Figueira M, Fernandes P, Pelton S I
Section of Pediatric Infectious Diseases, Maxwell Finland Laboratory for Infectious Diseases, Boston Medical Center, Boston, Massachusetts, USA.
Cempra, Inc., Chapel Hill, North Carolina, USA.
Antimicrob Agents Chemother. 2016 Aug 22;60(9):5533-8. doi: 10.1128/AAC.00863-16. Print 2016 Sep.
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.
索利霉素（CEM - 101）是一种“第四代”大环内酯类药物，因为它有三个结合位点且对酸稳定。这三个结合位点赋予其对耐旧大环内酯类和酮内酯类细菌的活性，包括多重耐药肺炎链球菌和不可分型流感嗜血杆菌（NTHi）。本研究的目的是在由肺炎链球菌或NTHi菌株引起的实验性中耳炎（EOM）的栗鼠模型中评估索利霉素的药代动力学（PK）、中耳液（MEF）浓度和微生物学疗效。测定了血浆PK（血清中药物的最大浓度[Cmax]和0至24小时浓度 - 时间曲线下面积[AUC0 - 24]）和中耳液（MEF）浓度。将具有特定抗菌药敏模式的分离株直接接种到中耳（ME）。收集血浆和MEF用于PK和MEF培养以确定疗效。以150mg/kg体重/天的剂量给予索利霉素，第1天时血浆中的Cmax和AUC0 - 24值分别为2.2μg/ml和27.4μg·h/ml，细胞外MEF中的值分别为1.7μg/ml和28.2μg·h/ml。到第3天时，血浆中的Cmax和AUC0 - 24值分别增加到4.5μg/ml和54μg·h/ml，细胞外MEF中的值分别为4.8μg/ml和98.6μg·h/ml。对于NTHi引起的EOM，选择了三株MIC/最低杀菌浓度（MBC）比值分别为0.5/1μg/ml（分离株BCH1）、2/2μg/ml（分离株BMC1247C）和4/4μg/ml（分离株BMC1213C）的菌株。感染BCH1和BMC1247C的动物中，超过85%的MEF被除菌。对于NTHi BMC1213，超过85%的MEF培养物仍为阳性。对于肺炎链球菌引起的EOM，选择了三株MIC/MBC比值分别为0.06/0.125μg/ml（肺炎链球菌331）、0.125/1μg/ml（肺炎链球菌CP - 645[MLSB表型]）和0.5/2μg/ml（CP - 712[mefA亚类mefA耐药]）的菌株。索利霉素使感染肺炎链球菌331和肺炎链球菌CP - 645的动物中100%的MEF除菌。感染CP - 712的动物中，60%的ME感染持续存在。在EOM模型中，索利霉素使MIC≤2μg/ml的NTHi攻击的动物中超过85%的MEF除菌，使MIC≤0.125μg/ml的肺炎链球菌感染的ME中100%除菌。
