Introduction

Cases of chronic or recurrent otitis are challenging. Successful treatment requires that all the underlying factors leading to persistence or recurrence of the otitis are identified and managed. In particular, it is important to recognise the role of inflammation in otitis. Most owners and clinicians recognise ear infections, which are then successfully managed. However, the ongoing inflammation is often missed. This leads to a cycle of recurrent infection and chronic inflammation leading to progressive pathological changes and end-stage otitis that requires surgical intervention. The chronic inflammation makes each bout of infection harder to treat and repeated antimicrobial use may select for resistance.

In recurrent otitis, the treatment that is prescribed is effective but the condition recurs after therapy is withdrawn. In refractory otitis, the infection persists even when treatment is being administered.

The Refractory Otitis Externa

Where to Start?

Some cases of refractory otitis externa develop infection with gram-negative organisms such as Pseudomonas aeruginosa. These most commonly follows treatment of a pre-existing ear infections with various antimicrobial agents. These organisms can be resistant to many commonly used antibiotics and can be difficult to treat.

1. Perform Cytology and Culture and Sensitivity

There is substantial controversy about whether to perform bacterial culture and sensitivity of infected ears. In my opinion, when there is chronic disease where rods or mixed populations are found on cytology, culture is useful.

Detecting rods on cytology is consistent with gram-negative bacteria such as Pseudomonas species, Proteus species, Escherichia coli. Pseudomonas are the most common. Bacterial culture and sensitivity testing definitively identifies the bacteria involved in the infection. This can be useful for less common organisms that are hard to differentiate on cytology, e.g., streptococci, enterococci, Escherichia coli, Klebsiella, Proteus and coryneforms.

The susceptibility pattern of these bacteria is hard to predict, although most first-time infections are susceptible to topical aminoglycosides, polymyxin B, silver sulfadiazine and fluoroquinolones. However, Pseudomonas species readily acquire resistance and most isolates from recurrent infections will be multi-drug resistant. Knowledge of their likely sensitivity patterns can then help guide treatment choices.

Antimicrobial susceptibility data is less useful for topical otic drugs because concentrations in the ear canal are much higher than those used with in vitro tests predict. The response to treatment is best assessed using clinical criteria and cytology. Antimicrobial sensitivity data can be used to predict the efficacy of systemic drugs, although the concentration in the ear tissues is often low and high doses are needed. For example, enrofloxacin would need to be given at 20 mg/kg to treat Pseudomonas isolates with an MIC of 0.5 µg/ml (middle of the susceptible range) in chronic otitis.

2. Systemic Corticosteroids

As otitis progresses, the inflammation created by primary factors leads to hyperplasia of the stratified squamous epithelial lining of the canal, resulting in narrowing of the lumen and glandular hyperplasia, leading in turn to an increased production of cerumen and hidradenitis. These chronic changes, often in tandem with recurrent courses of topical antibiotics, lead to the development of a more resistant population of bacteria, especially gram-negative bacteria, such as Pseudomonas species. Such cases require careful management as the canal is often ulcerated and painful and otitis media is a common sequel. Where the disease process becomes chronically irreversible, the lumen may be completely obliterated and in some of these cases ossification of the soft tissue may also take place. Once the damage to the ear has become this extensive, medical therapy is rarely effective. The most important perpetuating factors are listed in Table 1.

Table 1

Reducing pruritus, swelling, exudation and tissue proliferation is a key goal of therapy. Glucocorticoids (particularly dexamethasone) also reverse the ototoxic effect of Pseudomonas infections. Prednisolone (1 to 2 mg/kg every 12 to 24 hours) is sufficient to control inflammation and stenosis in most cases. Patients with severe fibrosis and stenosis, however, may respond better to dexamethasone (10 times as potent as prednisolone). Oclacitinib and lokivetmab are not effective. Ciclosporin has also been shown to be effective in some cases but is only useful for chronic otitis.

3. Remove Debris and Discharge

Ear flushing is imperative to remove discharge from the external ear canal and/or the middle ear. Removal of debris and purulent material greatly improves the efficacy of topical antimicrobials, especially aminoglycosides and polymixin B.

Excess hair should be clipped from the medial aspect of the pinna and excess exudate removed from the pinna and around the entrance to the external ear canal. One method of ear flushing is performed with a three-way tap or stopcock connected to a 10-ml syringe, warmed saline in a fluid bag and a 5-French feeding tube or 8-French polypropylene urinary catheter. It is often better to insert the feeding tube or catheter to a deeper part of the canal and backflush the material. A pulsing action can assist with dislodging trapped exudate. The external ear canal is alternately flushed and aspirated, removing the remaining exudate and debris allowing visualization of the tympanic membrane with an otoscope or video otoscope. For suppurative otitis externa, 2% acetic acid or 2% acetic acid and 2% malic acid can be used for flushing ears instead of saline for infections with Pseudomonas otitis. Two and five minute contact with 2% acetic acid is lethal to Pseudomonas and Staphylococcus respectively. Acidic cleaners may inactive some antimicrobials (especially aminoglycosides and fluoroquinolones), although ear canals have good buffering capacity and the pH rapidly returns to normal.

Biofilms

Biofilms can be physically broken up and removed by thorough flushing and aspiration. Topical trizEDTA and 2% n-acetylcysteine can disrupt biofilms, facilitating their removal and enhancing penetration of antimicrobials. Systemic administration of n-acetylcysteine is well tolerated and can help dissolve biofilms in the middle ear and other mucous surfaces.

Table 2. Ear cleaning regime

4. Treat Otitis Media

Inflammation in the ear canal will also affect the tympanic membrane, which may become oedematous, thickened or dilated. Rupture of the tympanum is common. Infection within the tympanic bulla leads to inflammation of the delicate mucoperiosteum lining of the bulla and the production of mucus, which traps infection within the bulla cavity, making it inaccessible to topical drugs. Biofilms are common within the middle ear of children.

Appropriate measures to resolve infection in the middle ear include: flushing of the bulla and the instillation of appropriate drugs into the site, which may include biofilm busting agents, anti-inflammatory drugs and antimicrobials. Where disease within the bulla is not managed, granulation tissue and bony change lead to irreversible damage that may only be successfully resolved by surgical intervention.

If the tympanic membrane is ruptured, repeated flushing of the middle ear should be performed. The tip of the feeding tube is placed adjacent to the tympanic membrane or, if the tympanic membrane is ruptured, into the middle ear under visualization through an operating otoscope. It is important to angle the tip ventrally to avoid the sensitive structures in the dorsal part of the middle ear cavity. The ear canals and middle ear are alternately flushed and aspirated until completely clean. Retrograde flushing using this technique is very effective at removing deep material and is the only effective way to clean the middle ear.

Opinion is divided on the systemic treatment of otitis media; some referral clinicians always use systemic treatment, others instill antimicrobials directly into the middle ear every three to 10 days (enrofloxacin, marbofloxacin, gentamicin appear to be safe used in this way), some use topical therapy and some a combination of approaches. It is likely that antimicrobials persist for several days following direct application into the middle ear, because this is effectively a blind-ending sac with limited drainage into the pharynx.

If the tympanic membrane is intact but appears abnormal and otitis media is suspected a myringotomy (the deliberate rupture of the tympanic membrane) should be performed to obtain samples for cytology, culture and sensitivity and to flush the middle ear cavity. An open-ended 3.5-French tomcat catheter is used to make the incision. Experimentally ruptured normal tympanic membranes heal in three to five weeks. If the ear is kept free from infection following myringotomy the tympanic membrane should heal.

5. Topical and Systemic Antimicrobial Therapy

Topical therapy should be used. This results in high concentrations in the ear canals. Systemic treatment is very useful in suppurative otitis externa and/or otitis media where there is an active inflammatory discharge with concurrent infection in the deep ear canal tissues and middle ear. Pseudomonas are resistant to many antimicrobials through low cell wall permeability, β-lactamases, clavulanate-resistance and efflux pumps. They readily develop further resistance if treatment is ineffective as they have a large genome to express resistance genes and mutations, and are capable of plasmid, transposon and bacteriophage transfer. Fluoroquinolones and gentamicin are usually effective against first time Pseudomonas infections. Fluoroquinolones, which have a high volume of distribution and penetrate well into most tissues, may have better efficacy in infections otherwise susceptible to other antimicrobials. Once fluoroquinolone resistance is established other anti-Pseudomonas antimicrobials are indicated; these are often expensive, not licensed for animals and have to been given intravenously if used systemically (Table 3).

Table 3

† Reconstituted solution stable for up to seven days at 4°C or one month if frozen
# Silver sulfadiazine shows additive activity with gentamicin and fluoroquinolones (although synergy has not been proven)

Potential Toxicity of Antimicrobial Agents

Tobramycin and amikacin are potentially ototoxic and should be used with care if the tympanic membrane is ruptured. Enrofloxacin, marbofloxacin, ceftazidime and silver sulfadiazine appear to be safe in the middle ear. There is potential for systemic toxicity with silver sulfadiazine and aminoglycosides in extensively ulcerated ears, although this is unlikely in practice as the total body dose will be low except in very small animals. The ototoxicity of gentamicin appears to depend on the preparation, and topical application of injectable solutions of gentamicin appears to be safe. Systemic aminoglycosides can be nephrotoxic and renal function should be monitored. Fluoroquinolones can cause cartilage damage in dogs under 12 months old (18 months in giant breeds) and neurotoxicity at high doses.

Tris EDTA

TrizEDTA damages bacterial cell walls and increases antimicrobial efficacy which can overcome partial resistance. It is best given 20 to 30 minutes before the antimicrobial but can be co-administered. It is well tolerated and non-ototoxic. TrizEDTA shows additive activity with chlorhexidine, gentamicin and fluoroquinolones at concentrations of 35.6/9.4 mg/ml, but there is no evidence of synergy and efficacy at lower concentrations. Solutions of 0.6 per cent enrofloxacin, 0.2% marbofloxacin, 0.3% gentamicin, 0.1% amikacin and 1.7% ceftazidime in trizEDTA are effective against many multi-drug-resistant bacteria including Pseudomonas.

Otitis media may need three to four weeks (and possibly longer) systemic treatment, which is a problem if parenteral drugs are used. Pseudomonas infections, however, usually clear quickly once effective cleansing, antimicrobial treatment and control of the primary cause are established.

6. Topical Glucocorticoids

Mild inflammation responds rapidly to low potency topical glucocorticoids, but progressively more severe inflammation requires longer courses of more potent products (Table 4). Very potent products should be avoided in severe bacterial infections, particularly Pseudomonas, as they may suppress neutrophil activity.

Once the infection has resolved, topical glucocorticoids should be used at the lowest frequency that controls the inflammation. Systemic treatment is necessary if there is stenosis, severe fibrosis or mineralisation, or if topical therapy cannot be safely administered. It is usually possible to switch to topical therapy once the ear canals have opened. Dogs better tolerate topical therapy once the pain and inflammation has decreased.

Table 4

This table should be used for guidance only, as the relative potency of topical glucocorticoids also varies with the concentration, formulation and preparation. Topical therapy is safer than systemic therapy but adverse effects can be seen, for example, the hypothalamic-pituitary-adrenal (HPA) axis can be affected for up to two to four weeks after otic administration of dexamethasone. Hydrocortisone aceponate and mometasone furoate show less local atrophy and systemic absorption than other glucocorticoids. Atrophic effects can be useful in reversing fibrosis and stenosis early in treatment, but may later interfere with epidermal migration allowing debris and desquamated cells to accumulate in the ear canals.