Microbiology of Otitis Media

The most common microbes recovered from chronic otitis media in the dog include Pseudomonas aeruginosa and Staphylococcus intermedius.^9,13 In one study, one or the other of these two bacteria was isolated in over 70% of the cases.² Other isolates include streptococci, Proteus, Klebsiella, E.

When microbiologic samples from the middle ear were compared with the same bacterial isolates found in the horizontal canal, the antibiotic sensitivity of organisms isolated from the horizontal ear canal was different from the antibiotic sensitivity of organisms from the middle ear. This occurred in almost 80% of these cases.² This supports the notion that different strains of the same bacteria may be better suited to survive on different tissue types.

Bacterial sensitivity reports are based on the amount of antibiotic in serum required to kill the organism. So an antibiotic reported capable of treating an external or middle ear infection may be useless if the antibiotic cannot get to the bacteria. Due to the poor blood supply in the external ear canal and middle ear, there is limited diffusion of antibiotic from the serum into the lumen of the ear canal or tympanic bulla. In some inflammatory conditions, blood supply increases and may slightly increase antibiotic levels. For example, enrofloxacin (Baytril, Bayer) has been shown to produce poor skin levels in the normal skin. When tissue levels were meas­ured in inflamed skin, the tissue level doubled. However, even with the doubling effect, the levels were much lower than the MIC for many resistant bacteria.

It is not uncommon for a number of different isolates of the same bacteria to be found in a microbiologic sample from the middle ear. This further confounds interpre­tation of culture and sensitivity results. The laboratory may report that the organism was Pseudomonas aeruginosa.

In ear disease, laboratory assessment based on culture and sensitivity does not usually correlate to clinical response. Antibiotic resistance mechanisms differ markedly, so even though the organism may be reported as resistant to an antibiotic, alterations in the use of the antibiotic may render it sensitive. In dogs that have been repeatedly treated for chronic otitis externa with a variety of topical antibiotics or suboptimal doses of systemic antibiotics, the bacteria adapt readily and become resistant to further antibiotic therapy.

Three mechanisms of antibiotic resistance are recognized. The first relates to the organisms producing substances that inactivate or modify the antibiotic. The second relates to the ability of the bacterium to provide a membrane barrier to antibiotic diffusion. Often resistant bacteria have undergone mutation and a gene expression of “efflux pumps” functions to extrude absorbed antibiotic actively from the bacteria through the cell membrane. The third mechanism of resistance involves the bacteria altering the sites at which antibiotics bind to them, rendering the antibiotic incapable of acting on the bacteria.⁸ The challenge to the veterinarian treating dogs with resistant external and middle ear infections is to provide different therapeutic options to outwit the bacteria.

Examples of the first mechanism of resistance include penicillinase-producing bacteria and β-lactamase enzyme-producing bacteria. These enzymes either bind to penicillins or cleave the penicillins and prevent them from interfering with bacterial wall synthesis. Semisynthetic penicillins such as methicillin fool the penicillinase enzyme by having a modified ring structure. Strategies for treating β-lactamase enzyme producers include formulating the antibiotic with compounds that inactivate the enzyme such as clavulanic acid.

When there is an efflux pump mechanism involved in bacterial resistance, increasing the extracellular concentration of the drug to overwhelm the pumps increases the intracellular concentration of the drug. In the middle ear, this can be achieved by using topically infused antibiotics with 100 to 1000 times the concen­trations in the tympanic bulla compared with their parenteral administration. Much current research is underway to identify substances that act as efflux pump inhibitors that can inactivate the pumps and allow antibiotics to concentrate in the bacteria. Increased antibiotic concentrations can also be achieved in the middle ear by using certain antibiotics that concentrate in inflammatory cells. However, there is a limit to the concentrations of these drugs that can be achieved in tissue, ranging from 5 to 15 times serum levels.

By chelating metal ions (magnesium, calcium [Ca⁺⁺], and zinc) from the gram­negative bacterial cell membrane, tris-EDTA (TrizEDTA, DermaPet, Inc.) makes the bacterial cell membrane more porous so concentrated antibiotic solutions can diffuse more easily into the bacteria.¹⁰ Tris-EDTA may indirectly interfere with the efflux pump mechanism by chelating the Ca⁺⁺ ions required for the active pump mechanism. Future drug formulations may contain a mixture of an antibiotic and an efflux pump inhibitor.

When the bacteria become resistant by preventing the antibiotic from binding to it, another antibiotic with a different mechanism of action is required. For example, certain bacteria can add a methyl group to their ribosomal ribonucleic acid (RNA), inhibiting the binding of macrolide drugs such as erythromycin and lincomycin to the 50S ribosome, so they become resistant to these drugs. Cross-resistance among the lincosamides and the macrolides is common because all of these drugs bind to the same site.

In cats with otitis media and polyps, the most common bacterial organism isolated was Staphylococcus intermedius. Other bacteria have been isolated from cat middle ears, including Pseudomonas, Bordetella, Bacteroides, Fusobacterium, and Mycoplasma.¹¹ Fortunately, bacterial resistance problems are not usually a feature of feline otitis media.

Antibiotic sensitivity patterns are important in treating otitis media because systemic antibiotics alone are often used to achieve levels within the bulla. If a bacterium is reported as sensitive to an antibiotic, and that antibiotic can get to the site of infection, systemic therapy may help. Unlike treating otitis externa, where topical antibiotics can achieve many times the blood MIC, systemic antibacterial therapy for otitis media relies on lower levels of antibiotics arriving in the middle ear hematogenously or through inflammatory cells.

Certain antibiotics can achieve therapeutic levels in the tympanic bulla when administered parenterally. Both clindamycin and the fluoroquinolones concentrate in inflammatory cells. They may be carried into areas of inflammation by these cells. Suppurative otitis media with purulent exudation provides the pathway for increas­ing the amount of antibiotic within the bulla. Azithromycin (Zithromax, Pfizer) also concentrates in inflammatory cells, but this erythromycin analogue also tends to concentrate in respiratory tissues at many times the level in serum.⁹ Due to its intra­cellular accumulation, azithromycin has a long half-life of 48 hours in cats and 72 hours in dogs.¹² Its spectrum in cats includes those upper respiratory bacteria that are commonly isolated from the middle ear (staphylococci, Mycoplasma, and Bordetella). Clindamycin and azithromycin can be used in dogs and cats for non- pseudomonal otitis media. Development of resistance to clindamycin is common, so its use should be limited to the first occurrence.

Topical antibiotic treatment of otitis media has gained recent favor in veterinary medicine. The use of topical antibiotics is based on the high levels of antibiotic that can be placed into the bulla, coupled with the poor drainage of the tympanic bulla. Aqueous solutions of non-ototoxic antibiotics can be placed directly onto the infected mucoperiosteum. Infused antibiotics can remain in contact with the inflamed, granu­lating middle ear mucosa much longer because the fluid filling the bulla cannot readily escape. Antibiotics for infusion should have a spectrum of activity against gram-negative organisms, which include Pseudomonas, and gram-positive organisms, which include Staphylococcus.

The dilemma facing the clinician treating otitis media is that systemic drug levels may not reach a sufficient MIC in the bulla and topical treatment requires frequent applications. Using maximal doses of oral antibiotics along with weekly bulla infu­sions of a fresh supply of antibiotic increases therapeutic successes.

Many infections are polymicrobial, including mixed infections of bacteria and yeasts. Cytology of a middle ear specimen may reveal Malassezia, which would not be reported if only bacterial culture was submitted to the laboratory. Cytology may not reveal bacteria because they are often protected from the cytology stains by mucus. Many cytology-negative specimens have been reported as culture positive.

Malassezia yeasts found in the middle ear may cause disease, but their presence there is the result of cellular and ceruminous debris falling into the middle ear through a perforation or rupture. This condition responds to systemic antifungal therapy.