Doxycycline not recommended for COVID-19 outpatient treatment in older adults

Daily treatment with doxycycline did not shorten recovery time or reduce hospitalization or death in community-dwelling older adults with COVID-19, according to a study from the PRINCIPLE Collaborative Group.

“This … trial, in people in the community in the UK with suspected or PCR-confirmed COVID-19 who were at high risk of adverse outcomes, showed that doxycycline did not meaningfully shorten time to recovery or reduce hospitalizations or deaths related to COVID-19 compared with usual care only,” said the authors.

The PRINCIPLE randomized trials comprised various open-label, multi-arm, adaptive platform trials assessing various interventions against COVID-19 in individuals aged ≥65 years or ≥50 years with comorbidities in the UK. Participants were limited to community-dwelling individuals with symptomatic (≤14 days) suspected COVID-19 or PCR-confirmed SARS-CoV-2 infection. They were randomized to receive usual care only, usual care plus oral doxycycline (200 mg on day 1, followed by 100 mg QD for 6 days), or usual care plus other interventions.

Included in this analysis are the 1,792 patients (mean age 61.1 years, 55.7 percent female) who received either usual care plus doxycycline (n=798) or usual care only (n=994). Patients were primarily White (87 percent) and aged <65 years (63.1 percent). About 87 percent had comorbidities, the most common being hypertension requiring medication (41.5 percent) and asthma, COPD, or lung disease (37.3 percent). Median duration of illness pre-randomization was 6 days. Of the 1,544 patients with available PCR results, 51.2 percent tested positive.

At 28 days post-randomization, time to first self-reported recovery did not differ between patients who received usual care plus doxycycline and usual care only (median 9.6 vs 10.1 days; hazard ratio [HR], 1.04, 95 percent Bayesian Credible Interval [BCI], 0.93–1.17; estimated median benefit of usual care plus doxycycline, 0.5 days). [Lancet Respir Med 2021;doi:10.1016/S2213-2600(21)00310-6]

Hospitalization or death related to COVID-19 at 28 days occurred in 41 and 43 patients on usual care plus doxycycline and usual care only (crude percentage 5.3 percent vs 4.5 percent; estimated absolute percentage difference, -0.5 percent, 95 percent BCI, -2.6 to 1.4).

Five deaths occurred in the usual care plus doxycycline group vs two in the usual care-only group (0.6 percent vs 0.2 percent).

The probability of a clinically meaningful benefit in time to recovery (≥1.5 days) and reduced COVID-19–related hospitalizations or deaths (≥2 percent) with the addition of doxycycline to usual care was 0.10 and 0.005, respectively.

The results were consistent when the analysis was limited to the SARS-CoV-2 PCR-positive population (HR, 1.05; estimated median benefit of 0.70 days [time to recovery] and estimated absolute percentage difference of 1.2 percent [COVID-19–related hospitalizations or deaths]), with a probability of a clinically meaningful benefit of 0.24 and 0.35, respectively.

The addition of doxycycline to usual care conferred little benefit in time to first or sustained alleviation of symptoms, time to initial reduction of severity of all or individual symptoms, or WHO-5 Well-Being Index score compared with usual care only.

Subgroup analysis showed that age, comorbidities, duration of illness pre-randomization, and illness severity score at baseline, did not affect the efficacy of doxycycline on time to first self-reported recovery.

According to the authors, doxycycline has been used during the COVID-19 pandemic, for instance, in the treatment of suspected bacterial pneumonia in COVID-19. As such, randomized trials were needed to assess if doxycycline truly was effective, and if not, to prevent its unnecessary use.

“Our findings … do not support the routine use of doxycycline for suspected COVID-19 in the community in the absence of other indications such as bacterial pneumonia,” they pointed out.

Now that increasing evidence has suggested that bacterial co-infection is uncommon in COVID-19, there appears to be little benefit to using doxycycline, particularly in “well-resourced countries,” they said. “[Furthermore,] wider use of doxycycline could lead to public health harm through increased antimicrobial resistance,” they noted, calling for more research into identifying which patients with COVID-19 would benefit from antibiotic treatment.