- Background: Levofloxacin has excellent activity against common respiratory pathogens and therefore is likely to be effective in treating children with persistent or recurrent otitis media. Objective: The objective of this study was to assess the efficacy and safety of levofloxacin treatment in the eradication of bacterial pathogens from the middle ear fluid (MEF) of children with, or at high risk for, persistent or recurrent otitis media. Methods: An open-label multicenter trial was conducted that involved tympanocentesis at entry and selectively 3 to 5 days after starting levofloxacin (10 mg/kg twice a day for 10 days). Results: Two hundred five children (80% ≤2 years) were enrolled. One child did not have a confirmed diagnosis of acute otitis media and did not return for follow-up visits. Of the remaining 204 children, 94 (46%) had bilateral infection and 63 (31%) were receiving antimicrobials immediately before entry. One hundred five isolates of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus. pyogenes were recovered in pure or mixed cultures. All isolates were susceptible to levofloxacin. During-treatment bacterial eradication from MEF occurred in 88% (78 of 89) of bacteriologically evaluable patients, including 90% (65 of 72) of children ≤24 months of age. Bacteria initially isolated from MEF were eradicated in 31 of 37 (84%) children infected with S. pneumoniae and in 54 of 54 (100%) children infected with H. influenzae. Overall, clinical success rate after therapy was 94% for the total study population and 92% for the bacteriologically evaluable population. Levofloxacin was well tolerated. Vomiting (4%) was the most common treatment-limiting adverse event. Conclusions: Levofloxacin was safe and effective in treating and eradicating common bacterial pathogens from MEF in children with, or at risk for, recurrent or persistent otitis media.