Efficacy of Solithromycin (CEM-101) for Experimental Otitis Media Caused by Nontypeable Haemophilus influenzae and Streptococcus pneumoniae.

Solithromycin (CEM-101) is a "fourth-generation" macrolide, as it has three binding site and is acid stable. The three binding sites confer activity against bacteria resistant to the older macrolides and ketolides, including multidrug-resistant Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi). The objective of this study was to evaluate solithromycin pharmacokinetics (PK), middle ear fluid (MEF) concentrations, and microbiologic efficacy in a chinchilla model of experimental otitis media (EOM) due to strains of S. pneumoniae or NTHi. Plasma PK (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve from 0 to 24 h [AUC0-24]) and middle ear fluid (MEF) concentrations were determined. Isolates with specified antimicrobial susceptibility patterns were inoculated directly into the middle ear (ME). Plasma and MEF were collected for PK and MEF cultures performed to determine efficacy. Solithromycin administered at 150 mg/kg of body weight/day resulted in Cmax and AUC0-24 values of 2.2 µg/ml and 27.4 µg · h/ml in plasma and 1.7 µg/ml and 28.2 µg · h/ml in extracellular MEF on day 1. By day 3, Cmax and AUC0-24 values had increased to 4.5 µg/ml and 54 µg · h/ml in plasma and 4.8 µg/ml and 98.6 µg · h/ml in extracellular MEF. For NTHi EOM, three isolates with MIC/minimal bactericidal concentration (MBC) ratios of 0.5/1 µg/ml (isolate BCH1), 2/2 µg/ml (isolate BMC1247C), and 4/4 µg/ml (isolate BMC1213C) were selected. The MEF of >85% of animals infected with BCH1 and BMC1247C was sterilized. For NTHi BMC1213, >85% of MEF cultures remained positive. For S. pneumoniae EOM, 3 isolates with MIC/MBC ratios of 0.06/0.125 µg/ml (S. pneumoniae 331), 0.125/1 µg/ml (S. pneumoniae CP-645 [MLSB phenotype]), and 0.5/2 µg/ml (CP-712 [mefA subclass mefA resistance]) were selected. Solithromycin sterilized MEF in 100% of animals infected with S. pneumoniae 331 and S. pneumoniae CP-645. ME infection persisted in 60% of animals infected with CP-712. In a model of EOM, solithromycin sterilized MEF in >85% of animals challenged with NTHi with an MIC of ≤2 µg/ml and 100% of ME infected with S. pneumoniae with an MIC of ≤0.125 µg/ml.

Defining resistance: breakpoints and beyond implications for pediatric respiratory infection.

The emergence of isolates of Streptococcus pneumoniae with reduced susceptibility to penicillins, cephalosporins, trimethoprim-sulfamethoxazole, and macrolide antibiotics requires a re-evaluation of strategies for the treatment of community-acquired respiratory disease. One response has been the consideration of withholding initial antimicrobial therapy for children with acute otitis media (AOM). Review of clinical studies supports a reduction in suppurative complications, and a more rapid resolution of signs and symptoms as well as the course of middle ear disease in children treated with antimicrobial agents. Breakpoints established by the NCCLS for in vitro susceptibility reporting may not reflect clinical efficacy at all sites of disease. Clinical studies of AOM due to penicillin-resistant S. pneumoniae report success with both cefuroxime and amoxicillin-clavulanic acid, however, microbiologic studies suggest an increase in persistent infection in children with disease due to isolates with reduced susceptibility. Successful therapy for AOM due to highly resistant isolates (MIC > or = 2.0 micrograms/ml for penicillin) has been reported with clindamycin, ceftriaxone, and high-dose amoxicillin. The current risk of AOM due to a resistant S. pneumoniae remains low in most U.S. communities. Amoxicillin remains appropriate for most children, ongoing surveillance for resistance and close monitoring of response to therapy is necessary.