红霉素对支气管扩张症患者呼吸道细菌的影响

Effect of Erythromycin on respiratory tract bacteria in patients with stable bronchiectasis

目的观察长期口服小剂量红霉素对稳定期支气管扩张症患者细菌耐药性的影响,以及呼吸道微生物群构成的变化。方法采取双盲、对照方法进行为期6个月的观察,纳入患者既往1年内有2次急性加重史,治疗组口服红霉素250 mg/次,2次/d,评估治疗前后两组急性加重次数的不同、呼吸道定植菌的耐药率变化,以及细菌构成的变化。结果 176例患者随机分组,治疗组90例,对照组86例;与对照组相比较,铜绿假单胞菌定植亚组的急性加重次数减少,但非铜绿定植亚组无变化;治疗组呼吸道革兰阴性菌群耐药率无变化,而革兰阳性菌群耐药率升高,尤其是对大环内酯类药物;治疗组较对照组痰菌负荷减少,微生物构成发生变化,但铜绿假单胞菌定植亚组患者微生物构成变化不大,非铜绿假单胞菌定植亚组微生物构成变化大,流感嗜血杆菌定植率降低,但耐大环内酯类药物细菌包括铜绿假单胞菌定植率升高。结论长期小剂量红霉素治疗造成支气管扩张症患者呼吸道革兰阳性菌群耐药率升高,尤其是对大环内酯类药物;呼吸道微生物群构成发生变化,在非铜绿假单胞菌定植亚组,急性加重次数并没有减少,而红霉素治疗使其流感嗜血杆菌定植率降低,但铜绿假单胞菌、金黄色葡萄球菌等对大环内酯类药物耐药的细菌定植率升高,该类患者尚需进一步寻找更好的治疗方案。

Objective To assess whether long-term, low-dose Erythromycin treatment can change the bacteria resistance and the composition of respiratory microbiota in people with stable non-cystic fibrosis bronchiectasis. Methods A 6-month, double-blind and placebo-controlled trial was conducted in adult patients with non-cystic fibrosis bronchiectasis and at least twice infective exacerbations in the preceding year. The 176 patients were randomly assigned into two groups, 86 in the placebo group and 90 in the Erythromycin group. Erythromycin ethylsuccinate 250 mg was given twice daily. The times of acute exacerbation, the changes of bacteria resistance and respiratory microbiota composition were compared between the Erythromycin group and the placebo group. Results Compared with placebo, Erythromycin reduced the rate of pulmonary exacerbations over the 6 months of study in the patients with Pseudomonas aeruginosa-dominated infection, but not in those with P. aeruginosa-nondominated infection. In the treatment group, the rate of Gram-negative bacteria resistance in respiratory tract had no obvious change, but the rate of Gram-positive bacteria resistance significantly increased, especially to Macrolides. Sputum bacteria load in the treatment group reduced significantly compared to the placebo group. The change in microbiota composition between baseline and month 6 was significantly greater in the Erythromycin group than in the placebo group. In the patients with baseline airway infection dominated by P. aeruginosa, Erythromycin did not significantly change microbiota composition. In those with infection dominated by organisms other than P. aeruginosa, Erythromycin caused a significant change in microbiota composition, representing a reduced relative abundance of Haemophilus influenzae and increased relative abundance of P. Aeruginosa. Conclusions Long-term oral low-dose Erythromycin increases the rate of resistance of Gram-positive bacteria in the lower respiratory tract of the treatment group, especially to Macrolides. Long-term Erythromycin treatment changes the composition of respiratory microbiota in patients with bronchiectasis. In the patients without P. aeruginosa airway infection, Erythromycin could not significantly reduce exacerbations but promote displacement of H. influenza by more Macrolide-resistant pathogens including P. aeruginosa and Staphylococcus aureus. These findings argue for a cautious approach to chronic Macrolide use in patients without P. aeruginosa airway infection.