Impact of Long-Term Erythromycin Therapy on the Oropharyngeal Microbiome and Resistance Gene Reservoir in Non-Cystic Fibrosis Bronchiectasis.
Impact of Long-Term Erythromycin Therapy on the Oropharyngeal Microbiome and Resistance Gene Reservoir in Non-Cystic Fibrosis Bronchiectasis.
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DOI：
10.1128/msphere.00103-18
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发表时间：
2018-04-25
期刊：
影响因子：
4.8
通讯作者：
Rogers GB
中科院分区：
文献类型：
--
作者：
Choo JM;Abell GCJ;Thomson R;Morgan L;Waterer G;Gordon DL;Taylor SL;Leong LEX;Wesselingh SL;Burr LD;Rogers GB
最近的研究表明，长期大环内酯类药物治疗可以预防慢性气道疾病的恶化，导致其使用量急剧增加。然而，人们对这些治疗更广泛的潜在不利影响知之甚少。上呼吸道共生微生物群的严重破坏可能会降低其对宿主防御和局部免疫调节的贡献，而大环内酯类耐药性的增加将构成严重的公共卫生问题。使用随机对照试验的样本，我们发现服用 48 周以上的低剂量红霉素会影响口咽部共生微生物群的组成。我们报告说，大环内酯治疗与放线菌属成员相对丰度的显着变化以及可传播的大环内酯耐药性的显着增加有关。确定这些变化相对于治疗益处的临床意义，现在是研究的重点。长期大环内酯类药物治疗可降低支气管扩张症肺部恶化的发生率。然而，人们对大环内酯类药物治疗改变口咽共生微生物群的组成和功能或增加传播性抗菌药物耐药性的潜力知之甚少。我们评估了 84 名患有支气管扩张症的成人长期服用红霉素对口咽部微生物群组成和传播性大环内酯类耐药基因携带的影响，这些成年人参加了支气管扩张和低剂量红霉素研究 (BLESS)，为期 48 周的安慰剂对照试验，每天两次使用乙基琥珀酸红霉素（400 毫克）。分别通过16S rRNA基因扩增子测序和定量PCR测定口咽部微生物群组成和大环内酯类抗性基因携带。长期红霉素治疗与口咽部副流感嗜血杆菌的相对丰度显着增加相关（P = 0.041），并且与伪肺炎链球菌（P = 0.024）和溶齿放线菌（P = 0.027）的相对丰度显着下降相关。通过定量 PCR 验证测序结果证实放线菌属丰度显着下降。 （P = 0.046）。红霉素治疗并未导致携带 erm(A)、erm(B)、erm(C)、erm(F)、mef(A/E) 和 msrA 大环内酯耐药基因的受试者数量显着增加。然而，接受红霉素治疗的携带者体内erm(B)和mef(A/E)基因拷贝的丰度显着增加(P < 0.05)。我们的研究结果表明，长期红霉素治疗引起的口咽微生物群组成的变化是适度的，并且仅限于一组离散的分类单元。口咽微生物群内可传播抗生素抗性基因水平的相关增加凸显了该微生物系统作为抗性储存库的潜力。重要性 最近的研究表明，长期大环内酯类药物治疗可以预防慢性气道疾病的恶化，导致其使用量急剧增加。然而，人们对这些治疗更广泛的潜在不利影响知之甚少。上呼吸道共生微生物群的严重破坏可能会降低其对宿主防御和局部免疫调节的贡献，而大环内酯类耐药性的增加将构成严重的公共卫生问题。使用随机对照试验的样本，我们发现服用 48 周以上的低剂量红霉素会影响口咽部共生微生物群的组成。我们报告说，大环内酯治疗与放线菌属成员相对丰度的显着变化以及可传播的大环内酯耐药性的显着增加有关。确定这些变化相对于治疗益处的临床意义，现在是研究的重点。
Recent demonstrations that long-term macrolide therapy can prevent exacerbations in chronic airways diseases have led to a dramatic increase in their use. However, little is known about the wider, potentially adverse impacts of these treatments. Substantial disruption of the upper airway commensal microbiota might reduce its contribution to host defense and local immune regulation, while increases in macrolide resistance carriage would represent a serious public health concern. Using samples from a randomized controlled trial, we show that low-dose erythromycin given over 48 weeks influences the composition of the oropharyngeal commensal microbiota. We report that macrolide therapy is associated with significant changes in the relative abundances of members of the Actinomyces genus and with significant increases in the carriage of transmissible macrolide resistance. Determining the clinical significance of these changes, relative to treatment benefit, now represents a research priority. Long-term macrolide therapy reduces rates of pulmonary exacerbation in bronchiectasis. However, little is known about the potential for macrolide therapy to alter the composition and function of the oropharyngeal commensal microbiota or to increase the carriage of transmissible antimicrobial resistance. We assessed the effect of long-term erythromycin on oropharyngeal microbiota composition and the carriage of transmissible macrolide resistance genes in 84 adults with bronchiectasis, enrolled in the Bronchiectasis and Low-dose Erythromycin Study (BLESS) 48-week placebo-controlled trial of twice-daily erythromycin ethylsuccinate (400 mg). Oropharyngeal microbiota composition and macrolide resistance gene carriage were determined by 16S rRNA gene amplicon sequencing and quantitative PCR, respectively. Long-term erythromycin treatment was associated with a significant increase in the relative abundance of oropharyngeal Haemophilus parainfluenzae (P = 0.041) and with significant decreases in the relative abundances of Streptococcus pseudopneumoniae (P = 0.024) and Actinomyces odontolyticus (P = 0.027). Validation of the sequencing results by quantitative PCR confirmed a significant decrease in the abundance of Actinomyces spp. (P = 0.046). Erythromycin treatment did not result in a significant increase in the number of subjects who carried erm(A), erm(B), erm(C), erm(F), mef(A/E), and msrA macrolide resistance genes. However, the abundance of erm(B) and mef(A/E) gene copies within carriers who had received erythromycin increased significantly (P < 0.05). Our findings indicate that changes in oropharyngeal microbiota composition resulting from long-term erythromycin treatment are modest and are limited to a discrete group of taxa. Associated increases in levels of transmissible antibiotic resistance genes within the oropharyngeal microbiota highlight the potential for this microbial system to act as a reservoir for resistance. IMPORTANCE Recent demonstrations that long-term macrolide therapy can prevent exacerbations in chronic airways diseases have led to a dramatic increase in their use. However, little is known about the wider, potentially adverse impacts of these treatments. Substantial disruption of the upper airway commensal microbiota might reduce its contribution to host defense and local immune regulation, while increases in macrolide resistance carriage would represent a serious public health concern. Using samples from a randomized controlled trial, we show that low-dose erythromycin given over 48 weeks influences the composition of the oropharyngeal commensal microbiota. We report that macrolide therapy is associated with significant changes in the relative abundances of members of the Actinomyces genus and with significant increases in the carriage of transmissible macrolide resistance. Determining the clinical significance of these changes, relative to treatment benefit, now represents a research priority.