Effective pharmaceutical management of Acute Otitis Externa: guidance and prescribing considerations

Acute otitis externa (AOE), also known as swimmer's ear, is defined by widespread inflammation of the external auditory canal and is considered acute if it lasts three weeks or less (National Institute for Health and Care Excellence (NICE), 2018). The symptoms of AOE range from mild to severe and include ottorhoea, erythema, pain and oedema. One third of patients may also suffer from some form of hearing loss (Hui et al, 2013).

The condition usually occurs due to bacterial infection, and the microbiology surrounding AOE is widely established. The principle pathogens of the condition are Pseudomonas aeruginosa and Staphylococcus aureus, and the infection often occurs in a polymicrobial setting (NICE, 2018). Fungal involvement is uncommon in primary AOE, but is more common in cases of chronic otitis externa or when AOE has previously been treated with topical antibiotics (Rosenfield et al, 2014).

AOE frequently occurs in patients that swim, as water containing bacteria (and/or fungi) can initiate infection through nicks in the skin of the ear canal. These breaks in the skin can occur a number of ways, including through skin conditions such as psoriasis, or from local trauma due to the use of cotton-tipped swabs (Singh, 2017). Moreover, use of cotton-tipped swabs as a method of cleaning the ear can remove cerumen which is a barrier to moisture and infection (Rosenfield et al, 2014). Some individuals may also be more susceptible to AOE. Children are particularly susceptible due to the size of their ear canal, and five out of six children will suffer from AOE once before their third birthday (National Institute on Deafness and Other Communication Disorders, 2017).

AOE is frequently encountered in primary care and around 97% of cases are managed in this setting (NICE, 2018; Kaushik et al, 2011). Current recommendations for AOE treatment are based on the severity of the condition. Uncomplicated AOE can be managed with analgesics for pain management and prescribing of a topical antibiotic (NICE, 2018). Oral antibiotics are rarely indicated, unless there is extension of AOE outside the ear canal, or specific host factors that necessitate the need for systemic intervention, such as patients with diabetes or compromised immunity (NICE, 2018).

As antibiotic resistance is an increasing concern within the modern healthcare setting, preventing the use of antibiotics, particularly systemic antibiotics, wherever possible is key. Although antibiotics are rarely indicated for the treatment of AOE, it is estimated 20-40% of patients with AOE are treated with oral antibiotics, with or without concurrent topical therapy (Rosenfield et al, 2014). Where treatment with an antibiotic is considered to be beneficial, a topical alternative should be considered. Bacterial resistance is less of a concern with topical antibiotics, as the local high concentration of the drug in the ear canal eradicates both susceptible microorganisms and those resistant to oral antibiotics (Rosenfield et al, 2014).

Topical formulations are also associated with fewer systemic side effects as they are locally applied to the ear canal and therefore only a negligible amount of the antibiotic is absorbed systemically. This reduces the risk of many potentially severe adverse effects that are associated with systemic antibiotics, including digestive issues and allergic reactions (NHS, 2019).

The management of AOE has been subject to a variety of reviews, including a Cochrane systematic review in 2010 and a meta-analysis by the American Academy of Otolaryngology-Head and Neck Surgery in 2014 (Hui et al, 2013). Differential misdiagnosis of AOE is common and may lead to the use of inappropriately prescribed systemic antibiotics. Furthermore, care is required when prescribing topical preparations as some have associated ototoxic side effects, including hearing loss. This is of great importance in cases of complicated AOE where the tympanic membrane is perforated, leaving the ear more vulnerable to ototoxicity.

The NICE clinical knowledge summary for AOE was revised in 2018 and includes recommendations for the management of AOE (NICE, 2018). If an infection is present, this summary states that oral antibiotics are rarely indicated, and should only be considered for people with severe infection or who are at high risk for severe infection. This includes cases where cellulitis spreads beyond the ear canal to the pinna, neck or face, or when systemic signs of infection are evident. In such cases, a 7-day course of a suitable oral antibiotic is recommended. In cases of uncomplicated AOE, NICE advises prescribing of a topical antibiotic as a first-line treatment, along with an analgesic for pain relief.

A variety of preparations of topical antibiotics are available, and NICE advises consideration of a variety of factors when choosing which to prescribe to a patient. There is no evidence to suggest that a particular topical preparation is more effective, so the following factors should be considered; patient preference, risk of adverse effects, cost, dosing frequency, and the status of the eardrum. Patient compliance is also another important factor that should be taken into consideration. Preparations that require multiple daily doses may increase the risk of a missed dose and subsequently prevent administration of the full course of treatment. This might not only hinder therapeutic resolution but may also contribute to an increase in antimicrobial resistance. Ensuring a patient is administering the correct dose is also important in terms of over-dosing, as too high a concentration of topical antibiotic may initiate fungal infection (Anwar, 2014).

Topical treatment options for AOE

Topical antibiotic therapy is a well-established and effective treatment for uncomplicated AOE. Many clinical trials have shown topical preparations to be effective, with excellent bacteriologic outcomes in comparison to placebo (Rosenfield et al, 2014). The main classes of antibiotics used are aminoglycosides and fluoroquinolones, which have varying degrees of antimicrobial resistance and differing safety profiles. Furthermore, some ear drops may not be used in cases of complicated AOE where the tympanic membrane is perforated. Some cases of AOE may be treated with topical preparations that do not include antibiotics, such as acetic acid-containing ear drops. Such preparations have been proven to be comparable to antibiotic/steroid preparations at week one, however treatment is less effective beyond this. Fungal AOE may also be treated with an antifungal such as topical clotrimazole (NICE, 2018).

Many topical treatments also contain corticosteroids, such as hydrocortisone and dexamethasone. Such preparations may be used in cases of AOE where there is a significant inflammatory component, to reduce inflammation and associated pain. Some studies have also stated that the use of a topical antibiotic with a corticosteroid is more effective than use of a topical antibiotic alone (Hui et al, 2013; Rosenfield et al, 2014).

Aminoglycoside topical preparations

Aminoglycosides are highly potent, broad-spectrum antibiotics that impair bacterial protein synthesis. They are active against a variety of bacteria, particularly Gram-negative organisms such as Pseudomonas aeruginosa (Baxter Corporation, 2013). Aminoglycosides are used to treat a wide range of infections, such as urinary tract infections, pneumonia and skin infections, such as AOE.

Gentamicin is a common aminoglycoside found in topical preparations for the treatment of AOE and such preparations may also include a corticosteroid such as hydrocortisone. The usual dosing regimen for treatment of AOE is 2-3 drops in the affected ear, 3-4 times a day and night, respectively (Electronic Medicines Compendium, 2019). The efficacy of gentamicin for the treatment of AOE has been long established and it remains a treatment option listed by NICE (NICE, 2018).

Neomycin is another aminoglycoside that has been used to treat AOE, and is found in many topical preparations such as Betnesol-N® (betamethasone sodium phosphate 0.1%, neomycin sulphate 0.5%) and Otosporin® (hydrocortisone 1%, neomycin sulphate 3400 units, polymyxin B sulphate (PNH) 10 000 units/mL (NICE, 2018). Many trials have confirmed the efficacy of neomycin-containing ear drops, and PNH has often been used as a comparison for newer preparations in non-inferiority studies. In one such study PNH showed clinical cure in 81.1% of patients and showed activity against a variety of pathogens (Drehobl et al, 2008). Neomycin-containing preparations often require administration of 3 drops into the affected ear 3-4 times a day, the same as gentamicin-containing preparations (Electronic Medicines Compendium, 2017a).

Topical aminoglycoside preparations have been associated with ototoxicity in a multitude of studies. This is particularly evident in cases of a perforated tympanic membrane or when a patient has a tympanostomy tube inserted. Aminoglycosides may induce toxicity of the vestibular or cochlear systems of the inner ear, depending on the antibiotic used. The risk of ototoxicity increases with prolonged exposure, so when an aminoglycoside is indicated, the duration of therapy should be minimised (Leis et al, 2015).

Gentamicin is implicated in irreversible damage of the auditory and vestibular systems, and neomycin is associated with cochleotoxic effects. Symptoms of cochleotoxicity include tinnitus and hearing loss, compared to the disequilibrium and dizziness associated with vestibulotoxicity. Unfortunately, symptoms are often not detected until after the acute phase of infection, and so diagnosis is frequently delayed (Huth et al, 2011).

It is difficult to predict how many patients will suffer from ototoxicity after aminoglycoside use, as patients may suffer from high frequency hearing loss that isn't routinely tested (Huth et al, 2011). This could indicate that the incidence of aminoglycoside-induced ototoxicity is underestimated. Furthermore, it has been suggested that some people have an inherited predisposition that results in an increased risk of aminoglycoside-induced ototoxicity (Bitner et al, 2007). Nevertheless, aminoglycoside preparations are contraindicated in patients with a perforated tympanic membrane and NICE (2018) states they must not be used in such patients.

Quinolone topical preparations

Quinolone-containing topical preparations are an antibiotic alternative to aminoglycoside preparations. Most quinolone antibiotics are fluoroquinolones, which are active against a wide range of Gram-positive and Gram-negative bacteria, including the two most common pathogens implicated in AOE; S. aureus and P. aeruginosa. Fluoroquinolone antibiotics are used routinely for a variety of infections including those of the skin, urinary tract and respiratory system. In the UK, there are two types of fluoroquinolones that are routinely used in cases of AOE; ofloxacin and ciprofloxacin (NCBI, 2012).

Ofloxacin is a well-established treatment for AOE and has been used in such cases for over 30 years. The efficacy of Ofloxacin is comparable to that of Otosporin®, and in one study there was no significant difference in the clinical or microbiological cure rates between the two. Furthermore, the two had a similar safety profile with no significant adverse events reported (Jones et al, 1997). In the UK, ofloxacin is not currently available as an otic solution, so healthcare professionals often prescribe ofloxacin as an ophthalmic solution off-license. Such drops may be prescribed when no other preparations are appropriate for a patient, such as in cases of hypersensitivity or allergy.

Ciprofloxacin is another fluoroquinolone, which has proven efficacy and an established safety profile when used as an otic preparation. In one study, ciprofloxacin 0.2% otic solution cured a higher percentage of AOE cases in comparison to PNH, although this did not reach clinical significance (Drehobl et al, 2008). It has been demonstrated that P. aeruginosa is more resistant to neomycin than ciprofloxacin in some studies. One such study showed 100% resistance of 46 P. aeruginosa isolates to neomycin, compared to the 65 isolates that were 100% sensitive to ciprofloxacin (Ninkovik, 2008). This perhaps suggests ciprofloxacin is more effective at treating P. aeruginosa, although more recent studies have noted an increasing resistance of Pseudomonas aeruginosa to ciprofloxacin.

Ciprofloxacin is available in combination with dexamethasone, as Cilodex® (ciprofloxacin 3mg/ml, + dexamethasone 1mg/ml otic solution). Cilodex can be used in both children (≥1 year old) and adults with uncomplicated AOE and those with acute otitis media with tympanostomy tube. The dosing regimen is 4 drops twice daily for 7 days (Electronic Medicines Compendium, 2017b).

Ciprofloxacin is also available as a ciprofloxacin-only solution named Cetraxal® and is indicated for treatment of AOE in adults and children >1 year. Cetraxal® has a twice daily dosing regimen, similar to Cilodex® but comes in single-dose preservative-free ampoules in comparison to a standard bottle.

Cetraxal(®) is also available as Cetraxal Plus(®), which contains the corticosteroid fluocinolone acetonide. Cetraxal Plus(®) is indicated for patients with AOE from 6-months old and is packaged in single-dose preservative-free ampoules. The dosing regimen is one ampoule into the affected ear twice a day.

Fluoroquinolone-containing preparations have rarely been associated with ototoxicity in the literature and are widely thought suitable as a treatment for AOE. Current NICE clinical knowledge guidelines state that preparations containing quinolone (for example ciprofloxacin, or ofloxacin) can be used in people with a perforated ear drum (NICE, 2018). This suggests there is little to no risk of fluoroquinolones causing damage if they enter the middle ear. However, a study published earlier this year suggests that fluroquinolone preparations may be capable of inducing tympanic membrane perforation. The study was a retrospective cohort study between 1999 and 2010 of 94 333 patients prescribed either:

• Fluoroquinolone alone (ofloxacin) – not available in the UK
• Fluoroquinolone and a corticosteroid (ciprofloxacin/dexamethasone)
• Fluoroquinolone and a corticosteroid (ciprofloxacin/hydrocortisone) – not available in the UK
• Neomycin and hydrocortisone ear drops – not available in the UK.

The study found that there is an increased risk for tympanic membrane perforation in patients prescribed a fluoroquinolone ear drop in comparison to those prescribed neomycin and hydrocortisone (Wang, 2019). Thus, the risk for tympanic membrane perforation should perhaps be considered when prescribing a fluroquinolone ear drop to patients with an intact membrane.

Potential sensitisers in topical preparations

Ototoxicity, although among the most serious adverse effects, is not the only side effect that should be considered when prescribing topical preparations for AOE. Many antibiotic ear drops contain known sensitisers that can cause hypersensitivity reactions in certain individuals. NICE recognised sensitisers are displayed in Table 1.

Of the antibiotics listed as sensitisers, both aminoglycosides commonly used to treat AOE are listed. Neomycin is a very common sensitiser in topical ear preparations and is reported to cause reactions in 10-15% of patients with chronic external otitis (NICE, 2018). The only listed corticosteroid is hydrocortisone, and most excipients known to cause sensitisation are preservatives. Preservatives are needed to prevent bacterial contamination of the dropper bottle, but many are known to be skin irritants that may make symptoms worse. Benzalkonium chloride (BAK) is a common preservative found in ear and eye drops and has long been known to cause both irritation and allergic contact dermatitis in certain individuals (Basketter et al, 2004). Patients with preservative-related hypersensitivity may be prescribed preservative-free topical ear preparations to prevent such reactions occurring.

Conclusion

Topical ear preparations appear to be the most appropriate first-line treatment option for the majority of AOE cases where antibiotic therapy is required. Topical formulations are a much better alternative to oral antibiotics in the setting of AOE. They have far fewer systemic side effects because they are applied locally to the affected ear. Furthermore, antimicrobial resistance is of key importance in the modern climate, and topical ear formulations are associated with a reduced likelihood of contributing to this. Although this is largely known, oral antibiotics are still being prescribed to treat cases of uncomplicated AOE. Such prescribing is usually unnecessary and can be avoided by prescribing an appropriate topical antibiotic ear preparation.

Many studies have confirmed that there is no preference for topical antibiotic ear formulation, so alternative factors must be considered to decide which preparation is most appropriate for each patient.

The NICE Clinical Knowledge Summary (NICE, 2018) states factors such as cost, patient preference, risk of adverse events, status of the eardrum and dosing frequency should be considered (Table 2).

As aminoglycosides are contraindicated in patients with a perforated ear drum, this subset of AOE sufferers should be prescribed a quinolone formulation, or an acetic acid-containing preparation, to reduce potential for ototoxicity. When accounting for risk of adverse events, ototoxicity and hypersensitivity reactions are both important to consider. For instance, an individual with a history of hypersensitivity to any of the known sensitisers should be prescribed a formulation free of these. In the case of preservative-related sensitivity a preservative-free option may be prescribed.

Dosing frequency is another important factor to be considered, as dosing regimens that are less frequent may aid in patient compliance to treatment. It is important that individuals take their full course of treatment in order to increase the likelihood of therapeutic resolution. Therefore, dosing that is more frequent may increase risk of a dose being missed. Aminoglycoside preparations have a more frequent dosing schedule than quinolone preparations.

Patient compliance can also be helped in other ways, such as through the use of single-dose ampoules. Single-dose ampoules ensure that the correct dose is delivered each time, which is not assured with use of a standard dropper bottle. One study found that significantly more patients found it easy to place drops inside the ear and to ensure they were administering the correct dose when using a single-dose ampoule as opposed to a dropper bottle (Drehobl et al, 2008). Ensuring the correct dose is taken is particularly important, as under-dosing may prevent therapeutic cure, whilst over-dosing may induce fungal infection (Anwar, 2014). However, most antibiotic topical ear preparations aren't available as single-dose ampoules, and this may make it more difficult for clinicians to supply them.

Patient preference could be overlooked when prescribing a topical ear preparation, but it may be a key factor to consider. If a patient feels more comfortable with the formulation, they may be more likely to correctly administer the treatment. This can help with patient adherence with treatment, which may improve therapeutic efficacy (Drehobl, 2008).

A summary of common antibiotic topical ear preparations available in the UK can be seen in Table 2. It is clear to see that prescribing of a topical formulation is largely down to both prescriber and patient preference, as no antibiotic drop is significantly more effective. Therefore, NICE listed factors should be considered to ensure treatment can be tailored to each patient.

Key Points

• Topical ear preparations are an appropriate flrst-line treatment option for Acute Otitis Externa, and should be prescribed before systemic antibiotics in the majority of cases
• Choosing which topical antibiotic to prescribe can be challenging, so the following factors should be considered; patient preference, risk of adverse effects, cost, dosing frequency and the status of the eardrum (NICE, 2018)
• Patient preference should not be underestimated when choosing a particular topical preparation, as increased patient compliance helps ensure the treatment is taken correctly.

CPD reflective questions

• List the treatments for Acute Otitis Externa?
• Which patient-led questions will you ask for a patient presenting with ear ache?