COPD増悪って、まぁ嫌ですよね。安定期の管理でいかに増悪をさせないかが重要だと思います。

マクロライド系の抗菌薬を長期内服することでCOPD増悪が抑制されるというデータがあります。例えば、エリスロマイシンはAm J Respir Crit Care Med. 2008、アジスロマイシンはN Engl J Med. 2011、Lancet Respir Med. 2014といった研究。

「他の抗菌薬ではどうなのか？」という疑問が浮かびます。今回はテトラサイクリン系であるドキシサイクリンについてのRCTをご紹介します。

A Double-Blind, Randomised, Placebo-controlled Trial of Long-Term Doxycycline Therapy on Exacerbation Rate in Patients with Stable COPD

llinson JP, Vlies BH, Brill SE, et al. published online ahead of print, 2023 Jul 14. Am J Respir Crit Care Med.

Rationale: COPD exacerbations are a major cause of morbidity and mortality and preventing them is a key treatment target. Long-term macrolide treatment is effective at reducing exacerbations but there is a paucity of evidence for other antibiotic classes. To assess whether 12-month use of doxycycline reduces exacerbation rate in people with COPD.

Methods: People with moderate to very severe COPD and an exacerbation history were recruited from 3 UK centres and randomised to 12-months doxycycline 100mg once daily or placebo. The primary study outcome was exacerbation rate per person year.

Results: 222 people were randomised. Baseline mean FEV1 was 1.35 (SD 0.35) L; 52.5 (SD 15.9) % predicted. Median number of treated exacerbations in the year before the study was 2 (1-4). 71% of patients reported ≥2 exacerbations. 81% were already prescribed inhaled corticosteroids at baseline. COPD exacerbation rate did not differ between the groups – doxycycline/placebo rate ratio 0.86 (0.67, 1.10); p=0.23. No difference was seen if only treated exacerbations or hospitalisations were considered. In pre-planned sub-group analysis, doxycycline appeared to better reduce the exacerbation rate among people with severe COPD (RR:0.36 (0.15, 0.85); p=0.019), and in those with an eosinophil count <300 cells/μL (RR:0.50 (0.29, 0.84); p=0.01). Health status measured by SGRQ was 5.2 points worse in the doxycycline group at 12-months (p<0.007).

Conclusions: Doxycycline did not significantly reduce exacerbation rate, over 12-months, in participants with COPD, who exacerbated regularly, but may have benefitted those with more severe COPD or blood eosinophil counts <300 cells/μL. Clinical trial registration available at www.

Clinicaltrials: gov, ID: NCT02305940.

PMID: 37450935

ドキシサイクリンではマクロライドほど大きなCOPD増悪の抑制効果はなさそうです。やはりマクロライドは抗菌作用というより、免疫調整作用や抗炎症作用を持つことが利点のようですね。ただサブグループ解析では重症例や好酸球の少ない場合はドキシサイクリンでも有意に増悪を抑制しています。デュピルマブがCOPD増悪を抑制するという結果（BOREAS; N Engl J Med. 2023）からも、Type 2炎症の関与があれば抗炎症を、そうでなければ抗菌薬を今後は検討していくことになるでしょうか。