otomycosis Exclusion criteria: Chronic suppurative otitis media Previous surgeries for discharging ears Patients with bilateral disease
Interventions	Intervention (n = 72): clotrimazole 1% ear drops, 3 to 5 drops 3 times a day in affected ear. Length not stated. Comparator group(n = 71): 2 applications of miconazole cream in affected ear, once during the initial visit and a second application during the first week review for persistent disease Comparator group(n = 71): fluconazole drops, 3 to 5 drops 3 times a day in affected ear for 2 weeks. Length not stated. Use of additional interventions (common to all treatment arms): aural toileting was done in all participants with suction.
Outcomes	Primary outcomes: Response to treatment Good response: external auditory canal is dry Moderate response: external auditory canal is filled with minimal secretion No response: external auditory canal is filled with full secretion Secondary outcomes: Microbiological confirmation of fungal growth either in smear identification or culture growth
Funding sources	No information provided
Declarations of interest	No information provided
Notes	Participants lost to follow‐up at 2 weeks (%): 69 (32%) Unit of randomisation: person Methods for including patients with bilateral disease: patients with bilateral disease were excluded from the study Study meeting statistical power: information on power calculation was not provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "to ensure double blindness and proper administration of medication, a trained nursing assistant, who was not involved in evaluating the patients was utilised. She grouped the patients randomly.” Comment: rather rudimentary without involvement of a computer.
Allocation concealment (selection bias)	High risk	Quote: "to ensure double blindness and proper administration of medication, a trained nursing assistant, who was not involved in evaluating the patients was utilised She grouped the patients randomly." Comment: no further information available about allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: easy to tell the difference between the drops (clotrimazole and fluconazole) and miconazole cream. Blinding would not be possible.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "The patients and investigators remained blinded throughout the study." Comment: difficult to comment on whether the outcome assessments were blinded in spite of this statement.
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "One hundred and seventy seven patients who attended our OP department in the first week, 19 patients came with negative report in microbiological analysis of fungus and remaining 158 patients were advised for second week review." Comment: a significant number of dropouts were seen in each arm at the 2‐week follow‐up. The estimated number is (214 ‐ 145)/214*100 = 32%.
Selective reporting (reporting bias)	High risk	Quote: "One hundred and seventy seven patients who attended our OP department in the first week, 19 patients came with negative report in microbiological analysis of fungus and remaining 158 patients were advised for second week review." Comment: no follow‐up information available on the outcomes of the 19 patients. No trial protocol was identified on clinicaltrials.gov. Even though follow‐up mycological results were not included in the protocol this was mentioned in the results section under Table 3. This is considered to be selective reporting bias.
Other bias	Unclear risk	Quote: "Response to the treatment in three groups are tabulated as follows" Comment: all clinically based without mycological confirmation and with an unvalidated scale.

Prabhakaran 2018.

Study characteristics
Methods	Two‐arm, likely open, parallel‐group, randomised, prospective comparative clinical study, with 3 weeks duration of treatment and 4 weeks duration of follow‐up
Participants	Location: India Setting of recruitment and treatment: single centre in ENT Department in Association with the Microbiology Laboratory, Chettinad Health Centre and Research Institute, Kelambakkam Sample size: Number randomised: 60 in intervention, 60 in comparison group Number completed: 60 in intervention, 60 in comparison group Sample size derived from power calculation: 64 per group Participant (baseline) characteristics: Age (percentage): Clotrimazole group: 0 to 18 years (16.7); 19 to 60 years (81.7); > 60 years (1.7) Fluconazole group: 0 to 18 years (16.7); 19 to 60 years (78.3); > 60 years (5) Gender: clotrimazole group: 28 males and 32 females; fluconazole group: 27 males and 33 females Main diagnosis: age > 12 with culture + fungal otitis externa Other important effect modifiers: both immunocompetent and immunocompromised patients were included Inclusion criteria: Age > 12 years Patients of either sex Culture‐positive fungal otitis externa Both immunocompetent and immunocompromised patients Exclusion criteria: Culture‐negative cases Otomycosis associated with otitis media Prior usage of topical antifungals Patients not consenting for participation Non‐compliance with medication/follow‐up
Interventions	Intervention (n = 60): clotrimazole 1%, topically, 3 drops thrice daily for 3 weeks Comparator group(n = 60): fluconazole 0.3%, topically 3 drops thrice daily for 3 weeks Use of additional interventions (common to both treatment arms): all patients underwent microscopic suction clearance and the material was forwarded for fungal smear and culture
Outcomes	Outcomes of interest in the review: Primary outcomes: Resolution of signs and symptoms as determined by the amount of debris in the ear canal Mycological resolution: none reported Secondary outcomes: None reported
Funding sources	None declared
Declarations of interest	Financial or other competing interest: none
Notes	Participants lost to follow‐up (%): 0 Unit of randomisation: person Methods for including patients with bilateral disease: not stated Study meeting statistical power: no Number of immunocompromised patients reported: not stated
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "study participants who fulfilled inclusion criteria were randomly allocated into two groups with the help of random table numbers. The ratio of allocation was 1:1. Odd number lot were allocated to Group A to receive 1% clotrimazole ear drops and even number lot were allocated to Group B to receive 0.3% fluconazole ear drops." Comment: there could be systematic bias in the random sequence generation.
Allocation concealment (selection bias)	Unclear risk	Quote: "study participants who fulfilled inclusion criteria were randomly allocated into two groups with the help of random table numbers. The ratio of allocation was 1:1. Odd number lot were allocated to Group A to receive 1% clotrimazole ear drops and even number lot were allocated to Group B to receive 0.3% fluconazole ear drops." Comment: no further information available regarding allocation concealment although the consistencies of both drugs were similar.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: blinding was not mentioned.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: blinding was not mentioned.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: no dropouts were reported. All 120 participants finished the study and underwent follow‐ups.
Selective reporting (reporting bias)	High risk	Quote: "All patients were reviewed weekly for 4 weeks for reduction in symptoms and signs." Comment: no trial protocol was identified on clinicaltrials.gov. No symptoms outcome data available in follow‐up, only the amount of debris seen. No mycological follow‐up data were available.
Other bias	Unclear risk	Comment: symptoms were not mentioned as an outcome. There is a lack of information as to what defines the outcome (NAD, minimal and debris). The way in which the outcome was measured has not been shown to be validated and consistent.

NAD: no abnormality detected; RCT: randomised controlled trial

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Albano 1966	STUDY: not a RCT
Beck 1969	INTERVENTIONS AND COMPARISONS: not azoles
Berjis 2012	COMPARISON: tolnaftate is a synthetic thiocarbamate and not an azole
Boncalon 2009	INTERVENTION: kalachuchi is not an azole
Carrat 2001	COMMENT: not a RCT
Cojocaru 1970	COMMENT: not a RCT
del Palacio 2002	INTERVENTION: ciclopiroxolamine is not an azole
Diaz‐Pavon 2018	COMPARISON: tolnaftate is a synthetic thiocarbamate and not an azole
Gordana 2007	INVERVENTION AND COMPARISON: neither Castellani tintura rubra nor dexamethasone neomycin are azoles
Jimenez‐Garcia 2019	INTERVENTION: tolnaftate is not an azole
Joiemon 2006	INTERVENTION: topical azole and topical gentamicin COMPARISON: systemic azole
Khamaganova 2010	METHODOLOGY: not a RCT
Malik 2012	COMPARISON: salicylic acid is not an azole
Mofatteh 2017	INTERVENTION: betadine is not an azole
Nunez Navarrete 2000	COMPARISON: thimerosal is not an azole
Pal'chun 2012	METHODOLOGY: not a RCT INVERVENTION: pimafucort is not an azole
Rafique 2014	INTERVENTION: suction clearance; COMPARISON: azoles were used in both groups
Romsaithong 2016	COMPARISON: boric acid is not an azole
Wei 2018	Not a RCT
Zhang 2010	COMPARISON: salicylic acid and alcohol are not azoles

RCT: randomised controlled trial

Characteristics of studies awaiting classification [ordered by study ID]

Bambule 1978.

Methods	Unclear
Participants	Otomycosis
Interventions	Unclear
Outcomes	Unclear
Notes	Unable to obtain full text

Ben Rejeb 1984.

Methods	Unclear
Participants	Otomycosis
Interventions	Unclear
Outcomes	Unclear
Notes	Unable to obtain full text

Hu 2007.

Methods	Randomised trial
Participants	Otomycosis
Interventions	Fluconazole drops; comparison: not clear
Outcomes	Clinical cure rate
Notes	Unable to contact investigators regarding the comparison treatment and the outcome details

Ren 2015.

Methods	Unclear
Participants	Otomycosis
Interventions	Triamcinolone acetonide and econazole nitrate cream
Outcomes	Unclear
Notes	Unable to obtain full text

Characteristics of ongoing studies [ordered by study ID]

IRCT201502241138N15.

Study name	Efficacy of clotrimazole 1% and miconazole 1% in otomycosis
Methods	Single‐centre randomised controlled trial
Participants	Participants with otomycosis; no age or gender restrictions
Interventions	All arms receive topical treatment (dry mopping) plus: Group A: placebo Group B: miconazole cream 1% Group C: clotrimazole cream 1%
Outcomes	Patients to be examined clinically weekly up to 2 weeks and at the end of the 4th week
Starting date	Expected recruitment start date: 21 March 2015 Expected recruitment end date: 22 October 2015 Actual recruitment start date: N/A Actual recruitment end date: N/A Trial completion date: N/A
Contact information	We attempted to contact the person responsible for this trial, Dr. Hooshang Gerami (hg_gerami@yahoo.com) for further information but received no response
Notes	https://en.irct.ir/trial/187

IRCT2015040513136N3.

Study name	The effect of clotrimazole 1% on recurrence of otomycosis after treatment
Methods	Randomised single‐blind controlled trial
Participants	Participants with suspected otomycosis referred to the ear, nose and throat clinic of Ayatollah Rouhani Hospital of Babol in Iran; no age or gender exclusion criteria
Interventions	All participants to receive dry mopping plus: Group 1: clotrimazole 1% solution Group 2: no drugs
Outcomes	Recurrence of otomycosis at 3 months follow‐up
Starting date	Expected recruitment start date: 4 February 2016 Expected recruitment end date: 3 February 2018 Actual recruitment start date: N/A Actual recruitment end date: N/A Trial completion date: N/A
Contact information	We attempted to contact the person responsible for this trial, Dr. Saeid Mahdavi Omran (s.mahdavi@mubabol.ac.ir) for further information but received no response
Notes	https://en.irct.ir/trial/13057

IRCT2016082313136N4.

Study name	The treatment effect of ceftizoxime powder and clotrimazole ointment on fungal otitis media
Methods	Randomised single‐blind controlled trial
Participants	Participants of all ages and both genders with otomycosis accompanied with ruptured tympanic membrane referred to the ear, nose and throat clinic of Ayatollah Rouhani Hospital of Babol in Iran
Interventions	All arms to receive dry mopping plus: Group 1: topical clotrimazole cream Group 2: topical clotrimazole cream and ceftizoxime powder
Outcomes	Primary outcome: presence of symptoms 2 weeks after start of treatment Secondary outcome: drug sensitivity 2 weeks after start of treatment
Starting date	Expected recruitment start date: 22 September 2016 Expected recruitment end date: 21 March 2018 Actual recruitment start date: N/A Actual recruitment end date: N/A Trial completion date: N/A
Contact information	We attempted to contact the person responsible for this trial, Dr. Saeid Mahdavi Omran (s.mahdavi@mubabol.ac.ir) for further information but received no response
Notes	https://en.irct.ir/trial/13058

NCT03686397.

Study name	Clinical trial to assess the efficacy and safety of clotrimazole 1% otic solution compared to placebo for the treatment of fungal otitis externa (otomycosis)
Methods	Phase III, multicentre, randomised, double‐blind clinical
Participants	Participants over 18 years old with otomycosis
Interventions	Group 1: clotrimazole 1% otic solution Group 2: placebo
Outcomes	Therapeutic cure at 14‐day follow‐up in the intention‐to‐treat population
Starting date	29 April 2020 Estimated primary completion date: July 2021
Contact information	spain.regulatory@medpace.com
Notes	https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-003463-22

Differences between protocol and review

In our protocol the unit of randomisation was to be the participant, whereas the included study del Palacio 1993 used randomisation by ear. However, in this study only five out of 35 participants had bilateral disease, two of whom received the same treatment in both ears whereas the remainder were treated with an azole solution on one side and an azole cream on the other. The majority of participants had unilateral disease. We considered that the correlation in outcomes between ears of the small number of participants with bilateral disease (5/35) was unlikely to have a significant impact on the effect estimates. We therefore felt it appropriate to include this study in the review as it addresses a relevant clinical question.

It should be noted that del Palacio 1993 compared bifonazole cream versus solution, which represents a comparison not planned in our protocol.

We specified that we would include "participants over the age of 16" in our protocol. However, three out of the four included studies did not set an age limit to their inclusion criteria. In addition, we were unable to procure evidence from the literature to support a difference in the pathogenesis of otomycosis between adults and children. Therefore we decided that there should not be an age restriction for this review.

In the protocol, under 'Electronic searches' we planned to search KoreaMed, PakMedinet and IndMed. It has been deemed by Cochrane ENT that these sources are not worth searching for the majority of reviews. These searches were therefore not performed.

Contributions of authors

Ambrose Lee (lead author): original concept, obtaining the papers, writing the early drafts, protocol development, risk of bias assessment, analysis and interpretation of data, writing of review.

James Tysome: protocol development, risk of bias assessment, analysis and interpretation of data, writing of review.

Shakeel Saeed: clinical, methodological and editorial input and advice.

Sources of support

Internal sources

• No sources of support provided

External sources

• National Institute for Health Research, UK

  Infrastructure funding for Cochrane ENT

Declarations of interest

Ambrose Lee: none known.

James Tysome: none known.

Shakeel Saeed: none known.

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