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Ototopical agents are superior to systemic therapy for the treatment of acute and chronic otitis media.

I believe we should use topical rather than systemic agents as first-line therapy for infections in patients with perforated tympanic membranes.

Disadvantages of ototopicals

Certainly, topical agents have some disadvantages, particularly those that are related to discomfort, the need for direct contact, inflammation, systemic effects, ototoxicity, and sensitization.

Discomfort. The mucosa of the middle car space is much more sensitive than the skin of the external auditory canal. Consequently, most problems pertaining to discomfort occur when topical medications enter the middle ear space. Children in particular find eardrops to be uncomfortable, and therefore drops can be difficult to administer; no parent likes to instill drops into the ears of a screaming, squirming child.

The normal pH of the external auditory canal is acidic (pH: 6.1). The acidic environment suppresses bacterial growth (especially that of Pseudomonas aeruginosa) and can help prevent infection. Therefore, many topical medications designed for use in the external auditory canal are buffered to an acidic pH. The normal pH of the middle ear mucosa, on the other hand, is neutral. When acidic drops--for example, neomycin/polymyxin B/hydrocortisone preparations, whose pH levels range between 3.0 and 3.5 depending on the manufacturer--are placed in the middle ear, they can cause intense burning and pain. Medications buffered to a higher pH are often entirely painless. Likewise, alcohol-containing drops sting and burn intensely, and their use should be avoided when they can enter the middle ear space.

Finally, the temperature of eardrops is a potential disadvantage. Cold solutions placed in the external auditory canal can be quite uncomfortable, especially in children. Children may have difficulty distinguishing between pain and the unpleasant sensation of cold medication. Fluids that are significantly warmer or cooler than body temperature can produce caloric stimulation of the inner ear and result in dizziness. When possible, medication should be delivered close to body temperature. Therefore, it is recommended that you warm the drops before instilling them, either by rubbing the dropper in your hands or by immersing it in tepid water for a few minutes.

Direct contact. Another potential disadvantage is that therapy necessitates that the drops come into direct contact with infected tissue. However, the external auditory canal might be so filled with desquamated epithelium, cerumen, and mucopurulence that medications cannot effectively reach the target tissues. Therefore, if topical therapy is to be effective, these materials must be removed. This can be accomplished in the physician's office by mechanical removal or by gentle irrigation with 3% hydrogen peroxide at full or half strength.

Inflammation. Some medications have direct inflammatory effects. They include some antibiotics, as well as vehicles such as propylene glycol. Because inflammation is already part of the pathologic process, additional inflammation is an undesirable side effect that should be minimized or counteracted. The steroid component present in many preparations can serve this function.

Systemic effects. If a systemic effect is desirable, then, of course, the absence of a systemic effect is a disadvantage. For example, if infection has spread beyond the external auditory canal and the middle ear, topical preparations will not be effective. Other examples of such a situation include bacterial external otitis that has spread to the periauricular areas with cellulitis, otitis that disseminates to regional lymph nodes, and otitis media that develops into mastoiditis. Fortunately, these circumstances are uncommon, and there is usually no need for systemic medication.

Ototoxicity. The aminoglycoside antibiotics and polymyxin B are devastatingly ototoxic in animals. A single dose of neomycin/polymyxin B/hydrocortisone into the external auditory canal of a chinchilla passes easily through a tympanostomy tube and produces a significant loss of hair cells in the basal turn of the cochlea. (1) Even a single dose of antibiotic drops instilled directly into the middle ear can produce total hair-cell loss. (2)

The extent to which these animal data can be extrapolated to humans has always been a source of speculation. The incidence of hearing loss associated with the use of ototoxic drops is certainly less catastrophic in humans, but a number of case reports do exist? Researchers at the University of Toronto have demonstrated that vestibular toxicity may be significantly higher. A recent consensus panel convened by the American Academy of Otolaryngology--Head and Neck Surgery has therefore recommended that antibiotic drops that are not potentially ototoxic should be used instead of drops that might cause inner ear injury (page 13). (4)

Sensitization. The aminoglycosides and especially neomycin have a propensity to cause topical sensitization. While fulminant hypersensitivity reactions are usually relatively easy to recognize, hypersensitivity may take a more subtle form. Oftentimes, the only manifestations of hypersensitivity are persistent erythema, edema, and otorrhea, which simply represent a failure of the ear to respond to therapy. In such circumstances, it may be impossible to distinguish between hypersensitivity reactions and clinical treatment failures.

Advantages of ototopicals

By using a topical agent, the physician can deliver a concentration of medication that is several orders of magnitude higher than the concentration of a systemic agent. Topical delivery systems maximize the therapeutic ratio.

A 3- to 5-drop dose of 0.3% solution contains only 90 to 150 [micro]g of antibiotic, but its concentration is 3,000 [micro]g/ml, which exceeds the minimum inhibitory concentration of any known relevant pathogen. In contrast, consider the typical drug levels in middle ear fluid that can be achieved by three systemic antibiotics:

* cefuroxime: 1 to 2 [micro]g/ml

* amoxicillin: 8 to 10 [micro]g/ml

* ceftriaxone: 25 to 30 [micro]/ml

Despite the high concentrations in topical eardrops, the risk of systemic side effects or adverse reactions is very low. Moreover, the very high concentrations also make the emergence of resistant strains much less likely.

Ohyama et al measured the persistence of a single dose of topically applied 0.3% ofloxacin in otorrhea fluid, serum, and middle ear mucosa at various time intervals following administration. (5) They found a very high level of antibiotic in the otorrhea fluid several hours later (table). Perhaps their most surprising finding was the relatively high concentration of drug in biopsy specimens of middle ear mucosa immediately following administration in some patients. Drug concentrations in serum were very low. Ohyama et al documented that topical antibiotic solutions can be and often are effectively delivered to the middle ear space.

Another advantage of ototopicals is that they can alter the microenvironment (1) by changing the pH; (2) by removing debris, purulence, and cerumen within the canal; and (3) by the actions of their emollient effects. Finally, ototopicals are generally less expensive than systemic equivalents.

Comparisons of topical and systemic therapy

Esposito et al conducted two studies of the clinical and bacteriologic efficacy of topical ciprofloxacin in chronic otitis media.

In 1990, they reported their study of three groups of 20 adults who were randomized to receive one of three regimens for 5 to 10 days. (6) One group received oral ciprofloxacin at 250 mg twice daily, another received 3 drops of ciprofloxacin (250 [micro]g/ml in a saline solution) twice a day, and the third received both the oral and topical ciprofloxacin doses twice a day. The topical group had a clinical response rate of 100% and a bacteriologic cure rate of 95%, and the topical/oral group had rates of 95 and 85%, respectively. By contrast, the oral group had corresponding rates of 65 and 40%, a statistically significant difference. When clinical and bacteriologic cure rates were combined, the differences between the topical groups and the oral group were also statistically significant (p < 0.05) (figure 1).

Two years later, Esposito et al published the results of their comparison of topical ciprofloxacin and intramuscular gentamicin in 60 adults. (7) All patients had perforated eardrums and Pseudomonas infection susceptible in vitro to both agents, and none had cholesteatoma; 40 of them had previously undergone systemic therapy. Half the group was randomized to receive 4 drops of ciprofloxacin (250 [micro]g/ml in a saline solution) twice a day for 5 to 10 days, and the other half received twice-daily 80-mg injections of gentamicin for 5 to 10 days. Patients were assessed clinically and microbiologically 12 hours following the cessation of treatment and again 2 to 3 weeks later. Favorable clinical responses were seen in 26 ciprofloxacin patients (87%) and in 20 gentamicin patients (67%). Only 13 gentamicin patients (43%) achieved microbiologic eradication, compared with 25 ciprofloxacin patients (83%) (figure 2).

Topicals in CSOM

Two other studies of note looked at the efficacy of topical fluoroquinolones in chronic suppurative otitis media (CSOM).

In 1994, Yuen at al published the results of their prospective comparison of topical 0.3% ofloxacin and oral amoxicillin/clavulanate in 56 patients. (8) One week after the completion of treatment, 76% of the ofloxacin group had dry ears, compared with only 26% of the other group.

Three years later, Fradis et al reported the findings of their placebo-controlled study of topical ciprofloxacin and topical tobramycin. (9) P aeruginosa was the most common isolate. A total of 51 patients (60 ears) with CSOM without cholesteatoma were randomized to take one of the three preparations at 5 drops 3 times a day for 3 weeks. At the completion of therapy, a clinical response was seen in 79, 72, and 41% of the ears, respectively; corresponding bacteriologic cure rates were 67, 67, and 20%. The sensitivity of P aeruginosa to ciprofloxacin and tobramycin was 94 and 71%, respectively.

Antibiotic/steroid combinations in AOMT

Two studies have shown that the addition of a steroid to a quinolone is more effective than quinolone monotherapy in the treatment of children with acute otitis media through tympanostomy tubes (AOMT).

A combination of 0.3% ciprofloxacin and 0.1% dexamethasone was compared with ciprofloxacin alone in a patient-blinded, parallel-group, multicenter study of 201 patients aged 6 months to 12 years with AOMT of 3 weeks' duration or less and with visible otorrhea. (10) Patients were randomized to receive their respective drops twice daily for 7 days. Patients were evaluated on days 1, 3, 8, and 14 (test-of-cure visit). Patients or their parents also kept diaries to record the status of their otorrhea twice a day. Of the 201 patients, 167 were microbiologically culture-positive. Among this subgroup, the time to cessation of otorrhea was significantly shorter among those who had received the combination drop (4.22 vs. 5.31 days; p = 0.004); the combination-therapy group also exhibited significantly better clinical responses on days 3 and 8 (p < 0.0001 and p < 0.0499, respectively). At the test-of-cure visit, clinical and microbiologic cure rates in the two groups were similar. The authors concluded that the benefit of adding the steroid, which led to a 20% reduction in the time to cessation of otorrhea, is clinically meaningful.

In a similar study, topical ciprofloxacin/dexamethasone otic suspension and ofloxacin otic solution were compared in 599 patient--aged 6 months to 12 years (mean: 2.5 yr)--with AOMT of 3 weeks' duration or less. (11) Patients were randomized to receive the same ciprofloxacin/dexamethasone combination (4 drops twice daily for 7 days) or 0.3% ofloxacin (5 drops twice daily for 10 days, which is its indicated dosage). According to findings at the test-of-cure visit (day 18), ciprofloxacin/dexamethasone was superior to ofloxacin in terms of clinical (overall 86 vs. 79% and for culture positive patients 90 vs. 78%) and microbiologic (92 vs. 81.8%) cure. Treatment failure rates were 4.4 and 14.1%, respectively, and the time to cessation of otorrhea was 4 days and 6 days, respectively. All of these differences were statistically significant (p < 0.05).
Table. Antibiotic concentrations in otorrhea fluid and middle ear
mucosa

Measured No. Time after Mean concentration
substance patients administration (range)

Otorrhea fluid 17 30 min to 2 hr 1,569 [micro]g/g (388 to
 2,849)
 16 3 to 5 hr 262 [micro]g/g (81 to
 1,099)
Mucosa 16 -1 hr 31.7 [micro]g/g (0 to 602)

Source: Ohyama et al, 1999. Reference 5.

Figure 1. In the comparison of oral and topical ciprofloxacin in
the acute stage of chronic otitis media, combined clinical and
bacteriologic cure rates were significantly higher in the topically
treated groups. Source: Esposito et al, 1990. Reference 6.

 Oral Topical
 ciprofloxacin ciprofloxacin Both

Cured 40 85 75
Improved 25 15 20
Failed 35 0 5

Notes: Table made from bar graph.

Figure 2. In the comparison of topical ciprofloxacin and intramuscular
gentamicin in the acute stage of chronic otitis media, the bacterial
eradication rate was significantly higher in the topical
ciprofloxacin groups. Source: Esposito et al, 1992. Reference 7.

 Topical Intramuscular
 ciprofloxacin gentamicin

Cured 83 43
Improved 4 24
Failed 13 33

Notes: Table made from bar graph.


References

(1.) Wright CG, Meyerhoff WL, Halama AR. Ototoxicity of neomycin and polymyxin B following middle ear application in the chinchilla and baboon. Am J Otol 1987;8:495-9.

(2.) Rohn GN, Meyerhoff WL, Wright CG. Ototoxicity of topical agents. Otolaryngol Clin North Am 1993;26:747-58.

(3.) Matz G, Rybak L, Roland PS, et al. Ototoxicity of ototopical antibiotic drops in humans. Otolaryngol Head Neck Surg 2004;130(3 suppl):S79-82.

(4.) Roland PS, Stewart MG, Hannley M, et al. Consensus panel on role of potentially ototoxic antibiotics for topical middle ear use: Introduction, methodology, and recommendations. Otolaryngol Head Neck Surg 2004; 130(3 suppl):S51-6.

(5.) Ohyama M, Furuta S, Ueno K, et al. Ofloxacin otic solution in patients with otitis media: An analysis of drug concentrations. Arch Otolaryngol Head Neck Surg 1999;125:337-40.

(6.) Esposito S, D'Errico G, Montanaro C. Topical and oral treatment of chronic otitis media with ciprofloxacin. A preliminary study. Arch Otolaryngol Head Neck Surg 1990;116:557-9.

(7.) Esposito S, Noviello S, D'Errico G, Montanaro C. Topical ciprofloxacin vs intramuscular gentamicin for chronic otitis media. Arch Otolaryngol Head Neck Surg 1992;118:842-4.

(8.) Yuen PW, Lau SK, Chau PY, et al. Ofloxacin eardrop treatment for active chronic suppurative otitis media: Prospective randomized study. Am J Otol 1994;15:670-3.

(9.) Fradis M, Brodsky A, Ben-David J, et al. Chronic otitis media treated topically with ciprofloxacin or tobramycin. Arch Otolaryngol Head Neck Surg 1997;123:1057-60.

(10.) Roland PS, Anon JB, Moe RD, et al. Topical ciprofloxacin/ dexamethasone is superior to ciprofloxacin alone in pediatric patients with acute otitis media and otorrhea through tympanostomy tubes. Laryngoscope 2003;113:2116-22.

(11.) Roland PS, Kreisler LS, Reese B, et al. Topical ciprofloxacin/ dexamethasone otic suspension is superior to ofloxacin otic solution in the treatment of children with acute otitis media with otorrhea through tympanostomy tubes. Pediatrics 2004;113:e40-6.
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Author:Roland, Peter S.
Publication:Ear, Nose and Throat Journal
Geographic Code:1USA
Date:Sep 1, 2004
Words:2431
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