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Scrub typhus is a life-threatening zoonotic bacterial infection. In this randomized, controlled trial, combination therapy with doxycycline and azithromycin led to better outcomes than either drug alone.

Patients with confirmed or suspected Covid-19 were randomly assigned to receive hydroxychloroquine with azithromycin, hydroxychloroquine alone, or usual care. The primary outcome was clinical status at 15 days, assessed on a seven-level ordinal scale. There were no significant differences between groups in the primary outcome.

The use of azithromycin reduces maternal infection in women during unplanned cesarean delivery, but its effect on those with planned vaginal delivery is unknown. Data are needed on whether an intrapartum oral dose of azithromycin would reduce maternal and offspring sepsis or death. In this multicountry, placebo-controlled, randomized trial, we assigned women who were in labor at 28 weeks' gestation or more and who were planning a vaginal delivery to receive a single 2-g oral dose of azithromycin or placebo. The two primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis. During an interim analysis, the data and safety monitoring committee recommended stopping the trial for maternal benefit. A total of 29,278 women underwent randomization. The incidence of maternal sepsis or death was lower in the azithromycin group than in the placebo group (1.6% vs. 2.4%), with a relative risk of 0.67 (95% confidence interval [CI], 0.56 to 0.79; P<0.001), but the incidence of stillbirth or neonatal death or sepsis was similar (10.5% vs. 10.3%), with a relative risk of 1.02 (95% CI, 0.95 to 1.09; P = 0.56). The difference in the maternal primary outcome appeared to be driven mainly by the incidence of sepsis (1.5% in the azithromycin group and 2.3% in the placebo group), with a relative risk of 0.65 (95% CI, 0.55 to 0.77); the incidence of death from any cause was 0.1% in the two groups (relative risk, 1.23; 95% CI, 0.51 to 2.97). Neonatal sepsis occurred in 9.8% and 9.6% of the infants, respectively (relative risk, 1.03; 95% CI, 0.96 to 1.10). The incidence of stillbirth was 0.4% in the two groups (relative risk, 1.06; 95% CI, 0.74 to 1.53); neonatal death within 4 weeks after birth occurred in 1.5% in both groups (relative risk, 1.03; 95% CI, 0.86 to 1.24). Azithromycin was not associated with a higher incidence in adverse events. Among women planning a vaginal delivery, a single oral dose of azithromycin resulted in a significantly lower risk of maternal sepsis or death than placebo but had little effect on newborn sepsis or death. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; A-PLUS ClinicalTrials.gov number, NCT03871491.).

Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulatory properties. We tested the hypothesis that azithromycin would decrease the frequency of exacerbations, increase lung function, and improve health-related quality of life in patients with non-cystic fibrosis bronchiectasis. We undertook a randomised, double-blind, placebo-controlled trial at three centres in New Zealand. Between Feb 12, 2008, and Oct 15, 2009, we enrolled patients who were 18 years or older, had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year, and had a diagnosis of bronchiectasis defined by high-resolution CT scan. We randomly assigned patients to receive 500 mg azithromycin or placebo three times a week for 6 months in a 1:1 ratio, with a permuted block size of six and sequential assignment stratified by centre. Participants, research assistants, and investigators were masked to treatment allocation. The coprimary endpoints were rate of event-based exacerbations in the 6-month treatment period, change in forced expiratory volume in 1 s (FEV1) before bronchodilation, and change in total score on St George's respiratory questionnaire (SGRQ). Analyses were by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000641493. 71 patients were in the azithromycin group and 70 in the placebo group. The rate of event-based exacerbations was 0·59 per patient in the azithromycin group and 1·57 per patient in the placebo group in the 6-month treatment period (rate ratio 0·38, 95% CI 0·26–0·54; p<0·0001). Prebronchodilator FEV1 did not change from baseline in the azithromycin group and decreased by 0·04 L in the placebo group, but the difference was not significant (0·04 L, 95% CI −0·03 to 0·12; p=0·251). Additionally, change in SGRQ total score did not differ between the azithromycin (–5·17 units) and placebo groups (–1·92 units; difference −3·25, 95% CI −7·21 to 0·72; p=0·108). Azithromycin is a new option for prevention of exacerbations in patients with non-cystic fibrosis bronchiectasis with a history of at least one exacerbation in the past year. Health Research Council of New Zealand and Auckland District Health Board Charitable Trust.

ObjectiveTo test whether azithromycin eradicates Ureaplasma from the respiratory tract in preterm infants.DesignProspective, phase IIb randomised, double-blind, placebo-controlled trial.SettingSeven level III–IV US, academic, neonatal intensive care units (NICUs).PatientsInfants 240–286 weeks’ gestation (stratified 240–266; 270–286 weeks) randomly assigned within 4 days following birth from July 2013 to August 2016.InterventionsIntravenous azithromycin 20 mg/kg or an equal volume of D5W (placebo) every 24 hours for 3 days.Main outcome measuresThe primary efficacy outcome was Ureaplasma-free survival. Secondary outcomes were all-cause mortality, Ureaplasma clearance, physiological bronchopulmonary dysplasia (BPD) at 36 weeks’ postmenstrual age, comorbidities of prematurity and duration of respiratory support.ResultsOne hundred and twenty-one randomised participants (azithromycin: n=60; placebo: n=61) were included in the intent-to-treat analysis (mean gestational age 26.2±1.4 weeks). Forty-four of 121 participants (36%) were Ureaplasma positive (azithromycin: n=19; placebo: n=25). Ureaplasma-free survival was 55/60 (92% (95% CI 82% to 97%)) for azithromycin compared with 37/61 (61% (95% CI 48% to 73%)) for placebo. Mortality was similar comparing the two treatment groups (5/60 (8%) vs 6/61 (10%)). Azithromycin effectively eradicated Ureaplasma in all azithromycin-assigned colonised infants, but 21/25 (84%) Ureaplasma-colonised participants receiving placebo were culture positive at one or more follow-up timepoints. Most of the neonatal mortality and morbidity was concentrated in 21 infants with lower respiratory tract Ureaplasma colonisation. In a subgroup analysis, physiological BPD-free survival was 5/10 (50%) (95% CI 19% to 81%) among azithromycin-assigned infants with lower respiratory tract Ureaplasma colonisation versus 2/11 (18%) (95% CI 2% to 52%) in placebo-treated infants.ConclusionA 3-day azithromycin regimen effectively eradicated respiratory tract Ureaplasma colonisation in this study.Trial registration number NCT01778634.

The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19. We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278. 447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94–1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups. In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. COALITION COVID-19 Brazil and EMS.

Azithromycin, an antibiotic with potential antiviral and anti-inflammatory properties, has been used to treat COVID-19, but evidence from community randomised trials is lacking. We aimed to assess the effectiveness of azithromycin to treat suspected COVID-19 among people in the community who had an increased risk of complications. In this UK-based, primary care, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in people at increased risk of an adverse clinical course (PRINCIPLE), we randomly assigned people aged 65 years and older, or 50 years and older with at least one comorbidity, who had been unwell for 14 days or less with suspected COVID-19, to usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone. The trial had two coprimary endpoints measured within 28 days from randomisation: time to first self-reported recovery, analysed using a Bayesian piecewise exponential, and hospital admission or death related to COVID-19, analysed using a Bayesian logistic regression model. Eligible participants with outcome data were included in the primary analysis, and those who received the allocated treatment were included in the safety analysis. The trial is registered with ISRCTN, ISRCTN86534580. The first participant was recruited to PRINCIPLE on April 2, 2020. The azithromycin group enrolled participants between May 22 and Nov 30, 2020, by which time 2265 participants had been randomly assigned, 540 to azithromycin plus usual care, 875 to usual care alone, and 850 to other interventions. 2120 (94%) of 2265 participants provided follow-up data and were included in the Bayesian primary analysis, 500 participants in the azithromycin plus usual care group, 823 in the usual care alone group, and 797 in other intervention groups. 402 (80%) of 500 participants in the azithromycin plus usual care group and 631 (77%) of 823 participants in the usual care alone group reported feeling recovered within 28 days. We found little evidence of a meaningful benefit in the azithromycin plus usual care group in time to first reported recovery versus usual care alone (hazard ratio 1·08, 95% Bayesian credibility interval [BCI] 0·95 to 1·23), equating to an estimated benefit in median time to first recovery of 0·94 days (95% BCI −0·56 to 2·43). The probability that there was a clinically meaningful benefit of at least 1·5 days in time to recovery was 0·23. 16 (3%) of 500 participants in the azithromycin plus usual care group and 28 (3%) of 823 participants in the usual care alone group were hospitalised (absolute benefit in percentage 0·3%, 95% BCI −1·7 to 2·2). There were no deaths in either study group. Safety outcomes were similar in both groups. Two (1%) of 455 participants in the azothromycin plus usual care group and four (1%) of 668 participants in the usual care alone group reported admission to hospital during the trial, not related to COVID-19. Our findings do not justify the routine use of azithromycin for reducing time to recovery or risk of hospitalisation for people with suspected COVID-19 in the community. These findings have important antibiotic stewardship implications during this pandemic, as inappropriate use of antibiotics leads to increased antimicrobial resistance, and there is evidence that azithromycin use increased during the pandemic in the UK. UK Research and Innovation and UK Department of Health and Social Care.

Background Prophylactic azithromycin in pregnancy has been shown to lower infections in birthing parents and newborns, particularly skin and soft tissue infections (SSTIs) which are common in Fiji. We aimed to determine the safety and efficacy of 2 g of oral azithromycin administered during labour on infant SSTIs. Methods This blinded, randomised placebo-control trial included healthy, pregnant adults and their infants presenting for delivery at a tertiary hospital in Suva, Fiji. Participants in labour were randomly assigned a single dose of 2 g of oral azithromycin or placebo in a 1:1 ratio, stratified by ethnicity. Active and placebo drugs were identical to mask treatment allocation. The primary outcome was cumulative incidence of infant SSTIs by 3 months of age. Intention-to-treat analysis was used and included participants with SSTI data collected at all visits. Safety outcomes were described as percentages by arm at specified time points. Results From June 2019 to January 2022, 2110 pregnant persons were enrolled and randomised, with 1059 and 1063 births in the azithromycin and placebo groups, respectively. 1671 infants were included in the primary analysis (816 in azithromycin and 855 in placebo group). We found a 27% decrease in infant SSTIs in the azithromycin group (5.8%; 95% CI 4.4–7.6) compared to placebo (7.8%; 95% CI 6.2–9.8), but the 95% confidence interval crossed the null value (RR 0.73; 95% CI 0.51–1.06). We observed similar numbers of serious adverse events in both arms, and no cases of infant hypertrophic pyloric stenosis. Conclusions There was a modest relative reduction in infant SSTIs but this was small in absolute terms with no statistically discernible difference. Our findings do not support routine intrapartum azithromycin prophylaxis for this outcome alone. However, the rates of SSTIs highlight the importance of prevention and timely treatment in Fiji. Trial registration 2019–04-18, ClinicalTrials.gov identifier: NCT03925480

Intrapartum azithromycin prophylaxis reduced maternal infections but showed no effect on neonatal sepsis and mortality. Although antibiotic exposure may indirectly alter the mycobiota (community of fungi that live in a given environment), there is no data available on how intrapartum azithromycin impacts gut mycobiota development. We hereby assess the impact of intrapartum azithromycin on gut mycobiota development from birth to the age of three years, by ITS2 gene profiling of rectal samples from 102 healthy Gambian infants selected from a double-blind randomized placebo-controlled clinical trial (PregnAnZI-2 – ClinicalTrials.org NCT03199547). In the trial, women received 2 g oral azithromycin or placebo (1:1) during labour with the intension of assessing effect on neonatal sepsis or mortality. Secondary objectives included effects on bacterial carriage and resistance, puerperal infections, and infant growth. Our analysis show that season and parity were key factors that influenced gut mycobiota development. Intrapartum azithromycin increased the abundance of Candida orthopsilosis but only in the wet season and did not show different effects by sex of the child. These data suggest that season and parity can be key factors influencing gut mycobiota development and may inform strategies for a wider implementation of intrapartum azithromycin intervention. Here, via ITS2 gene profiling of rectal samples from 102 healthy Gambian infants, the authors show that intrapartum azithromycin has an overall mild effect on gut mycobiota development but associates with increased abundance of C. orthopsilosis in the wet season.

Background Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections (LRTI). Severe asthma is heterogeneous, encompassing eosinophilic and non-eosinophilic (mainly neutrophilic) phenotypes. Patients with neutropilic airway diseases may benefit from macrolides. Methods We performed a randomised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma. Subjects received low-dose azithromycin (n=55) or placebo (n=54) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting β2 agonists for 6 months. The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase. Secondary efficacy outcomes included lung function and scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). Results The rate of primary endpoints (PEPs) during 6 months was not significantly different between the two treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per subject in the azithromycin group versus 0.81 PEPs (95% CI 0.61 to 1.09) in the placebo group (p=0.682). In a predefined subgroup analysis according to the inflammatory phenotype, azithromycin was associated with a significantly lower PEP rate than placebo in subjects with non-eosinophilic severe asthma (blood eosinophilia ≤200/µl): 0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% CI 0.72 to 1.48) (p=0.013). Azithromycin significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function. Azithromycin was well tolerated, but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci. Conclusions Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma. However, the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study. ClinicalTrials.gov number NCT00760838.