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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.

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.

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.).

In this trial involving women who received standard antibiotic prophylaxis for nonelective cesarean section, the risk of infection after surgery was lower with the addition of azithromycin than with placebo. Globally, pregnancy-associated infection is a major cause of maternal death and is the fourth most common cause in the United States. 1 Maternal infection is also associated with a prolonged hospital stay and increased health care costs. 2 , 3 Cesarean delivery is the most common major surgical procedure 4 and is associated with a rate of surgical-site infection (including endometritis and wound infection) that is 5 to 10 times the rate for vaginal delivery. 5 Despite routine use of antibiotic prophylaxis (commonly, a cephalosporin given before skin incision 6 ), infection after cesarean section remains an important concern, particularly among women who undergo nonelective procedures . . .

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.

Intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin–piperaquine is more effective than IPTp with sulfadoxine–pyrimethamine at reducing malaria infection during pregnancy in areas with high-grade resistance to sulfadoxine–pyrimethamine by Plasmodium falciparum in east Africa. We aimed to assess whether IPTp with dihydroartemisinin–piperaquine, alone or combined with azithromycin, can reduce adverse pregnancy outcomes compared with IPTp with sulfadoxine–pyrimethamine. We did an individually randomised, double-blind, three-arm, partly placebo-controlled trial in areas of high sulfadoxine–pyrimethamine resistance in Kenya, Malawi, and Tanzania. HIV-negative women with a viable singleton pregnancy were randomly assigned (1:1:1) by computer-generated block randomisation, stratified by site and gravidity, to receive monthly IPTp with sulfadoxine–pyrimethamine (500 mg of sulfadoxine and 25 mg of pyrimethamine for 1 day), monthly IPTp with dihydroartemisinin–piperaquine (dosed by weight; three to five tablets containing 40 mg of dihydroartemisinin and 320 mg of piperaquine once daily for 3 consecutive days) plus a single treatment course of placebo, or monthly IPTp with dihydroartemisinin–piperaquine plus a single treatment course of azithromycin (two tablets containing 500 mg once daily for 2 consecutive days). Outcome assessors in the delivery units were masked to treatment group. The composite primary endpoint was adverse pregnancy outcome, defined as fetal loss, adverse newborn baby outcomes (small for gestational age, low birthweight, or preterm), or neonatal death. The primary analysis was by modified intention to treat, consisting of all randomised participants with primary endpoint data. Women who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT03208179. From March-29, 2018, to July 5, 2019, 4680 women (mean age 25·0 years [SD 6·0]) were enrolled and randomly assigned: 1561 (33%; mean age 24·9 years [SD 6·1]) to the sulfadoxine–pyrimethamine group, 1561 (33%; mean age 25·1 years [6·1]) to the dihydroartemisinin–piperaquine group, and 1558 (33%; mean age 24·9 years [6.0]) to the dihydroartemisinin–piperaquine plus azithromycin group. Compared with 335 (23·3%) of 1435 women in the sulfadoxine–pyrimethamine group, the primary composite endpoint of adverse pregnancy outcomes was reported more frequently in the dihydroartemisinin–piperaquine group (403 [27·9%] of 1442; risk ratio 1·20, 95% CI 1·06–1·36; p=0·0040) and in the dihydroartemisinin–piperaquine plus azithromycin group (396 [27·6%] of 1433; 1·16, 1·03–1·32; p=0·017). The incidence of serious adverse events was similar in mothers (sulfadoxine–pyrimethamine group 17·7 per 100 person-years, dihydroartemisinin–piperaquine group 14·8 per 100 person-years, and dihydroartemisinin–piperaquine plus azithromycin group 16·9 per 100 person-years) and infants (sulfadoxine–pyrimethamine group 49·2 per 100 person-years, dihydroartemisinin–piperaquine group 42·4 per 100 person-years, and dihydroartemisinin–piperaquine plus azithromycin group 47·8 per 100 person-years) across treatment groups. 12 (0·2%) of 6685 sulfadoxine–pyrimethamine, 19 (0·3%) of 7014 dihydroartemisinin–piperaquine, and 23 (0·3%) of 6849 dihydroartemisinin–piperaquine plus azithromycin treatment courses were vomited within 30 min. Monthly IPTp with dihydroartemisinin–piperaquine did not improve pregnancy outcomes, and the addition of a single course of azithromycin did not enhance the effect of monthly IPTp with dihydroartemisinin–piperaquine. Trials that combine sulfadoxine–pyrimethamine and dihydroartemisinin–piperaquine for IPTp should be considered. European & Developing Countries Clinical Trials Partnership 2, supported by the EU, and the UK Joint-Global-Health-Trials-Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, Department of Health and Social Care, Wellcome, and the Bill-&-Melinda-Gates-Foundation.

In small community-based trials, mass drug administration of ivermectin has been shown to substantially decrease the prevalence of both scabies and secondary impetigo; however, their effect at large scale is untested. Additionally, combined mass administration of drugs for two or more neglected diseases has potential practical advantages, but efficacy of potential combinations should be confirmed. The azithromycin ivermectin mass drug administration (AIM) trial was a prospective, single-arm, before-and-after, community intervention study to assess the efficacy of mass drug administration of ivermectin for scabies and impetigo, with coadministration of azithromycin for trachoma. Mass drug administration was offered to the entire population of Choiseul Province, Solomon Islands, and of this population we randomly selected two sets of ten sentinel villages for monitoring, one at baseline and the other at 12 months. Participants were offered a single dose of 20 mg/kg azithromycin, using weight-based bands. Children weighing less than 12·5 kg received azithromycin oral suspension (20 mg/kg), and infants younger than 6 months received topical 1% tetracycline ointment. For ivermectin, participants were offered two doses of oral ivermectin 200 μg/kg 7–14 days apart using weight-based bands, or 5% permethrin cream 7–14 days apart if ivermectin was contraindicated. Our study had the primary outcomes of safety and feasibility of large-scale mass coadministration of oral ivermectin and azithromycin, which have been previously reported. We report here the prevalence of scabies and impetigo in residents of the ten baseline villages compared with those in the ten 12-month villages, as measured by examination of the skin, which was a secondary outcome of the trial. Further outcomes were comparison of the number of all-cause outpatient attendances at government clinics in Choiseul Province at various timepoints before and after mass drug administration. The trial was registered with the Australian and New Zealand Trials Registry (ACTRN12615001199505). During September, 2015, over 4 weeks, 26 188 people (99·3% of the estimated population of Choiseul [n=26 372] as determined at the 2009 census) were treated. At baseline, 1399 (84·2%) of 1662 people living in the first ten villages had their skin examined, of whom 261 (18·7%) had scabies and 347 (24·8%) had impetigo. At 12 months after mass drug administration, 1261 (77·6%) of 1625 people in the second set of ten villages had their skin examined, of whom 29 (2·3%) had scabies (relative reduction 88%, 95% CI 76·5–99·3) and 81 (6·4%) had impetigo (relative reduction 74%, 63·4–84·7). In the 3 months after mass drug administration, 10 614 attended outpatient clinics for any reason compared with 16 602 in the 3 months before administration (decrease of 36·1%, 95% CI 34·7–37·6), and during this period attendance for skin sores, boils, and abscesses decreased by 50·9% (95% CI 48·6–53·1). Ivermectin-based mass drug administration can be scaled to a population of over 25 000 with high efficacy and this level of efficacy can be achieved when mass drug administration for scabies is integrated with mass drug administration of azithromycin for trachoma. These findings will contribute to development of population-level control strategies. Further research is needed to assess durability and scalability of mass drug administration in larger, non-island populations, and to assess its effect on the severe bacterial complications of scabies. International Trachoma Initiative, Murdoch Children's Research Institute, Scobie and Claire Mackinnon Trust, and the Wellcome Trust.

Background. Ceftriaxone is the foundation of currently recommended gonorrhea treatment. There is an urgent need for backup treatment options for patients with cephalosporin allergy or infections due to suspected cephalosporin-resistant Neisseria gonorrhoeae. We evaluated the efficacy and tolerability of 2 combinations of existing non-cephalosporin antimicrobials for treatment of patients with urogenital gonorrhea. Methods. We conducted a randomized, multisite, open-label, noncomparative trial in 5 outpatient sexually transmitted disease clinic sites in Alabama, California, Maryland, and Pennsylvania. Patients aged 15–60 years diagnosed with uncomplicated urogenital gonorrhea were randomly assigned to either gentamicin 240 mg intramuscularly plus azithromycin 2 g orally, or gemifloxacin 320 mg orally plus azithromycin 2 g orally. The primary outcome was microbiological cure of urogenital infections (negative follow-up culture) at 10–17 days after treatment among 401 participants in the per protocol population. Results. Microbiological cure was achieved by 100% (lower 1-sided exact 95% confidence interval [CI] bound, 98.5%) of 202 evaluable participants receiving gentamicin/azithromycin, and 99.5% (lower 1-sided exact 95% CI bound, 97.6%) of 199 evaluable participants receiving gemifloxacin/azithromycin. Gentamicin/azithromycin cured 10 of 10 pharyngeal infections and 1 of 1 rectal infection; gemifloxacin/azithromycin cured 15 of 15 pharyngeal and 5 of 5 rectal infections. Gastrointestinal adverse events were common in both arms. Conclusions. Gentamicin/azithromycin and gemifloxacin/azithromycin were highly effective for treatment of urogenital gonorrhea. Gastrointestinal adverse events may limit routine use. These non-cephalosporin-based regimens may be useful alternative options for patients who cannot be treated with cephalosporin antimicrobials. Additional treatment options for gonorrhea are needed. Clinical Trials Registration. NCT00926796.

Exacerbations of chronic obstructive pulmonary disease (COPD) are a source of substantial morbidity. In this randomized, controlled trial involving patients with moderately severe COPD, daily treatment with azithromycin for 1 year was associated with fewer exacerbations. Acute exacerbations of chronic obstructive pulmonary disease (COPD) result in frequent visits to physicians' offices and emergency rooms and numerous hospitalizations and days lost from work; they also account for a substantial percentage of the cost of treating COPD. 1 – 5 Patients who have acute exacerbations of COPD, as compared with patients with COPD who do not have acute exacerbations, have an increased risk of death, a more rapid decline in lung function, and reduced quality of life. 6 – 11 Although inhaled glucocorticoids, long-acting beta 2 -agonists, and long-acting muscarinic antagonists reduce the frequency of acute exacerbations of COPD, 12 – 24 patients receiving . . .

In this trial, rural communities in Niger were randomly assigned to distribute azithromycin or placebo to children (1 to 59 months of age) or infants (1 to 11 months). All-cause mortality was reduced in the child-treated group.