ObjectivesUnderstand treatment failure rates of cipro‐floxacin/steroid‐ vs. Neomycin/Polymyxin B/Hydrocortisone (NPH)‐containing ear drops against the two major pathogens in acute otitis externa (AOE), Pseudomonas aeruginosa and Staphylococcus aureus.MethodsRetrospective analysis of clinical studies involving NPH versus either 0.3% ciprofloxacin/0.1% dexamethasone (CDX)(2 trials, 1998–1999) or 0.2% ciprofloxacin/1% hydrocortisone (CHC) (3 trials, 1994–1996) in the treatment of patients diagnosed with AOE. Patients were randomized to treatment with either CHC, CDX (both bid) or NPH (tid), 3–4 drops per ear for 7 days. Microbiology specimens were collected from infected ears prior to the initiation of therapy, and at exit visit if there were any clinical signs of infection.ResultsThe therapy failure rate of P. aeruginosa for CDX and CHC was 6.7% (20/300) versus NPH at 12.8% (39/306), p = 0.017. The failure rate of S. aureus for CDX and CHC was 9.2% (6/65) vs. NPH at 8.3% (4/48), p = 0.87. In no instance of treatment failure was the pre‐therapy pathogen resistant in vitro to the antibiotics used to treat the infection. All of the persisting P. aeruginosa and S. aureus isolates were susceptible to fluoroquinolones and neomycin/polymyxin B.ConclusionsBased on data from 5 separate AOE clinical trials, ciprofloxacin‐containing ear drops, CDX and CHC, provided significantly greater eradication (93.3%) of P. aeruginosa compared to NPH ear drops (87.2%). There was no significant difference in the rate of eradication of S. aureus between the two groups of ear drops.