Treatment of Pseudomonas otitis in the dog (Sponsored by Pfizer)

Otitis externa is a common presenting problem in clinical practice. In chronic cases, the infection frequently extends to the middle ear. While multiple factors contribute to otitis development and subsequent secondary infections, the organisms found most often in affected ears include Staphylococcus species, Malassezia pachydermatis, and Pseudomonas aeruginosa.1

P. aeruginosa, a gram-negative bacillus, is ubiquitous in the environment but an uncommon inhabitant of the normal external ear canal and middle ear of dogs. As small animal veterinarians can attest, ears infected with P. aeruginosa can be some of their most challenging cases. Studies have reported moderate to high levels of resistance to some commonly used antimicrobials of P. aeruginosa isolates from cases of otitis externa.1-4

Clinical signs

Animals with P. aeruginosa ear infections typically exhibit one or more of the following clinical signs or conditions:

• head shaking or ear scratching

• purulent exudate (occasionally hemopurulent or mucoid) (Figure 1)

• malodor

• swelling, inflammation, and pain

• ulceration

• otitis media

It has been reported that otitis media is present in as many as 83% of dogs with chronic otitis externa.1 The most common feature of otitis media is persistent and chronic otitis externa. Neurologic abnormalities (e.g., Horner's syndrome, facial nerve paralysis, peripheral vestibular disease, and deafness) are present in some cases of otitis media. In addition, the tympanic membrane may be ruptured or intact, so don't rule out the possibility of otitis media if you find an intact membrane. Intact tympanic membranes may be bulging, hemorrhagic, brown, gray, or opaque, and exudate may be visible in the middle ear.

Figure 1: Chronic otitis with Pseudomonas aeruginosa infection. Note the purulent discharge and the erosive and ulcerative lesions of the anthelix and tragus around the ear canal opening.

Diagnostic procedures

All otitis cases require swab cytology of the otic exudate. Evaluate prepared slides for bacteria (cocci and rods), yeast (M. pachydermatis), and the type and number of leukocytes under high-dry (×400 to ×800) or oil-immersion (×1000) magnification. P. aeruginosa appear as rod-shaped organisms, typically in the presence of neutrophils (Figure 2). Practitioners should also repeat the cytology at each recheck to monitor the patient's response to treatment.

Figure 2: Cytology preparation of the exudate obtained from the dog shown in Figure 1. Note the rod-shaped Pseudomonas organisms that are visible both extracellularly and intracellularly within neutrophils (Diff-Quik stain, 31000 magnification).

In some otitis cases, patients fail to respond to initial empirical therapy or the condition recurs rapidly after apparently successful therapy. If this occurs, perform culture and susceptibility testing of the otic exudate. Samples are easily obtained by inserting sterile swabs to the junction of the vertical and horizontal external ear canals.

If you suspect otitis media, obtain a sample from the middle ear (tympanic bulla cavity) using either a sterile calcium alginate (Calgi) swab or a syringe attached to a 3-F tomcat catheter to instill, and subsequently suction, 0.5 ml of sterile saline. If the tympanic membrane is intact—as is often the case—you must perform a myringotomy in the caudoventral quadrant of the pars flaccida tensa to gain entry into the middle ear.

In otitis media cases, it's important to obtain separate cultures from the external and middle ears because the organisms and their antibiotic susceptibility patterns often differ between these two locations.1

I find it useful to conduct computed tomography (CT) or magnetic resonance imaging (MRI) on the ear canal and middle ear as a guide to the most appropriate therapy. For example, if considerable cartilage calcification is found in the external ear canal or bony changes are present in the tympanic bulla, then the prognosis is poor for resolving otitis with medical therapy alone, and surgery (total ear canal ablation with bulla osteotomy) is indicated. The absence of fluid in the middle ear or bony changes in the tympanic bulla does not rule out the possibility of otitis media.

Treating Pseudomonas otitis

The two most critical elements of treating Pseudomonas otitis are: 1) keeping the ear clean, and 2) administering antimicrobial therapy.

In addition, in chronic otitis cases with swelling and inflammation of the ear canal epithelium (leading to canal stenosis), it's vital to reduce swelling and open the ear canal. Swollen and stenotic external ear canals prevent canal and tympanic membrane evaluation, ear canal cleaning, and antimicrobial agent application.

Cleaning the ear of debris and exudate is important for several reasons, including the following:

• It removes the nidus for reinfection.

• It removes bacterial and inflammatory debris.

• It allows antimicrobial agents to penetrate the entire ear canal.

• It prevents purulent debris from inactivating some antimicrobial agents.

If otitis media is present, a deep ear flush under general anesthesia is essential. Veterinarians can flush the middle ear with a 3-F tomcat catheter or 5-F urinary catheter after collecting swab specimens for cytology and culture. (You may need to perform a myringotomy first if the tympanic membrane is intact.) Flushing may need to be repeated one to two weeks later if home cleaning does not control exudate accumulation.

In chronic otitis cases with substantial swelling, hyperplasia, and inflammation leading to stenosis of the ear canal, effective ear cleaning (in the clinic or at home) can be achieved only after reducing the swelling and inflammation and opening the ear canal.

Owners should also be taught proper ear-cleaning techniques. After filling the ear canal with the cleanser, an owner should gently massage the vertical canal for as long as possible—preferably one minute—while preventing the dog from shaking its head. Otherwise, much of the cleanser will be lost prematurely through head shaking. If necessary, the process can be repeated immediately.

Owners can use cotton balls to wipe away excess cleanser around the external ear canal opening. They should not put cotton swabs or cotton balls inside the ear canal because this could cause trauma, including epithelium maceration or debris impaction.

In acute otitis cases, owners should clean the affected ears every 24 to 72 hours, depending on the degree of exudate accumulation. For chronic otitis or cases where otitis media is present, they should clean the ears daily.

For Pseudomonas otitis, I use either Epi-Otic (Virbac) or an acid-based cleaner, such as OtiRinse (DVM Pharmaceuticals), Oti-Clens (Pfizer), or MalAcetic Otic (DermaPet). Epi-Otic has been shown to have considerable antimicrobial activity both in vitro5 and in vivo. In one study, flushing the ears twice daily with Epi-Otic alone resolved Pseudomonas otitis within two weeks in four dogs.6

Antimicrobial therapy

P. aeruginosa is often resistant to multiple antimicrobial agents. Successful treatment depends on selecting appropriate antibiotics for aggressive topical and systemic administration. Table 1 lists the antibiotics that may be used to treat P. aeruginosa infections.

Table 1: Antibiotics with Potential Activity Against Pseudomonas Aeruginosa

Topical antimicrobials. Topical antibiotic administration exposes Pseudomonas bacteria to high concentrations of an antibiotic (often more than 1,000 times the minimum inhibitory concentration [MIC] of the organism). In some strains of Pseudomonas with in vitro resistance, high antibiotic concentrations can overcome the bacteria's resistance mechanisms and kill them. Therefore, topical antimicrobials must be used in all Pseudomonas otitis cases. As a general guideline, five to 10 drops (depending on the dog's size) of topical antimicrobial agent should be applied to the ear twice daily.

In cases with ruptured tympanic membranes, all topically applied antibiotics are potentially ototoxic. When the tympanic membrane is not intact or its patency is unknown, pet owners must be warned of potential adverse reactions. In my experience, these cases are rare, and the benefits of topical antibiotics far outweigh the risk of ototoxicity.

Furthermore, many suggested antibiotic treatments for Pseudomonas otitis are formulated in clinics, and their stability and safety is typically unknown. Fortunately, numerous products are licensed and available for topical use in dogs' ears.

In acute Pseudomonas otitis cases, first-line topical antibiotics include neomycin, polymyxin, and gentamicin. Cases that fail to respond to initial therapy or cases of chronic Pseudomonas otitis call for second-line topical antibiotics, such as tobramycin, amikacin, enrofloxacin, ticarcillin, and silver sulfadiazine.

In these circumstances, presoaking the ear canal with Tris-EDTA (T8 Solution—DVM Pharmaceuticals or TrizEDTA—DermaPet) enhances the activity of the subsequently applied topical antibiotic. Tris-EDTA disrupts the cell membranes of gram-negative bacteria, such as Pseudomonas species, allowing the antibiotics to permeate the bacteria and work more effectively.7

Systemic antimicrobials. Adding systemic antibiotics to treatment plans for Pseudomonas otitis depends on one or more of the following indications:

• the presence of otitis media,

• marked swelling and hyperplasia of the ear canal epithelium (indicating tissue infection),

• ulceration of the ear canal epithelium (indicating a portal of entry for bacteria into deeper tissue),

• inability of the owner to treat topically,

• adverse reactions to topical medications.

Few antibiotics with activity against P. aeruginosa are available for systemic use. Many of these antibiotics (e.g., amikacin, ticarcillin, carbenicillin, and ceftazidime) must be administered subcutaneously or intravenously, which is impractical for medium- to long-term treatment.

Orally administered antibiotics for Pseudomonas infection are limited to fluoroquinolones, which should be selected based on bacterial culture and susceptibility testing results. In theory, two specific ratios help determine whether the antibiotic is efficacious and whether resistance is likely to develop. These ratios are based on the susceptibility of the infective organism and the pharmacokinetics of the selected fluoroquinolone:

• Maximum plasma concentration (Cmax)/MIC90: A ratio of at least 8 is preferable. If the ratio is less than 8, then it's more likely that resistant Pseudomonas strains will emerge.8

• Area under the curve (AUC)/MIC: A ratio of at least 125 will likely indicate clinical efficacy.9

Unfortunately, it is seldom—if ever—possible to select a specific fluoroquinolone that meets these target ratios. One reason is that many veterinarians don't receive the MIC results reported by laboratories for the isolated bacteria. Most labs supply Kirby-Bauer disk diffusion results, which merely indicate whether the organism is susceptible, intermediately susceptible, or resistant to the antibiotic. Second, no published reports exist listing the tissue levels of any fluoroquinolone in the ear epithelium of dogs with otitis externa. Thus, the Cmax and AUC for the target tissue are unknown. Finally, clinical studies have not determined if failure to achieve these target ratios equates to treatment failure and resistance.

However, there are some published data, albeit limited, that practitioners can refer to for general guidance when selecting fluoroquinolones.

In one study, the MICs for various fluoroquinolones for the ATCC strain 27853 of P. aeruginosa were measured. The results (in order of increasing resistance on a µg-to-µg basis): ciprofloxacin (0.52 µg/ml), marbofloxacin (2.1 µg/ml), enrofloxacin (4.4 µg/ml), and orbifloxacin (10 µg/ml).10 According to the package inserts, the MIC ranges for P. aeruginosa are 0.25 to 1.1 µg/ml for marbofloxaxin (seven isolates), 0.5 to 8 µg/ml for enrofloxacin (four isolates), and 0.39 to 25 µg/ml for orbifloxacin (14 isolates). The insert for difloxacin does not list the P. aeruginosa MIC range.

Studies of the susceptibility of clinical isolates of P. aeruginosa to various fluoroquinolones have been reported: 93.4% of isolates were susceptible to ciprofloxacin and marbofloxacin and 71% of isolates were susceptible to enrofloxacin (106 of the 183 isolates were from infected ears);2 89.9% of isolates were susceptible to marbofloxacin and 42.1% of isolates were susceptible to enrofloxacin (19 isolates from ears with chronic otitis externa).3

In another study, there was susceptibility to enrofloxacin in 51% of 38 isolates from the middle ear of dogs with otitis media (some isolates [6/10] resistant to enrofloxacin using the Kirby-Bauer method were susceptible with MIC testing);4 another report showed susceptibility to enrofloxacin in 12.5% of isolates from the external ear canal and 35% of isolates from the middle ear (in dogs with chronic otitis externa).1

In yet another study, 54 dogs with suppurative otitis (43.8% were infected with Pseudomonas species) were treated only with marbofloxacin (5 mg/kg orally once daily) for 21 to 42 days. A topical otic treatment was not used. In this study, 27.8% of the dogs were cured, 42.6% showed partial to marked improvement, and 29.6% failed to respond.11

Finally, the half-life of marbofloxacin is considerably longer than other veterinary fluoroquinolones, resulting in a higher AUC and a potentially greater AUC/MIC ratio.

Based on these studies and my experience with Pseudomonas isolated from ear canals at The Ohio State University, I most commonly use marbofloxacin for systemic treatment of Pseudomonas otitis when susceptibility testing indicates that the organisms are susceptible or intermediately susceptible. I also prescribe at the high end of the flexible dosing range—5.5 mg/kg once daily.

Although ciprofloxacin appears to have good activity against P. aeruginosa,10 the product is not labeled for veterinary use and has low bioavailability after oral dosing. If Pseudomonas is cultured from the ear and susceptible to other fluoroquinolones, then those fluoroquinolones may also be appropriate choices for systemic use at the high end of the flexible dosing range.

It should be noted that some organisms are resistant to all fluoroquinolones, and even exceptionally high doses won't resolve the infection with systemic treatment alone.

Treatment for hyperplastic and stenotic ear canals

In many patients with chronic Pseudomonas otitis, the ear canals are swollen, hyperplastic, and severely inflamed, leading to stenosis of the canal. These chronic changes must be reduced and reversed from the outset so the ear canal and tympanic membrane can be evaluated, the ear canal cleaned, and appropriate topical antimicrobial agents applied.

To achieve this, veterinarians should administer corticosteroids, even in cases with severe infection. In all these cases, patients should receive 1 to 2 mg/kg of prednisone orally once daily for one to three weeks. If necessary, additional high-potency, topical corticosteroids may be used (e.g., fluocinolone, betamethasone, dexamethasone, or triamcinolone).

A few cases of acute Pseudomonas otitis are also associated with significant swelling, edema, and inflammation. In these cases, I recommend dispensing 1 to 2 mg/kg of prednisone once daily for three to seven days. Table 2 provides guidelines for treating Pseudomonas otitis in dogs.

Table 2: Treatment Summary for Acute and Chronic Pseudomonas Otitis

Follow-up

Treatment for acute otitis is likely to be successful within one to three weeks. In chronic otitis cases, treatment duration is typically at least four weeks and may last as long as three months or more. If systemic corticosteroid therapy, general anesthesia, imaging, deep ear flushing, and aggressive topical and systemic therapy are necessary, the costs and the risk of side effects increase.

In some cases, despite the best efforts of veterinarians and dog owners, a few patients with Pseudomonas otitis don't respond to medical therapy. At this point, the best option is a total ear canal ablation and bulla osteotomy. Thankfully, this is rarely necessary if veterinarians pursue an aggressive diagnostic and therapeutic approach like the one outlined above.

Finally, and most important, preventing a recurrence of otitis depends on the determination and control of the primary and underlying causes of ear disease. In my practice, the primary cause of otitis is allergic, such as atopic dermatitis or adverse food reactions. Less common causes include parasites, endocrine disorders, keratinization disorders, and neoplasia.

Conclusion

P. aeruginosa is one of the most common bacteria isolated from cases of infectious otitis. Although many cases of acute infection respond to empirical topical treatment, dogs with chronic Pseudomonas otitis present an important challenge to clinicians. In these cases, successful outcomes depend on aggressive ear cleaning with topical otic and systemic antibiotic therapy. If responses to initial empirical therapy are incomplete or unsatisfactory, clinicians should immediately institute a bold diagnostic and therapeutic plan to effectively resolve the infection.

References

1. Cole LK, Kwochka KW, Kowalski JJ, et al. Microbial flora and antimicrobial susceptibility patterns of isolated pathogens from the horizontal ear canal and middle ear in dogs with otitis media. J Am Vet Med Assoc 1998;212:534-538.

2. Seol B, Naglic T, Madic J, et al. In vitro antimicrobial susceptibility of 183 Pseudomonas aeruginosa strains isolated from dogs to selected antipseudomonal agents. J Vet Med B Infect Dis Vet Public Health 2002;49:188-192.

3. Martin Barrasa JL, Lupiola Gomez P, Gonzalez Lama Z, et al. Antibacterial susceptibility patterns of Pseudomonas strains isolated from chronic canine otitis externa. J Vet Med B Infect Dis Vet Public Health 2000;47:191-196.

4. Colombini S, Merchant SR, Hosgood G. Microbial flora and antimicrobial susceptibility patterns from dogs with otitis media. Vet Dermatol 2000;11:235-239.

5. Lloyd DH, Bond R, Lamport I. Antimicrobial activity in vitro and in vivo of a canine ear cleanser. Vet Rec 1998;143:111-112.

6. Cole LK, Kwochka KW, Kowalski JJ, et al. Evaluation of an ear cleanser for the treatment of infectious otitis externa in dogs. Vet Ther 2003;4:12-23.

7. Lambert RJ, Hanlon GW, Denyer SP. The synergistic effect of EDTA/antimicrobial combinations on Pseudomonas aeruginosa. J Appl Microbiol 2004;96:244-253.

8. Lode H, Borner K, Koeppe P. Pharmacodynamics of fluoroquinolones. Clin Infect Dis 1998;27:33-39.

9. Nicolau DP, Quintiliani R, Nightingale CH. Antibiotic kinetics and dynamics for the clinician. Med Clin North Am 1995;79:477-495.

10. Riddle C, Lemons CL, Papich MG, et al. Evaluation of ciprofloxacin as a representative of veterinary fluoroquinolones in susceptibility testing. J Clin Microbiol 2000;38:1636-1637.

11. Carlotti DN, Guagere E, Koch HJ, et al. Marbofloxacin for the systemic treatment of Pseudomonas spp., suppurative otitis externa in the dog (poster abstract). In: Kwochka KW, Willemse T, von Tscharner C, eds, Advances in Veterinary Dermatology (Vol 3), Butterworth Henemann, Oxford, 1998; 463-464.