Azithromycin during Routine Well-Infant Visits to Prevent Death.

BACKGROUND: Mass distribution of azithromycin to children 1 to 59 months of age has been shown to reduce childhood all-cause mortality in some sub-Saharan African regions, with the largest reduction seen among infants younger than 12 months of age. Whether the administration of azithromycin at routine health care visits for infants would be effective in preventing death is unclear. METHODS: We conducted a randomized, placebo-controlled trial of a single dose of azithromycin (20 mg per kilogram of body weight) as compared with placebo, administered during infancy (5 to 12 weeks of age). The primary end point was death before 6 months of age. Infants were recruited at routine vaccination or other well-child visits in clinics and through community outreach in three regions of Burkina Faso. Vital status was assessed at 6 months of age. RESULTS: Of the 32,877 infants enrolled from September 2019 through October 2022, a total of 16,416 infants were randomly assigned to azithromycin and 16,461 to placebo. Eighty-two infants in the azithromycin group and 75 infants in the placebo group died before 6 months of age (hazard ratio, 1.09; 95% confidence interval [CI], 0.80 to 1.49; P = 0.58); the absolute difference in mortality was 0.04 percentage points (95% CI, -0.10 to 0.21). There was no evidence of an effect of azithromycin on mortality in any of the prespecified subgroups, including subgroups defined according to age, sex, and baseline weight, and no evidence of a difference between the two trial groups in the incidence of adverse events. CONCLUSIONS: In this trial conducted in Burkina Faso, we found that administration of azithromycin to infants through the existing health care system did not prevent death. (Funded by the Bill and Melinda Gates Foundation; CHAT ClinicalTrials.gov number, NCT03676764.).

Australian Gonococcal Surveillance Programme Annual Report, 2022.

The Australian Gonococcal Surveillance Programme (AGSP) has continuously monitored antimicrobial resistance in Neisseria gonorrhoeae for more than 40 years. In 2022, a total of 8,199 isolates from patients in the public and private sectors, in all jurisdictions, were tested for in vitro antimicrobial susceptibility by standardised methods. The current treatment recommendation for gonorrhoea, for the majority of Australia, continues to be dual therapy with ceftriaxone and azithromycin. In 2022, of N. gonorrhoeae isolates tested, 0.51% (42/8,199) met the WHO criterion for ceftriaxone decreased susceptibility (DS), defined as a minimum inhibitory concentration value ≥ 0.125 mg/L. Resistance to azithromycin was reported in 3.9% of N. gonorrhoeae isolates, proportionally stable since 2019. There were nine isolates with high-level resistance to azithromycin (MIC value ≥ 256 mg/L) reported in Australia: Queensland (4), New South Wales (3), Victoria (1) and non-remote Western Australia (1). This is the highest number detected annually by the AGSP. In 2022, penicillin resistance was found in 38.8% of gonococcal isolates, and ciprofloxacin resistance in 63.3%, however, there was considerable variation by jurisdiction. In some remote settings, penicillin resistance remains low; in these settings, penicillin continues to be recommended as part of an empiric therapy strategy. In 2022, in remote Northern Territory, one penicillin-resistant isolate was reported; in remote Western Australia, 11.8% of gonococcal isolates (9/76) were penicillin resistant. There were three ciprofloxacin-resistant isolates reported from remote Northern Territory; ciprofloxacin resistance rates remain comparatively low in remote Western Australia (6/76; 7.9%).

Pulsed Oral Azithromycin vs 6-Week Oral Doxycycline for Moderate to Severe Meibomian Gland Dysfunction: A Randomized Clinical Trial.

Importance: The treatment of moderate to severe meibomian gland dysfunction (MGD) with oral doxycycline requires a 6-week course of treatment and has frequent adverse effects (AEs), which may be associated with poor compliance. Objective: To determine if the AEs of a 3-week course of oral azithromycin were equivalent to the AEs of a 6-week course of oral doxycycline. Design, Setting, and Participants: This double-masked randomized clinical trial was conducted at a referral center in Thailand from September 2018 to May 2022. Participants with moderate to severe MGD judged unresponsive to conservative management were included. Interventions: Patients were randomized 1:1 to receive oral azithromycin (1 g once per week for 3 weeks) or oral doxycycline (200 mg daily for 6 weeks). Main Outcomes and Measures: After initiating therapy, the study team assessed the total MGD score and Ocular Surface Disease Index (OSDI) score at the initial visit, at 6 weeks, and at 8 weeks, and assessed AEs at 6 weeks and 8 weeks. The prespecified equivalence margins for MGD score and OSDI score were set at ±2 and ±9, respectively. Results: A total of 137 eyes from 137 patients were randomized into groups, 68 eyes in the azithromycin group and 69 eyes in the doxycycline group (female, 66.4%; mean age, 62.0 [SD, 15.1] years). The adjusted mean difference of total MGD scores between groups at week 6 and week 8 were -0.33 (95% CI, -1.70 to 1.03; P for equivalence = .01) and 0.13 (95% CI, -1.59 to 1.84; P for equivalence = .02), respectively. The adjusted mean difference of OSDI between groups score at week 6 and week 8 was -1.20 (95% CI, -5.31 to 2.91; P for equivalence < .001) and -1.59 (95% CI, -5.73 to 2.55; P for equivalence < .001), respectively. In addition, patients treated with azithromycin had fewer gastrointestinal AEs (4.4% vs 15.9%; risk difference, 11.5%; 95% CI 1.6%-21.4%; P = .03). Conclusions and Relevance: These data support an equivalency of effects of azithromycin as compared with doxycycline for MGD score and OSDI score at both follow-up times. The study did not show more gastrointestinal AEs in the azithromycin group. The reduced dosing and potentially fewer gastrointestinal AEs associated with azithromycin support its use as an alternative to doxycycline for at least 6 weeks. Trial Registration: ThaiClinicalTrials.org Identifier: TCTR20180810001.

Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.

BACKGROUND: The appropriate antibiotic treatment for severe scrub typhus, a neglected but widespread reemerging zoonotic infection, is unclear. METHODS: In this multicenter, double-blind, randomized, controlled trial, we compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus. Patients who were 15 years of age or older with severe scrub typhus with at least one organ involvement were enrolled. The patients were assigned to receive a 7-day course of intravenous doxycycline, azithromycin, or both (combination therapy). The primary outcome was a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5. RESULTS: Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%). The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of -13.3 percentage points (95% confidence interval [CI], -21.6 to -5.1; P = 0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of -14.8 percentage points (95% CI, -23.1 to -6.5; P<0.001). No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points; 95% CI, -7.0 to 10.0; P = 0.73). The results in the per-protocol analysis were similar to those in the primary analysis. Adverse events and 28-day mortality were similar in the three groups. CONCLUSIONS: Combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug alone. (Funded by the India Alliance and Wellcome Trust; INTREST Clinical Trials Registry-India number, CTRI/2018/08/015159.).

Effect of Intrapartum Azithromycin vs Placebo on Neonatal Sepsis and Death: A Randomized Clinical Trial.

Importance: Neonatal sepsis is a leading cause of neonatal mortality. New interventions are needed to decrease neonatal sepsis and mortality in regions with highest burden. Objective: To evaluate the efficacy of intrapartum azithromycin to reduce neonatal sepsis or mortality, as well as neonatal and maternal infections. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial enrolled and followed up birthing parents and their infants at 10 health facilities in The Gambia and Burkina Faso, West Africa, between October 2017 and May 2021. Interventions: Participants were assigned at random to receive oral azithromycin (2 g) or placebo (ratio 1:1) during labor. Main Outcomes and Measures: The primary outcome was a composite of neonatal sepsis or mortality, with the former defined based on microbiologic or clinical criteria. Secondary outcomes were neonatal infections (skin, umbilical, eye and ear infections), malaria, and fever; postpartum infections (puerperal sepsis, mastitis), fever, and malaria; and use of antibiotics during 4-week follow-up. Results: The trial randomized 11 983 persons in labor (median age, 29.9 years). Overall, 225 newborns (1.9% of 11 783 live births) met the primary end point. The incidence of neonatal mortality or sepsis was similar in the azithromycin and placebo groups (2.0% [115/5889] vs 1.9% [110/5894]; risk difference [RD], 0.09 [95% CI, -0.39 to 0.57]), as was the incidence of neonatal mortality (0.8% vs 0.8%; RD, 0.04 [95% CI, -0.27 to 0.35]) and neonatal sepsis (1.3% vs 1.3%; RD, 0.02 [95% CI, -0.38 to 0.43]). Newborns in the azithromycin group compared with the placebo group had lower incidence of skin infections (0.8% vs 1.7%; RD, -0.90 [95% CI, -1.30 to -0.49]) and need for antibiotics (6.2% vs 7.8%; RD, -1.58 [95% CI, -2.49 to -0.67]). Postpartum parents in the azithromycin group had lower incidence of mastitis (0.3% vs 0.5%; RD, -0.24 [95% CI, -0.47 to -0.01]) and puerperal fever (0.1% vs 0.3%; RD, -0.19 [95% CI, -0.36 to -0.01]). Conclusions and Relevance: Azithromycin administered orally during labor did not reduce neonatal sepsis or mortality. These results do not support routine introduction of oral intrapartum azithromycin for this purpose. Trial Registration: ClinicalTrials.gov Identifier: NCT03199547.

Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).

Effect of periodontal debridement plus systemic azithromycin in subjects with stage III periodontitis: a randomized controlled clinical trial / Efecto del desbridamiento periodontal más azitromicina sistémica en sujetos con periodontitis estadio III: un ensayo clínico controlado aleatorio

Aim: To evaluate the effect of the systemic administration of azi-thromycin (AZM) as an adjunct to non-surgical periodontal therapy (NSPT) on the clinical and microbiological variables of patients with periodontitis. Material and Methods: Eighteen volunteers received NSPT combined with placebo or AZM (500 mg/day) for 3 days (n=9/group). They were monitored clinically for probing pocket depth (PPD), clinical attachment level (CAL), O'Leary index (OI), bleeding on probing (BoP) at baseline and during the first, third and sixth month and microbiologically, at baseline and at 3 and 6 months after therapy, by conventional polymerase chain reaction tests. Results: Fourteen patients completed the study (n=7/group). Differences statistically significant were observed among both groups. The experimental group presented: A PPD mean (p=0.04) significantly lower and PPD reduction (p=0.02), at 6-months post NSPT. Regarding changes (∆), at the third month post NSPT, there was a significant increase in the number of shallow sites (p<0.001) and a decrease in the intermediate sites (p<0.001). In addition, a significant decrease in the mean number of deep sites (p=0.04) was detected at 6 months post treatment. There was also a significant decrease in periodontal index BoP at 1 (p=0.01), 3 (p<0.001) and 6 (p=0.01) months and OI at 3- and 6-months (p<0.001), post treatment. Regarding the presence of periodontal pathogens, no significant differences were observed, intra and inter groups. Conclusion: AZM as an adjuvant to NSPT provides additional beneficial effects for PPD and BoP compared to NSPT alone.

Objetivo: Evaluar el efecto de la administración sistémica de azitromicina (AZM) como coadyuvante de la terapia periodontal no quirúrgica (TPNQ) en las variables clínicas y microbiológicas de pacientes con periodontitis. Material y Métodos: Dieciocho voluntarios recibieron TPNQ combinado con placebo o AZM (500 mg/día) durante 3 días (n=9/grupo). Fueron monitoreados clínicamente para determinar Profundidad de Sondaje del Saco (PSS), Nivel de Inserción Clínica (NIC), Índice de O'Leary (IO), Sangrado al sondaje (SS) al inicio y durante el primer, tercer y sexto mes y microbiológicamente, al inicio y a los 3 y 6 meses después de la terapia, mediante la reacción en cadena de la polimerasa convencional. Resultados: Catorce pacientes completaron el estudio (n=7/grupo). Se observaron diferencias estadísticamente significativas entre ambos grupos. El grupo experimental presentó una media de PSS significativamente menor (p=0,04) y una reducción de PSS (p=0,02), a los 6 meses post TPNQ. En cuanto al delta (∆) pre y post tratamiento, al tercer mes post TPNQ, hubo un aumento significativo en el número de sitios poco profundos (p<0.001) y una disminución en los sitios intermedios (p<0.001). Además, se detectó una disminución significativa en la media de los sitios profundos (p=0.04) a los 6 meses post tratamiento. También hubo una disminución significativa en el índice SS al primer (p=0.01), tercer (p<0. 0 01) y sexto mes (p=0.01) post TPNQ y del IO al tercer y sexto mes (p<0.001), post tratamiento. En cuanto a la presencia de patógenos periodontales, no se observaron diferencias significativas tanto intra como ínter grupos. Conclusión: AZM como adyuvante a TPNQ proporciona efectos benéficos adicionales en la PSS y SS en comparación a TPNQ solo.

Uso de macrólidos en niños hospitalizados en unidades de cuidados moderados e intensivos durante 2018 / Use of macrolides in children hospitalized in Intensive and moderate care units in 2018 / Uso de macrólidos em crianças hospitalizadas em unidades de cuidados intermediários e intensivos no 2018

Introducción: se describe a nivel mundial un aumento en la prescripción de macrólidos en niños y adolescentes, generando el riesgo de emergencia de cepas resistentes. Objetivo: caracterizar el uso de macrólidos en niños de 1 mes a 14 años hospitalizados en cuidados moderados e intensivos del Hospital Pediátrico del Centro Hospitalario Pereira Rossell (HP-CHPR). Metodología: estudio descriptivo transversal de niños hospitalizados tratados con macrólidos en el HP-CHPR en 2018. Variables: tipo de macrólido, duración del tratamiento, estudios y hallazgos microbiológicos y diagnóstico al egreso. Resultados: recibieron macrólidos 334 niños, mediana de edad 13 meses, 58,4% varones. 71,0% en Unidad de Terapia Intensiva (UTI). Predominó la prescripción de claritromicina (72,8%), durante los dos últimos cuatrimestres del año (77,5%) y por patología respiratoria (94%): bronquiolitis (23,3%), infección aguda no especificada de las vías respiratorias inferiores (21,9%) y crisis asmática (19,1%). Mediana de tratamiento con azitromicina y claritromicina 5 y 8 días respectivamente. Se realizaron estudios microbiológicos en 96,1% sin determinarse microorganismo en 58,3%. Conclusiones: se destaca el uso de macrólidos principalmente en la UTI y por patología respiratoria. La prescripción por fuera de las recomendaciones nacionales vigentes y la baja confirmación microbiológica que apoye el uso fueron los mayores problemas detectados, por lo que parece fundamental establecer estrategias tendientes a promover un uso racional de estos antibióticos.

Introduction: literature has described a global increase in the prescription of macrolides to children and adolescents , which has increased the risk of emergence of resistant strains. Objective: to characterize the use of macrolides in children from 1 month to 14 years of age hospitalized at the moderate and intensive care units of the Pereira Rossell Pediatric Hospital Center (HP-CHPR). Methodology: descriptive cross-sectional study of hospitalized children treated with macrolides at the HP-CHPR in 2018. Variables: macrolide type, treatment duration, microbiological studies and findings, and diagnosis at discharge. Results: 334 children received macrolides, median age 13 months, 58.4% males. 71.0% hospitalized atnan Intensive Care Unit (ICU). Clarithromycin was mainly prescribed in 72.8% of the cases, during the last two quarters of the year (77.5%), due to respiratory disease (94%): bronchiolitis (23.3%), lower respiratory tract unspecified acute infection (21.9%) and asthma crisis (19.1%). Median treatment included Azithromycin and Clarithromycin for 5 and 8 days respectively. Microbiological studies were carried out in 96.1% of the cases and 58.3% did not show the presence of microorganisms. Conclusions: the use of macrolides stands out, mainly at ICUs and due to respiratory pathologies. The main problems identified were prescriptions made outside the framework of the present national recommendations and the low microbiological confirmation for their use, which suggests it is essential to set strategies to promote a more rational use of these antibiotics.

Introdução: a literatura descreve um aumento a nível global na prescrição de macrolídeos para crianças e adolescentes, o que tem aumentado o risco de surgimento de cepas resistentes. Objetivo: caracterizar o uso de macrolídeos em crianças de 1 mês a 14 anos de idade internadas nas unidades de terapia moderada e intensiva do Centro Hospitalar Pediátrico Pereira Rossell (HP-CHPR). Metodologia: estudo transversal descritivo de crianças hospitalizadas tratadas com macrolídeos no HP-CHPR em 2018. Variáveis: tipo de macrolídeo, duração do tratamento, estudos e achados microbiológicos e diagnóstico no momento da alta. Resultados: 334 crianças receberam macrolídeos, idade mediana de 13 meses, 58,4% do sexo masculino. 71,0% internados em Unidade de Terapia Intensiva (UTI). A Claritromicina foi prescrita principalmente em 72,8% dos casos, nos últimos dois trimestres do ano (77,5%), devido a doença respiratória (94%): bronquiolite (23,3%), infecção aguda não especificada do trato respiratório inferior (21,9%) e crise de asma (19,1%). O tratamento médio incluiu Azitromicina e Claritromicina por 5 e 8 dias, respectivamente. Estudos microbiológicos foram realizados em 96,1% dos casos e 58,3% não evidenciaram a presença de microrganismos. Conclusões: destaca-se o uso de macrolídeos, principalmente em UTIs, e devido a patologias respiratórias. Os principais problemas identificados foram as prescrições feitas fora das atuais recomendações nacionais e a baixa confirmação microbiológica para sua utilização, o que sugere que é essencial definir estratégias para promover uma utilização mais racional destes antibióticos.

Effect of biannual azithromycin distribution on antibody responses to malaria, bacterial, and protozoan pathogens in Niger.

The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period (n = 5642 blood specimens, n = 3814 children ages 1-59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29% (hazard ratio = 0.71, 95% CI: 0.56, 0.89; P = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger.

Trial of Three Rounds of Mass Azithromycin Administration for Yaws Eradication.

BACKGROUND: Treponema pallidum subspecies pertenue causes yaws. Strategies to better control, eliminate, and eradicate yaws are needed. METHODS: In an open-label, cluster-randomized, community-based trial conducted in a yaws-endemic area of Papua New Guinea, we randomly assigned 38 wards (i.e., clusters) to receive one round of mass administration of azithromycin followed by two rounds of target treatment of active cases (control group) or three rounds of mass administration of azithromycin (experimental group); round 1 was administered at baseline, round 2 at 6 months, and round 3 at 12 months. The coprimary end points were the prevalence of active cases of yaws, confirmed by polymerase-chain-reaction assay, in the entire trial population and the prevalence of latent yaws, confirmed by serologic testing, in a subgroup of asymptomatic children 1 to 15 years of age; prevalences were measured at 18 months, and the between-group differences were calculated. RESULTS: Of the 38 wards, 19 were randomly assigned to the control group (30,438 persons) and 19 to the experimental group (26,238 persons). A total of 24,848 doses of azithromycin were administered in the control group (22,033 were given to the participants at round 1 and 207 and 2608 were given to the participants with yaws-like lesions and their contacts, respectively, at rounds 2 and 3 [combined]), and 59,852 doses were administered in the experimental group. At 18 months, the prevalence of active yaws had decreased from 0.46% (102 of 22,033 persons) at baseline to 0.16% (47 of 29,954 persons) in the control group and from 0.43% (87 of 20,331 persons) at baseline to 0.04% (10 of 25,987 persons) in the experimental group (relative risk adjusted for clustering, 4.08; 95% confidence interval [CI], 1.90 to 8.76). The prevalence of other infectious ulcers decreased to a similar extent in the two treatment groups. The prevalence of latent yaws at 18 months was 6.54% (95% CI, 5.00 to 8.08) among 994 children in the control group and 3.28% (95% CI, 2.14 to 4.42) among 945 children in the experimental group (relative risk adjusted for clustering and age, 2.03; 95% CI, 1.12 to 3.70). Three cases of yaws with resistance to macrolides were found in the experimental group. CONCLUSIONS: The reduction in the community prevalence of yaws was greater with three rounds of mass administration of azithromycin at 6-month intervals than with one round of mass administration of azithromycin followed by two rounds of targeted treatment. Monitoring for the emergence and spread of antimicrobial resistance is needed. (Funded by Fundació "la Caixa" and others; ClinicalTrials.gov number, NCT03490123.).

Hydroxychloroquine and azithromycin used alone or combined are not effective against SARS-CoV-2 ex vivo and in a hamster model.

Drug repositioning has been used extensively since the beginning of the COVID-19 pandemic in an attempt to identify antiviral molecules for use in human therapeutics. Hydroxychloroquine and azithromycin have shown inhibitory activity against SARS-CoV-2 replication in different cell lines. Based on such in vitro data and despite the weakness of preclinical assessment, many clinical trials were set up using these molecules. In the present study, we show that hydroxychloroquine and azithromycin alone or combined does not block SARS-CoV-2 replication in human bronchial airway epithelia. When tested in a Syrian hamster model, hydroxychloroquine and azithromycin administrated alone or combined displayed no significant effect on viral replication, clinical course of the disease and lung impairments, even at high doses. Hydroxychloroquine quantification in lung tissues confirmed strong exposure to the drug, above in vitro inhibitory concentrations. Overall, this study does not support the use of hydroxychloroquine and azithromycin as antiviral drugs for the treatment of SARS-CoV-2 infections.

Clinical Characteristics and Outcomes of COVID-19 in Turkish Patients with Hematological Malignancies

Objective: Patients with solid malignancies are more vulnerable to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection than the healthy population. The outcome of SARS-CoV-2 infection in highly immunosuppressed populations, such as in patients with hematological malignancies, is a point of interest. We aimed to analyze the symptoms, complications, intensive care unit admissions, and mortality rates of patients with hematological malignancies infected with SARS-CoV-2 in Turkey. Materials and Methods: In this multicenter study, we included 340 adult and pediatric patients diagnosed with SARS-CoV-2 from March to November 2020. Diagnosis and status of primary disease, treatment schedules for hematological malignancies, time from last treatment, life expectancy related to the hematological disease, and comorbidities were recorded, together with data regarding symptoms, treatment, and outcome of SARS-CoV-2 infection. Results: Forty four patients were asymptomatic at diagnosis of SARS-CoV- 2 infection. Among symptomatic patients, fever, cough, and dyspnea were observed in 62.6%, 48.8%, and 41.8%, respectively. Sixty-nine (20%) patients had mild SARS-CoV-2 disease, whereas moderate, severe, and critical disease was reported in 101 (29%), 71 (20%), and 55 (16%) patients, respectively. Of the entire cohort, 251 (73.8%) patients were hospitalized for SARS-CoV-2. Mortality related to SARS-CoV-2 infection was 26.5% in the entire cohort; this comprised 4.4% of those patients with mild disease, 12.4% of those with moderate disease, and 83% of those with severe or critical disease. Active hematological disease, lower life expectancy related to primary hematological disease, neutropenia at diagnosis of SARS-CoV-2, ICU admission, and first-line therapy used for coronavirus disease-2019 treatment were found to be related to higher mortality rates. Treatments with hydroxychloroquine alone or in combination with azithromycin were associated with a higher rate of mortality in comparison to favipiravir use. Conclusion: Patients with hematological malignancy infected with SARS-CoV-2 have an increased risk of severe disease and mortality.

Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings: A Randomized Clinical Trial.

Importance: World Health Organization (WHO) guidelines do not recommend routine antibiotic use for children with acute watery diarrhea. However, recent studies suggest that a significant proportion of such episodes have a bacterial cause and are associated with mortality and growth impairment, especially among children at high risk of diarrhea-associated mortality. Expanding antibiotic use among dehydrated or undernourished children may reduce diarrhea-associated mortality and improve growth. Objective: To determine whether the addition of azithromycin to standard case management of acute nonbloody watery diarrhea for children aged 2 to 23 months who are dehydrated or undernourished could reduce mortality and improve linear growth. Design, Setting, and Participants: The Antibiotics for Children with Diarrhea (ABCD) trial was a multicountry, randomized, double-blind, clinical trial among 8266 high-risk children aged 2 to 23 months presenting with acute nonbloody diarrhea. Participants were recruited between July 1, 2017, and July 10, 2019, from 36 outpatient hospital departments or community health centers in a mixture of urban and rural settings in Bangladesh, India, Kenya, Malawi, Mali, Pakistan, and Tanzania. Each participant was followed up for 180 days. Primary analysis included all randomized participants by intention to treat. Interventions: Enrolled children were randomly assigned to receive either oral azithromycin, 10 mg/kg, or placebo once daily for 3 days in addition to standard WHO case management protocols for the management of acute watery diarrhea. Main Outcomes and Measures: Primary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment. Results: A total of 8266 children (4463 boys [54.0%]; mean [SD] age, 11.6 [5.3] months) were randomized. A total of 20 of 4133 children in the azithromycin group (0.5%) and 28 of 4135 children in the placebo group (0.7%) died (relative risk, 0.72; 95% CI, 0.40-1.27). The mean (SD) change in length-for-age z scores 90 days after enrollment was -0.16 (0.59) in the azithromycin group and -0.19 (0.60) in the placebo group (risk difference, 0.03; 95% CI, 0.01-0.06). Overall mortality was much lower than anticipated, and the trial was stopped for futility at the prespecified interim analysis. Conclusions and Relevance: The study did not detect a survival benefit for children from the addition of azithromycin to standard WHO case management of acute watery diarrhea in low-resource settings. There was a small reduction in linear growth faltering in the azithromycin group, although the magnitude of this effect was not likely to be clinically significant. In low-resource settings, expansion of antibiotic use is not warranted. Adherence to current WHO case management protocols for watery diarrhea remains appropriate and should be encouraged. Trial Registration: ClinicalTrials.gov Identifier: NCT03130114.

Cognitive Outcomes at 18 Months: Findings from the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) Trial.

Micronutrient deficiencies and enteric infections negatively impact child growth and development. We enrolled children shortly after birth in a randomized, placebo-controlled, 2 × 2 factorial interventional trial in Haydom, Tanzania, to assess nicotinamide and/or antimicrobials (azithromycin and nitazoxanide) effect on length at 18 months of age. Cognitive score at 18 months using the Malawi Developmental Assessment Tool (MDAT), which includes gross motor, fine motor, language, and social assessments, was a secondary outcome. Here, we present the MDAT results of 1,032 children. There was no effect of nicotinamide (change in development-for-age Z score [DAZ] -0.08; 95% CI: -0.16, 0) or antimicrobials (change in DAZ 0.04; 95% CI: -0.06, 0.13) on overall MDAT score. The interventions had no effect on cognitive outcomes in subgroups defined by gender, socioeconomic status, birthweight, and birth season or on MDAT subscores. Further analyses are needed to identify targetable risk factors for impaired cognitive development in these settings.

Effect of Mass Azithromycin Distributions on Childhood Growth in Niger: A Cluster-Randomized Trial.

Importance: Mass azithromycin distributions may decrease childhood mortality, although the causal pathway is unclear. The potential for antibiotics to function as growth promoters may explain some of the mortality benefit. Objective: To investigate whether biannual mass azithromycin distributions are associated with increased childhood growth. Design, Setting, and Participants: This cluster-randomized trial was performed from December 2014 until March 2020 among 30 rural communities in Boboye and Loga departments in Niger, Africa, with populations from 200 to 2000 individuals. Communities were randomized in a 1:1 ratio to biannual mass distributions of azithromycin or placebo for children ages 1 to 59 months. Participants, field-workers, and study personnel were masked to treatment allocation. Height and weight changes from baseline to follow-up at 4 years were compared between groups. Data were analyzed from June through November 2021. Interventions: Participants received azithromycin at 20 mg/kg using height-based approximation or by weight for children unable to stand every 6 months at the participants' households. Placebo contained the vehicle of the azithromycin suspension. Main Outcomes and Measures: Longitudinal anthropometric assessments were performed on a random sample of children before the first treatment and then annually for 5 years. Height and weight were the prespecified primary outcomes. Results: Among 3936 children enrolled from 30 communities, baseline characteristics were similar between 1299 children in the azithromycin group and 2637 children in the placebo group (mean 48.2% [95% CI, 45.5% to 50.8%] girls vs 48.0% [95% CI, 45.7% to 50.3%] girls; mean age, 30.8 months [95% CI, 29.5 to 32.0 months] vs 30.6 months [95% CI, 29.2 to 31.6 months]). Baseline anthropometric assessments were performed among 2230 children, including 985 children in the azithromycin group and 1245 children in the placebo group, of whom follow-up measurements were available for 789 children (80.1%) and 1063 children (85.4%), respectively. At the prespecified 4-year follow-up visit, children in the azithromycin group gained a mean 6.7 cm (95% CI, 6.5 to 6.8 cm) in height and 1.7 kg (95% CI, 1.7 to 1.8 kg) in weight per year and children in the placebo group gained a mean 6.6 cm (95% CI, 6.4 to 6.7 cm) in height and 1.7 kg (95% CI, 1.7 to 1.8 kg) in weight per year. Height at 4 years was not statistically significantly different between groups when adjusted for baseline height (0.08 cm [95% CI, -0.12 to 0.28 cm] greater in the azithromycin group; P = .45), and neither was weight when adjusted for height and baseline weight (0.02 kg [95% CI, -0.10 to 0.06 kg] less in the azithromycin group; P = .64). However, among children in the shortest quartile of baseline height, azithromycin was associated with a 0.4 cm (95% CI, 0.1 to 0.7 cm) increase in height compared with placebo. Conclusions and Relevance: This study did not find evidence of an association between mass azithromycin distributions and childhood growth, although subgroup analysis suggested some benefit for the shortest children. These findings suggest that the mortality benefit of mass azithromycin distributions is unlikely to be due solely to growth promotion. Trial Registration: ClinicalTrials.gov Identifier: NCT02048007.

Impact of mass administration of azithromycin as a preventive treatment on the prevalence and resistance of nasopharyngeal carriage of Staphylococcus aureus.

Staphylococcus aureus is a major cause of serious illness and death in children, indicating the need to monitor prevalent strains, particularly in the vulnerable pediatric population. Nasal carriage of S. aureus is important as carriers have an increased risk of serious illness due to systemic invasion by this pathogen and can transmit the infection. Recent studies have demonstrated the effectiveness of azithromycin in reducing the prevalence of nasopharyngeal carrying of pneumococci, which are often implicated in respiratory infections in children. However, very few studies of the impact of azithromycin on staphylococci have been undertaken. During a clinical trial under taken in 2016, nasal swabs were collected from 778 children aged 3 to 59 months including 385 children who were swabbed before administration of azithromycin or placebo and 393 after administration of azithromycin or placebo. Azithromycin was given in a dose of 100 mg for three days, together with the antimalarials sulfadoxine-pyrimethamine and amodiaquine, on four occasions at monthly intervals during the malaria transmission season. These samples were cultured for S. aureus as well as for the pneumococcus. The S. aureus isolates were tested for their susceptibility to azithromycin (15 g), penicillin (10 IU), and cefoxitine (30 g) (Oxoid Ltd). S. aureus was isolated from 13.77% (53/385) swabs before administration of azithromycin and from 20.10% (79/393) six months after administration (PR = 1.46 [1.06; 2.01], p = 0.020). Azithromycin resistance found in isolates of S. aureus did not differ significantly before and after intervention (26.42% [14/53] vs 16.46% [13/79], (PR = 0.62 [0.32; 1.23], p = 0.172). Penicillin resistance was very pronounced, 88.68% and 96.20% in pre-intervention and in post-intervention isolates respectively, but very little Methicillin Resistance (MRSA) was detected (2 cases before and 2 cases after intervention). Monitoring antibiotic resistance in S. aureus and other bacteria is especially important in Burkina Faso due to unregulated consumption of antibiotics putting children and others at risk.