PDF(Pubmed)
Abstract：
Otitis media (OM) is one of the most globally pervasive pediatric conditions. Translocation of nasopharynx-resident opportunistic pathogens like nontypeable Haemophilus influenzae (NTHi) assimilates into polymicrobial middle ear biofilms, which promote OM pathogenesis and substantially diminish antibiotic efficacy. Oral or tympanostomy tube (TT)-delivered antibiotics remain the standard of care (SOC) despite consequences including secondary infection, dysbiosis, and antimicrobial resistance. Monoclonal antibodies (mAb) against two biofilm-associated structural proteins, NTHi-specific type IV pilus PilA (anti-rsPilA) and protective tip-region epitopes of NTHi integration host factor (anti-tip-chimer), were previously shown to disrupt biofilms and restore antibiotic sensitivity in vitro. However, the additional criterion for clinical relevance includes the absence of consequential microbiome alterations. Here, nine chinchilla cohorts (n = 3/cohort) without disease were established to evaluate whether TT delivery of mAbs disrupted nasopharyngeal or fecal microbiomes relative to SOC-OM antibiotics. Cohort treatments included a 7d regimen of oral amoxicillin-clavulanate (AC) or 2d regimen of TT-delivered mAb, AC, Trimethoprim-sulfamethoxazole (TS), ofloxacin, or saline. Fecal and nasopharyngeal lavage (NPL) samples were collected before and several days post treatment (DPT) for 16S sequencing. While antibiotic-treated cohorts displayed beta-diversity shifts (PERMANOVA, P < 0.05) and reductions in alpha diversity (q < 0.20) relative to baseline, mAb antibodies failed to affect diversity, indicating maintenance of a eubiotic state. Taxonomic and longitudinal analyses showed blooms in opportunistic pathogens (ANCOM) and greater magnitudes of compositional change (P < 0.05) following broad-spectrum antibiotic but not mAb treatments. Collectively, results showed broad-spectrum antibiotics induced significant fecal and nasopharyngeal microbiome disruption regardless of delivery route. Excitingly, biofilm-targeting antibodies had little effect on fecal and nasopharyngeal microbiomes.
摘要：
中耳炎（OM）是全球最普遍的儿科疾病之一。鼻咽位机会性病原体的易位，例如不可分型的流感嗜血杆菌（NTHi）同化为多微生物中耳生物膜，这促进了OM的发病机制并大大降低了抗生素的功效。尽管后果包括继发感染，但口服或鼓膜置管（TT）递送的抗生素仍然是护理标准（SOC）。生态失调,和抗菌素耐药性。针对两种生物膜相关结构蛋白的单克隆抗体，NTHi特异性IV型菌毛PilA（抗rsPilA）和NTHi整合宿主因子（抗tip-chimer）的保护性尖端区域表位，先前被证明在体外破坏生物膜并恢复抗生素敏感性。然而,临床相关性的额外标准包括不存在相应的微生物组改变。这里,我们建立了9个无疾病的栗鼠队列(n=3/队列),以评估相对于SOC-OM抗生素,TT递送mAb是否会破坏鼻咽或粪便微生物组.队列治疗包括口服阿莫西林克拉维酸（AC）的7d方案或TT递送的mAb的2d方案，AC,甲氧苄啶-磺胺甲恶唑(TS),氧氟沙星,或盐水。在处理前和处理后几天(DPT)收集粪便和鼻咽灌洗(NPL)样品用于16S测序。虽然抗生素治疗的队列显示出β-多样性变化(PERMANOVA，P<0.05）和相对于基线的α多样性减少（q<0.20），单克隆抗体未能影响多样性，表明维持优生状态。分类学和纵向分析显示，在广谱抗生素而不是mAb处理后，机会病原体（ANCOM）和成分变化幅度更大（P<0.05）。总的来说，结果显示,无论给药途径如何,广谱抗生素均可引起显著的粪便和鼻咽部微生物组破坏.令人兴奋的是,生物膜靶向抗体对粪便和鼻咽微生物组影响不大.
