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17th January 2023
Low procalcitonin levels in patients with a non-pneumonia lower respiratory tract infection, fails to identify those who might benefit from azithromycin therapy according to the findings of a randomised trial by US researchers.
Antibiotics are commonly prescribed for acute respiratory infections, although most of these infections are viral in nature and for which antibiotics are ineffective. It is therefore necessary to implement strategies that are able to identify those patients unlikely to benefit from antibiotics, thus mitigating the development and spread of resistant pathogens. Procalcitonin is a peptide for which serum levels are believed to increase during bacterial, but not during viral, infections. In fact, procalcitonin levels have been shown to improve the accuracy of currently recommended approaches for the diagnosis of community-acquired pneumonia, thereby complementing clinical signs and symptoms. Normal human procalcitonin serum levels are less than 0.1 ng/ml, whereas if levels increase above 0.25 ng/ml, this may indicate the presence of a bacterial infection.
In the present study, US researchers hypothesised that in patients with a procalcitonin concentration of 0·25 ng/mL or less, a placebo would be just as good, i.e., non-inferior (in terms of clinical efficacy) to antibiotics such as azithromycin, in adults with suspected lower respiratory tract infection. The team recruited adults aged 18 years or older, with clinically suspected non-pneumonia lower respiratory tract infection and a low procalcitonin level (i.e., 0·25 ng/mL or less). These individuals were randomised 1:1 to either oral azithromycin 250 mg or matching placebo (two capsules on day 1 followed by one capsule daily for 4 days). The primary outcome was the efficacy of azithromycin versus placebo in terms of clinical improvement at day 5 (assessed with several different measures) and the non-inferiority margin (to placebo) was set as a lower confidence interval of -12·5%.
Low procalcitonin and azithromycin outcomes
A total of 499 participants with a mean age of 52.3 years (35% female), all of whom had procalcitonin levels below 250 ng/ml, were included and randomised to azithromycin (249) or placebo.
A clinical improvement at day 5 was observed in 63% in the placebo group and 69%, in the azithromycin group (between-group difference -6%, 95% CI -15 to 2). As the lower confidence interval for this difference was numerically greater than –12·5%, it was not possible to conclude that there was non-inferiority for the placebo compared with azithromycin. This was despite there being no significant difference in the rates of any of the individual parameters comprising the primary outcome for clinical improvement. However, at day 11, clinical improvement was observed in 76% of the placebo group and 81% in the azithromycin group (between-group difference –4%, 95% CI –12 to 3). This time, since the lower confidence interval value was less than -12.5, non-inferiority for the placebo and azithromycin was demonstrated.
The authors concluded that it was not possible to confirm non-inferiority for a placebo and azithromycin in terms of clinical improvement at day 5 in adults with a lower respiratory tract infection and a low procalcitonin concentration. Consequently, it remained unclear whether antibiotics would be of benefit to such patients.
Tsalik EL et al. Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: a randomised, placebo-controlled, double-blind, non-inferiority trial. Lancet Infect Dis 2022
14th July 2021
The oral macrolide antibiotic, azithromycin, has antibacterial, anti-inflammatory and anti-viral properties and in a study examining drugs that could be repositioned for the management of COVID-19, azithromycin was identified as a potential candidate. Moreover, an in vitro study has also identified a synergistic effect between azithromycin and hydroxychloroquine. While based on only 20 patients, one preliminary study of hydroxychloroquine in COVID-19, found that adding azithromycin to prevent bacterial super-infection resulted in significantly more efficient elimination of the virus. However, despite these theoretical advantages, large-scale studies of patients hospitalised with COVID-19 have not demonstrated any benefit from the drug. For example, in the RECOVERY trial, among patients hospitalised because of COVID-19, addition of azithromycin did not lead to improved patient outcomes compared to standard care.
Nevertheless, as most studies have occurred within a hospital setting, it remained unclear whether the use of azithromycin could prevent disease progression and hence avoid the need for hospitalisation. With this important remaining gap in the current evidence, a team from the Respiratory Medicine Unit and National Institute for Health Research, Oxford University, undertook a prospective, open-label, randomised trial, among patients with mild-to-moderate COVID-19, to determine if azithromycin was effective at reducing the need for hospital admission. Eligible participants were adults (18 years and over) assessed in an acute hospital, where symptom onset was within 14 days. All eligible patients were randomised to either azithromycin 500mg daily plus standard care or standard care alone. Disease severity was assessed using an ordinal scale from 0 to 8, with higher scores indicating more severe disease. Subsequent assessments were performed after 14 and 28 days and the primary outcome was the proportion of participants with hospital admission or death (from any cause) within 28 days of randomisation. Secondary outcomes included the proportion of patients with admitted to hospital with respiratory failure or requiring non-invasive mechanical ventilation with 28 days of randomisation.
A total of 295 participants were enrolled and randomised to either arm. Among the 147 allocated to azithromycin, the mean age was 45.5 years (48% female) and the majority (73%) did not have any co-morbidities. More than 60% of participants in both arms had low baseline severity scores (either 0 or 1) and there was no difference in peak severity scores between the groups (odds ratio, OR = 0.91, 95% CI 0.57–1.46, p = 0.69). A total of 15 (10%) and 17(12%) of those assigned to azithromycin and standard care respectively, were hospitalised or died. The primary outcome was not significantly different between the two groups (OR = 0.91, 95% CI 0.43–1.92, p = 0.80) and there was also no difference in the time to hospitalisation.
Based on their findings, the authors concluded that the use of azithromycin in those with mild-to-moderate COVID-19 managed in an ambulatory care setting had no impact on hospital admissions or other relevant disease outcomes such as respiratory failure or death. They suggested that azithromycin should not be used in the management of COVID-19.
Hinks TSC et al. Azithromycin versus standard care in patients with mild-to- moderate COVID-19 (ATOMIC2): an open-label, randomised trial. Lancet 2021