Polymyxin B is active against P aeruginosa but not against S aureus.28
Combining neomycin and polymyxin B broadens the spectrum of antimicrobial activity. Hydrocortisone, a low-potency steroid, purportedly helps reduce associated inflammation. Several ophthalmic preparations that contain a corticosteroid or an aminoglycoside, such as gentamicin or tobramycin, have been used off-label for otitis externa.3,29
Neomycin/polymyxin B/hydrocortisone has been shown in earlier clinical trials to be efficacious in up to 97% of cases of otitis externa.16 However, S aureus has been increasingly resistant to aminoglycosides.30,31 More than 10% of S aureus strains were resistant to gentamicin between 1987 and 1999.26,32
Possible ototoxicity. Aminoglycoside drops may cause vestibular ototoxicity when the tympanic membrane is perforated. Aminoglycosides instilled into the inner ear of test animals have been shown to damage cochlear inner and outer hair cells.33-35 Only a few similar case studies in humans have been published.36-38 Assessment of the tympanic membrane is often difficult because of excessive swelling of the external ear canal1 or patient noncooperation due to pain. In such cases—though tympanic membrane perforation is uncommon in otitis externa—physicians may want to avoid aminoglycosides.
Beware hypersensitivity. Drug hypersensitivity is another concern with topical aminoglycosides. Neomycin and thimerosal are among the antibiotic allergens most commonly detected on patch testing.39,40 Thimerosal is a preservative added to common otic formulations of neomycin/polymyxin B/hydrocortisone.41 In a retrospective review of patch testing reactions from 587 adult patients, neomycin sulfate and thimerosal elicited a hypersensitivity reaction in 53% and 18% of the patients, respectively.40
Hypersensitivity to these agents has also been shown in children by skin testing, although it is apparently rare clinically.42,43 A patch testing study involving 562 healthy schoolchildren found that 18.4% and 14.9% of the children had hypersensitivity on skin testing to neomycin sulfate and thimerosal, respectively.43 The high incidence of sensitization to neomycin and thimerosal may be related to the common use of neomycin as a topical ointment on skin abrasions and of thimerosal as a bacteriostatic preservative in immunizations in the past.
Fluoroquinolones
Oral fluoroquinolone antibiotics have been available for adults since 1990. The fluoroquinolones ofloxacin and ciprofloxacin were approved as topical therapy for otitis externa in 1997 and 1998, respectively. In addition, ofloxacin is indicated for otorrhea from the middle ear through an implanted tympanostomy tube (tube otorrhea).
Fluoroquinolones inhibit DNA gyrase and topoisomerase, which are required for bacterial DNA synthesis.23 These are broad-spectrum antibiotics that have good in vitro activity against both S aureus and P aeruginosa.23 An in vitro analysis of antimicrobial activity against clinical isolates ofS aureus and P aeruginosa indicated that ofloxacin and ciprofloxacin were more active against these pathogens than was neomycin.44 The MIC90 values of ofloxacin and ciprofloxacin, respectively, were 1.0 μg/mL and 2.0 μg/mL for S aureus and 2.0 μg/mL and 0.25 μg/mL for P aeruginosa. In contrast, the MIC90 values of neomycin were 4.0 μg/mL forS aureus and 16.0 μg/mL for P aeruginosa. The MIC90 for polymyxin B against P aeruginosa was 2.0 g/mL.45
Clinically equivalent to neomycin compound. Recent clinical studies have shown that ofloxacin and ciprofloxacin are as efficacious as neomycin/polymyxin B/hydrocortisone in the treatment of otitis externa.21,22,46 In one study, the overall cure rate was 89% in patients treated with either ofloxacin (N=301) or neomycin/polymyxin B/hydrocortisone (N=300).21 In another study, ciprofloxacin was comparably effective as neomycin/polymyxin B/hydrocortisone therapy (93% [N=239] vs 87% [N=228]; 95% confidence interval, 0.0–10.5).22
S aureus resistance has increased. Fluoroquinolone use has been reported to lead to resistance in topical infections other than otitis externa. For example, the incidence of fluoroquinolone-resistant keratitis isolates of S aureus increased from 11% in 1990 to 28% in 1998.47 In another 5-year review of bacterial keratitis cases,48 the incidence of ciprofloxacin-resistant isolates of S aureus increased annually from 5.8% in 1993 to 35.0% in 1997, and the incidence of resistant isolates to ofloxacin increased from 4.7% to 35.0% over the same period.48 In contrast, P aeruginosa isolates remained susceptible to fluoroquinolones during the study periods.48 Resistance ofP aeruginosa to fluoroquinolones has increased only slightly.49 Between 1991 and 1994, 0.44% of ocular isolates of P aeruginosa were resistant to ciprofloxacin, while 4.1% showed in vitro resistance between 1995 and 1998.49
Fluoroquinolone has advantages over combination therapy. Ofloxacin and ciprofloxacin do not cause ototoxicity in humans and do not damage isolated cochlear cells, as can neomycin/polymyxin B/hydrocortisone combinations.34,50 In fact, both ofloxacin and ciprofloxacin/dexamethasone have been approved for use in patients with patent tympanostomy tube otorrhea.29