Administration Of Azithromycin Research Articles

Assessment of spillover of antimicrobial resistance to untreated children 7 to 12 years old after mass drug administration of azithromycin for child survival in Niger: a secondary analysis of the MORDOR cluster-randomized trial.

The risk of antibiotic resistance is complicated by the potential for spillover effects from one treated population to another. Azithromycin mass drug administration programs report higher rates of antibiotic resistance among treatment arms in targeted groups. This study aims to understand the risk of spillover of antibiotic resistance to non-target groups in these programs. Data was used from a cluster-randomized trial comparing the effect of biannual azithromycin and placebo distribution to children 1-59 months on child mortality. Nasopharyngeal samples from untreated children 7-12 years old were tested for genetic determinants of macrolide resistance (primary outcome) and resistance to other antibiotic classes (secondary outcomes). Linear regression was used to compare the community-level mean difference in prevalence by arm at the 24-month timepoint adjusting for baseline prevalence. 1,103 children 7-12 years old in 30 communities were included in the analysis (15 azithromycin, 15 placebo). Adjusted mean differences in prevalence of resistance determinants for macrolides, beta-lactams and tetracyclines were 3.4% (95% CI -4.1% to 10.8%, P-value 0.37), -1.2% (95% CI -7.9% to 5.5%, P-value 0.72), and -3.3% (95% CI -9.5% to 2.8%, P-value 0.61), respectively. We were unable to demonstrate a statistically significant increase in macrolide resistance determinants in untreated groups in an azithromycin mass drug administration program. While the result might be consistent with a small spillover effect, this study was not powered to detect such a small difference. Larger studies are warranted to better understand the potential for spillover effects within these programs.

Prolonged mass azithromycin distributions and macrolide resistance determinants among preschool children in Niger: A sub-study of a cluster-randomized trial (MORDOR).

Randomized controlled trials found that twice-yearly mass azithromycin administration (MDA) reduces childhood mortality, presumably by reducing infection burden. World Health Organization (WHO) issued conditional guidelines for mass azithromycin administration in high-mortality settings in sub-Saharan Africa given concerns for antibiotic resistance. While prolonged twice-yearly MDA has been shown to increase antibiotic resistance in small randomized controlled trials, the objective of this study was to determine if macrolide and non-macrolide resistance in the gut increases with the duration of azithromycin MDA in a larger setting. The Macrolide Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) study was conducted in Niger from December 2014 to June 2020. It was a cluster-randomized trial of azithromycin (A) versus placebo (P) aimed at evaluating childhood mortality. This is a sub-study in the MORDOR trial to track changes in antibiotic resistance after prolonged azithromycin MDA. A total of 594 communities were eligible. Children 1 to 59 months in 163 randomly chosen communities were eligible to receive treatment and included in resistance monitoring. Participants, staff, and investigators were masked to treatment allocation. At the conclusion of MORDOR Phase I, by design, all communities received an additional year of twice-yearly azithromycin treatments (Phase II). Thus, at the conclusion of Phase II, the treatment history (1 letter per 6-month period) for the participating communities was either (PP-PP-AA) or (AA-AA-AA). In Phase III, participating communities were then re-randomized to receive either another 3 rounds of azithromycin or placebo, thus resulting in 4 treatment histories: Group 1 (AA-AA-AA-AA-A, N = 51), Group 2 (PP-PP-AA-AA-A, N = 40), Group 3 (AA-AA-AA-PP-P, N = 27), and Group 4 (PP-PP-AA-PP-P, N = 32). Rectal swabs from each child (N = 5,340) were obtained 6 months after the last treatment. Each child contributed 1 rectal swab and these were pooled at the community level, processed for DNA-seq, and analyzed for genetic resistance determinants. The primary prespecified outcome was macrolide resistance determinants in the gut. Secondary outcomes were resistance to beta-lactams and other antibiotic classes. Communities recently randomized to azithromycin (groups 1 and 2) had significantly more macrolide resistance determinants than those recently randomized to placebo (groups 3 and 4) (fold change 2.18, 95% CI 1.5 to 3.51, Punadj < 0.001). However, there was no significant increase in macrolide resistance in communities treated 4.5 years (group 1) compared to just the most recent 2.5 years (group 2) (fold change 0.80, 95% CI 0.50 to 1.00, Padj = 0.010), or between communities that had been treated for 3 years in the past (group 3) versus just 1 year in the past (group 4) (fold change 1.00, 95% CI 0.78 to 2.35, Padj = 0.52). We also found no significant differences for beta-lactams or other antibiotic classes. The main limitations of our study were the absence of phenotypic characterization of resistance, no complete placebo arm, and no monitoring outside of Niger limiting generalizability. In this study, we observed that mass azithromycin distribution for childhood mortality among preschool children in Niger increased macrolide resistance determinants in the gut but that resistance may plateau after 2 to 3 years of treatment. Co-selection to other classes needs to be monitored. NCT02047981 https://classic.clinicaltrials.gov/ct2/show/NCT02047981.

Minimum inhibitory concentrations of azithromycin in clinical isolates of Mycobacterium avium complex in Japan.

The latest guidelines include azithromycin as a preferred regimen for treating Mycobacterium avium complex (MAC) pulmonary disease. However, serially collected susceptibility data on clinical MAC isolates are limited, and no breakpoints have been determined. We investigated the minimum inhibitory concentrations (MICs) of azithromycin and clarithromycin for all MAC strains isolated in 2021 from a single center in Japan, excluding duplicates. The MICs were determined using a panel based on the microbroth dilution method, according to the latest Clinical and Laboratory Standards Institute recommendations. The MICs were determined for 318 MAC strains. Although there was a significant positive correlation between the MICs of azithromycin and clarithromycin, the MICs of azithromycin tended to be higher than those of clarithromycin. Among the cases in which the strains were isolated, 18 patients initiated treatment, including azithromycin treatment, after sample collection. Some patients infected with stains with relatively high azithromycin MICs achieved a microbiological cure with azithromycin-containing regimens. This study revealed a higher MIC distribution for azithromycin than clarithromycin, raising questions about the current practice of estimating azithromycin susceptibility based on the clarithromycin susceptibility test result. However, this was a single-center study that included only a limited number of cases treated with azithromycin. Therefore, further multicenter studies that include a greater number of cases treated with azithromycin are warranted to verify the distribution of azithromycin MICs and examine the correlation between azithromycin MICs and treatment effectiveness.IMPORTANCEThe macrolides serve as key drugs in the treatment of pulmonary Mycobacterium avium complex infection, and the administration of macrolide should be guided by susceptibility test results. Azithromycin is recommended as a preferred choice among macrolides, surpassing clarithromycin; however, drug susceptibility testing is often not conducted, and clarithromycin susceptibility is used as a surrogate. This study represents the first investigation into the minimum inhibitory concentration of azithromycin on a scale of several hundred clinical isolates, revealing an overall tendency for higher minimum inhibitory concentrations compared with clarithromycin. The results raise questions about the appropriateness of using clarithromycin susceptibility test outcomes for determining the administration of azithromycin. This study highlights the need for future discussions on the clinical breakpoints of azithromycin, based on large-scale clinical research correlating azithromycin susceptibility with treatment outcomes.

A novel mutation in hERG gene associated with azithromycin-induced acquired long QT syndrome.

Mutations in human ether-à-go-go-related gene (hERG) potassium channels are closely associated with long QT syndrome (LQTS). Previous studies have demonstrated that macrolide antibiotics increase the risk of cardiovascular diseases. To date, the mechanisms underlying acquired LQTS remain elusive. A novel hERG mutation I1025N was identified in an azithromycin-treated patient with acquired long QT syndrome via Sanger sequencing. The mutant I1025N plasmid was transfected into HEK-293 cells, which were subsequently incubated with azithromycin. The effect of azithromycin and mutant I1025N on the hERG channel was evaluated via western blot, immunofluorescence, and electrophysiology techniques. The protein expression of the mature hERG protein was down-regulated, whereas that of the immature hERG protein was up-regulated in mutant I1025N HEK-293 cells. Azithromycin administration resulted in a negative effect on the maturation of the hERG protein. Additionally, the I1025N mutation exerted an inhibitory effect on hERG channel current. Moreover, azithromycin inhibited hERG channel current in a concentration-dependent manner. The I1025N mutation and azithromycin synergistically decreased hERG channel expression and hERG current. However, the I1025N mutation and azithromycin did not alter channel gating dynamics. These findings suggest that hERG gene mutations might be involved in the genetic susceptibility mechanism underlying acquired LQTS induced by azithromycin.

Azithromycin during Routine Well-Infant Visits to Prevent Death

BackgroundMass 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.MethodsWe 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.ResultsOf 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.ConclusionsIn 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.)

Characterization of Antibiotic Treatment among Children Aged 0-59 Months Hospitalized for Acute Bacterial Gastroenteritis in Israel.

We examined the extent and correlates of appropriate antibiotic use among children hospitalized with bacterial acute gastroenteritis (AGE) in Israel, a high-income country setting. Data were collected from children aged 0-59 months who participated in active hospital-based surveillance of AGE undertaken during 2007-2015. Bacterial AGE was defined as having a positive stool culture for Salmonella, Shigella, Campylobacter, or dysentery. Appropriate antibiotic use was defined as the administration of ciprofloxacin, azithromycin, or third-generation cephalosporins during hospitalization or at discharge. Overall, 550 children had bacterial AGE; of those, 369 (67.1% [95% CI 63.1-70.9]) received antibiotics, mostly azithromycin (61.8%) and third-generation cephalosporins (37.9%). Appropriate antibiotic treatment was given to 318/550 (57.8% [95% CI 53.7-61.9]). Children aged 0-11 months vs. 24-49 months were more likely to receive appropriate antibiotic treatment (OR = 1.90 [95% CI 1.09-3.33]). Having dysentery (OR = 5.30 [95% CI 3.35-8.39]), performing blood culture (OR = 1.59 [95% CI 1.02-2.48]), and C-reactive protein (CRP) levels (OR = 1.01 [95% CI 1.01-1.02]) were positively associated with receiving appropriate antibiotic treatment. Most children with bacterial AGE received appropriate antibiotic treatment, which correlated with young age, dysentery, CRP level, and performing blood culture, suggesting more severe illness, thus supporting the clinical decisions of physicians.

Neonatal anthropometric indicators of infant growth and mortality in Burkina Faso.

Most evidence supporting screening for undernutrition is for children aged 6-59 months. However, the highest risk of mortality and highest incidence of wasting occurs in the first 6 months of life. We evaluated relationships between neonatal anthropometric indicators, including birth weight, weight-for-age Z-score (WAZ), weight-for-length Z-score (WLZ), length-for-age Z-score (LAZ) and mid-upper arm circumference (MUAC) and mortality and growth at 6 months of age among infants in Burkina Faso. Data arose from a randomised controlled trial evaluating neonatal azithromycin administration for the prevention of child mortality. We evaluated relationships between baseline anthropometric measures and mortality, wasting (WLZ < -2), stunting (LAZ < -2) and underweight (WAZ < -2) at 6 months of age were estimated using logistic regression models adjusted for the child's age and sex. Five regions of Burkina Faso. Infants aged 8-27 d followed until 6 months of age. Of 21 832 infants enrolled in the trial, 7·9 % were low birth weight (<2500 g), 13·3 % were wasted, 7·7 % were stunted and 7·4 % were underweight at enrolment. All anthropometric deficits were associated with mortality by 6 months of age, with WAZ the strongest predictor (WAZ < -2 to ≥ -3 at enrolment v. WAZ ≥ -2: adjusted OR, 3·91, 95 % CI, 2·21, 6·56). Low WAZ was also associated with wasting, stunting, and underweight at 6 months. Interventions for identifying infants at highest risk of mortality and growth failure should consider WAZ as part of their screening protocol.

Зміни рівнів про- і протизапальних цитокінів у жінок із хронічним ендометритом та можливість медикаментозної корекції цих рівнів на преконцепційному етапі

The incidence of chronic endometritis is more than twice higher the prevalence of other clinical forms of intrauterine pathology, leading to infertility, unsuccessful attempts of in vitro fertilization and spontaneous abortion. There is a lack of data on the alteration of pro- and anti-inflammatory cytokine production in chronic endometritis and their role in the subsequent development of miscarriage. Purpose - to investigate the levels of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interferon gamma (INF-γ), as well as the anti-inflammatory cytokine interleukin 10 (IL-10) in cervical mucus of women with chronic endometritis and to assess the impact of the developed comprehensive preconception treatment on normalizing cytokine disorders in these women. Materials and methods. The levels of pro-inflammatory cytokines TNF-α and INF-γ, as well as the anti-inflammatory cytokine IL-10, were determined using the enzyme-linked immunosorbent assay method in the cervical mucus of 426 women with chronic endometritis who were planning pregnancy. Among them, 168 patients (the Group I) received preconception comprehensive treatment, which included broad-spectrum antibacterial agents (azithromycin), hormonal estrogen-progestin therapy (Femoston 2/10) and L-arginine. The remaining 258 women (the Group II) did not receive treatment for chronic endometritis at the preconception stage. The control group consisted of 30 healthy individuals. Data analysis was performed using mathematical statistical methods, calculating the mean sample values (M), variance (σ) and standard errors of the mean (m). The Student’s t-test was applied, and probabilities were determined using the statistical program «STATISTICA» (StatSoft Inc., USA). Results. In the cervical mucus of women with chronic endometritis, an increase in the levels of pro-inflammatory cytokines INF-γ by 2.8 times (p&lt;0.001) and TNF-α by 2 times (p&lt;0.001) was detected, along with a 2-fold decrease in the concentration of the anti-inflammatory cytokine IL-10 (p&lt;0.001). The shift in the cytokine balance towards pro-inflammatory cytokines is associated with a high frequency of miscarriage in these women. After the treatment of chronic endometritis, women had a 2.6 times lower level of INF-γ (p&lt;0.05), a 2 times lower level of TNF-α (p&lt;0.01), and a 1.7 times higher level of IL-10 (p&lt;0.05) compared to untreated patients. Conclusions. Women with chronic endometritis experience a cytokine imbalance, characterized by an excessive increase in pro-inflammatory cytokines and a decrease in anti-inflammatory cytokines. Women with chronic endometritis who are planning pregnancy require comprehensive preconception treatment, which includes the administration of azithromycin, femoston 2/10 and L-arginine in addition to traditional preconception folate prophylaxis. This treatment, by promoting improved conditions for implantation, leads to a 15% increase in the pregnancy rate and a 1.9-fold reduction in the frequency of spontaneous abortion. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Fixed drug eruption-induced balanoposthitis: a case report.

Fixed Drug Eruptions (FDE) represent a distinctive type of adverse drug reaction, typically characterized by recurring, sharply demarcated skin lesions occurring at identical sites with each administration of the causative drug. A less frequent, albeit significant manifestation of FDE, is balanoposthitis, an inflammatory condition affecting the glans penis and prepuce. This rare case report explores the clinical presentation, diagnosis, and therapeutic management of FDE-induced balanoposthitis in a 34-year-old male patient who developed this condition following azithromycin administration to treat a pulmonary infection. The patient's distinctive symptoms, coupled with a medical history of similar antibiotic-induced reactions, pointed strongly towards an FDE diagnosis. Management entailed immediate discontinuation of the offending drug and initiation of symptomatic treatment, culminating in a positive therapeutic outcome. This case illuminates the potential of commonly prescribed medications, such as antibiotics, to incite balanoposthitis via FDE. It underscores the critical need for healthcare professionals to include FDE in their differential diagnosis for balanoposthitis, especially when patient exposure to high-risk medications is evident. Furthermore, the report emphasizes the pressing requirement for additional research to elucidate the pathogenesis of FDE-induced balanoposthitis and to devise effective therapeutic and preventive measures.

Distance to Health Centers and Effectiveness of Azithromycin Mass Administration for Children in Niger

ImportanceThe MORDOR (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) trial demonstrated that mass azithromycin administration reduced mortality by 18% among children aged 1 to 59 months in Niger. The identification of high-risk subgroups to target with this intervention could reduce the risk of antimicrobial resistance.ObjectiveTo evaluate whether distance to the nearest primary health center modifies the effect of azithromycin administration to children aged 1 to 59 months on child mortality.Design, Setting, and ParticipantsThe MORDOR cluster randomized trial was conducted from December 1, 2014, to July 31, 2017; this post hoc secondary analysis was conducted in 2023 among 594 clusters (communities or grappes) in the Boboye and Loga departments in Niger. All children aged 1 to 59 months in eligible communities were evaluated.InterventionsBiannual (twice-yearly) administration of a single dose of oral azithromycin or matching placebo over 2 years.Main Outcomes and MeasuresA population-based census was used to monitor mortality and person-time at risk (trial primary outcome). Community distance to a primary health center was calculated as kilometers between the center of each community and the nearest health center. Negative binomial regression was used to evaluate the interaction between distance and the effect of azithromycin on the incidence of all-cause mortality among children aged 1 to 59 months.ResultsBetween December 1, 2014, and July 31, 2017, a total of 594 communities were enrolled, with 76 092 children (mean [SD] age, 31 [2] months; 39 022 [51.3%] male) included at baseline, for a mean (SD) of 128 (91) children per community. Median (IQR) distance to the nearest primary health center was 5.0 (3.2-7.1) km. Over 2 years, 145 693 person-years at risk were monitored and 3615 deaths were recorded. Overall, mortality rates were 27.5 deaths (95% CI, 26.2-28.7 deaths) per 1000 person-years at risk in the placebo arm and 22.5 deaths (95% CI, 21.4-23.5 deaths) per 1000 person-years at risk in the azithromycin arm. For each kilometer increase in distance in the placebo arm, mortality increased by 5% (adjusted incidence rate ratio, 1.05; 95% CI, 1.03-1.07; P &amp;amp;lt; .001). The effect of azithromycin on mortality varied significantly by distance (interaction P = .02). Mortality reduction with azithromycin compared with placebo was 0% at 0 km from the health center (95% CI, −19% to 17%), 4% at 1 km (95% CI, −12% to 17%), 16% at 5 km (95% CI, 7% to 23%), and 28% at 10 km (95% CI, 17% to 38%).Conclusions and RelevanceIn this secondary analysis of a cluster randomized trial of mass azithromycin administration for child mortality, children younger than 5 years who lived farthest from health facilities appeared to benefit the most from azithromycin administration. These findings may help guide the allocation of resources to ensure that those with the least access to existing health resources are prioritized in program implementation.Trial RegistrationClinicalTrials.gov Identifier: NCT02047981

Treatment coverage of mass administration of azithromycin among children aged 1-11 months in 21 districts of Kebbi state, Nigeria.

The WHO recommends mass drug administration (MDA) as a strategy to deliver safe and cost-effective medicines to prevent and treat diseases. The antibiotic, azithromycin, has been used during MDA for the treatment and prevention of trachoma in Nigeria. Azithromycin has recently been shown to reduce infant mortality in communities receiving it for trachoma-elimination purposes in sub-Saharan Africa. This article reports on the implementation strategies for the safety and antimicrobial resistance of mass administration of azithromycin to children aged 1-11 mo using the trachoma programme platform in Kebbi state. The mass administration of azithromycin among 1-11-mo-olds in Kebbi was implemented in three phases: (i) the preimplementation phase, during which specific activities were conducted to achieve government and community buy-in, ownership and capacity building; (ii) the implementation phase, which included the mass administration of azithromycin carried out by community volunteers (also known as community-directed distributors [CDDs]), monitoring (by health workers and independent monitors) and reporting of the distribution by all personnel; and (iii) the postimplementation phase, which included the validation of community data, where each item of community summary data is verified and checked for completeness and accuracy before uploading to the District Health Information System platform, where data are visualised, analysed and stored. In total, 97% of the target population received treatment; the remaining 3% were not treated due to signs of ill health, history of allergy to antibiotics, parental refusal or absence at the time of MDA. Children aged 1-11 mo accounted for 17% of the under-5 population, with females constituting 56% of the target population. In communities that were monitored, reports showed that only 5% lacked distribution materials (scales, slings or registers), >80% correctly entered data into community registers and 5% of children were not treated due to inadequate azithromycin provided to the CDDs for distribution. The implementation of azithromycin MDA for children aged 1-11 mo in Kebbi, utilising the trachoma platform, exhibited commendable coverage due to existing programme platform, healthcare and community structures, intensive advocacy and social mobilisation, real-time monitoring and progress-tracking strategies. It also demonstrated that the trachoma platform is suitable for implementing public health interventions, even after the elimination of trachoma in previously endemic districts.

Effectiveness of azithromycin and ciprofloxacin in the treatment of typhoid fever: a systematic review

Typhoid fever or commonly referred to as enteric fever is a systemic disease caused by Salmonella typhi. It often occurs in developing countries due to poor sanitation. Second-line antibiotics, including ciprofloxacin, have been widely used as the first choice treatment for typhoid fever. However, S. typhi has increased resistance to second-line antibiotics, so azithromycin has become an alternative treatment for the typhoid fever. This systematic review assessed the effectiveness of azithromycin and ciprofloxacin against typhoid fever in adults. This research used the PRISMA protocol with predefined Pubmed, Proquest, and EBSCO keywords. After removing duplicates and selecting studies according to inclusion and exclusion criterias, 17 studies about the effectiveness of azithromycin and ciprofloxacin in typhoid fever in adults from 1988-2020 were gathered. Studies were evaluated using JBI Critical Appraisal Tools. The results showed that administration of azithromycin and ciprofloxacin for typhoid fever yields average length of fever (3.5 d and 4.2 d) and average length of stay (9.3 d and 10 d), respectively. The susceptibility of S. typhi to azithromycin was 99.9%, whereas a significant decrease in its susceptibility to ciprofloxacin was observed in 2017-2020, from 4% to 2%. Azithromycin showed better effectiveness than ciprofloxacin in treating typhoid fever in adults based on S. typhi’s susceptibility, average length of fever and average length of stay from 17 studies reviewed.

Statistical analysis plan for the LAKANA trial: a cluster-randomized, placebo-controlled, double-blinded, parallel group, three-arm clinical trial testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1–11-month-old infants in Mali

BackgroundThe Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin (LAKANA) trial in Mali aims to evaluate the efficacy and safety of azithromycin (AZI) mass drug administration (MDA) to 1–11-month-old infants as well as the impact of the intervention on antimicrobial resistance (AMR) and mechanisms of action of azithromycin. To improve the transparency and quality of this clinical trial, we prepared this statistical analysis plan (SAP).Methods/designLAKANA is a cluster randomized trial that aims to address the mortality and health impacts of biannual and quarterly AZI MDA. AZI is given to 1–11-month-old infants in a high-mortality setting where a seasonal malaria chemoprevention (SMC) program is in place. The participating villages are randomly assigned to placebo (control), two-dose AZI (biannual azithromycin-MDA), and four-dose AZI (quarterly azithromycin-MDA) in a 3:4:2 ratio. The primary outcome of the study is mortality among the intention-to-treat population of 1–11-month-old infants. We will evaluate relative risk reduction between the study arms using a mixed-effects Poisson model with random intercepts for villages, using log link function with person-years as an offset variable. We will model outcomes related to secondary objectives of the study using generalized linear models with considerations on clustering.ConclusionThe SAP written prior to data collection completion will help avoid reporting bias and data-driven analysis for the primary and secondary aims of the trial. If there are deviations from the analysis methods described here, they will be described and justified in the publications of the trial results.Trial registrationClinicalTrials.gov ID NCT04424511. Registered on 11 June 2020.

Temporal Trends in Phenotypic Macrolide and Nonmacrolide Resistance for Streptococcus pneumoniae Nasopharyngeal Samples Up to 36 Months after Mass Azithromycin Administration in a Cluster-Randomized Trial in Niger.

Azithromycin mass drug administration decreases child mortality but also selects for antibiotic resistance. Herein, we evaluate macrolide resistance of nasopharyngeal Streptococcus pneumoniae after azithromycin MDA. In a cluster-randomized trial, children 1-59 months received azithromycin or placebo biannually. Fifteen villages from each arm were randomly selected for antimicrobial resistance testing, and 10-15 randomly selected swabs from enrolled children at each village were processed for S. pneumoniae isolation and resistance testing. The primary prespecified outcome was macrolide resistance fraction for azithromycin versus placebo villages at 36 months. Secondary non-prespecified outcomes were comparisons of azithromycin and placebo for: 1) macrolide resistance at 12, 24, and 36 months; 2) nonmacrolide resistance at 36 months; and 3) suspected-erm mutation. At 36 months, 423 swabs were obtained and 322 grew S. pneumoniae, (azithromycin: 146/202, placebo: 176/221). Mean resistance prevalence was non-significantly higher in treatment than placebo (mixed-effects model: 14.6% vs. 8.9%; OR = 2.0, 95%CI: 0.99-3.97). However, when all time points were evaluated, macrolide resistance prevalence was significantly higher in the azithromycin group (β = 0.102, 95%CI: 0.04-0.167). For all nonmacrolides, resistance prevalence at 36 months was not different between the two groups. Azithromycin and placebo were not different for suspected-erm mutation prevalence. Macrolide resistance was higher in the azithromycin group over all time points, but not at 36 months. Although this suggests resistance may not continue to increase after biannual MDA, more studies are needed to clarify when MDA can safely decrease mortality and morbidity in lower- and middle-income countries.

CHANGES IN CYTOKINE BALANCE IN PREGNANT WOMEN WITH CHRONIC ENDOMETRITIS IN THE PAST MEDICAL HISTORY AND THEIR ROLE IN THE DEVELOPMENT OF PREECLAMPSIA

CHANGES IN CYTOKINE BALANCE IN PREGNANT WOMEN WITH CHRONIC ENDOMETRITIS IN THE PAST MEDICAL HISTORY AND THEIR ROLE IN THE DEVELOPMENT OF PREECLAMPSIA

Perinatal Azithromycin Provides Limited Neuroprotection in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic brain injury/encephalopathy affects about 1.15 million neonates per year, 96% of whom are born in low- and middle-income countries. Therapeutic hypothermia is not effective in this setting, possibly because injury occurs significantly before birth. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal azithromycin administration in near-term lambs following global ischemic injury to support earlier treatment approaches. Ewes and their lambs of both sexes (n=34, 141-143 days) were randomly assigned to receive azithromycin or placebo before delivery as well as postnatally. Lambs were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion model. Outcomes were assessed over a 6-day period. While maternal azithromycin exhibited relatively low placental transfer, azithromycin-treated lambs recovered spontaneous circulation faster following the initiation of cardiopulmonary resuscitation and were extubated sooner. Additionally, peri- and postnatal azithromycin administration was well tolerated, demonstrating a 77-hour plasma elimination half-life, as well as significant accumulation in the brain and other tissues. Azithromycin administration resulted in a systemic immunomodulatory effect, demonstrated by reductions in proinflammatory IL-6 (interleukin-6) levels. Treated lambs exhibited a trend toward improved neurodevelopmental outcomes while histological analysis revealed that azithromycin supported white matter preservation and attenuated inflammation in the cingulate and parasagittal cortex. Perinatal azithromycin administration enhances neonatal resuscitation, attenuates neuroinflammation, and supports limited improvement of select histological outcomes in an ovine model of hypoxic-ischemic brain injury/encephalopathy.

Clinical significance of serum microRNA-146a and inflammatory factors in children with Mycoplasma pneumoniae pneumonia after azithromycin treatment

ObjectiveThis study aimed to investigate the clinical significance of serum microRNA-146a and pro-inflammatory factors in children with Mycoplasma pneumoniae pneumonia after azithromycin treatment. microRNA-146a is known to regulate inflammatory responses, and excessive inflammation is a primary characteristic of MPP. MethodsChildren with MPP received conventional symptomatic therapy along with intravenous administration of azithromycin for one week. Serum levels of microRNA-146a and pro-inflammatory factors were measured using RT-qPCR and ELISA kits, respectively. The correlation between microRNA-146a and pro-inflammatory factors was analyzed by the Pearson method. Pulmonary function indexes were assessed using a pulmonary function analyzer, and their correlation with microRNA-146a and pro-inflammatory factors after treatment was evaluated. Children with MPP were divided into effective and ineffective treatment groups, and the clinical significance of microRNA-146a and pro-inflammatory factors was evaluated using receiver operating characteristic curves and logistic multivariate regression analysis. ResultsSerum microRNA-146a was downregulated in children with MPP but upregulated after azithromycin treatment, contrasting with the trend observed for pro-inflammatory factors. MicroRNA-146a showed a negative correlation with pro-inflammatory cytokines. Pulmonary function parameters were initially reduced in children with MPP, but increased after treatment, showing positive/inverse associations with microRNA-146a and pro-inflammatory factors. Higher microRNA-146a and lower pro-inflammatory factors predicted better efficacy of azithromycin treatment. MicroRNA-146a, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) were identified as independent factors influencing treatment efficacy. ConclusionAzithromycin treatment in children with MPP upregulates microRNA-146a, downregulates pro-inflammatory factors, and effectively improves pulmonary function.

Effect of azithromycin administration in cases of acute bronchiolitis – A systematic review and meta-analysis

Acute Bronchiolitis is the most common viral lower respiratory tract infection in infants requiring hospitalization. Management is usually symptomatic and supportive with no specific treatment options. Although viral, Azithromycin by its anti-inflammatory properties might play a role in improving the clinical outcome. The objective was to assess the effect of azithromycin on length of hospital stay and duration of oxygen requirement in cases of acute bronchiolitis. Data sources such as PubMed and Google Scholar were systematically searched till June 2023. The meta-analysis included all published, randomized controlled trials that investigated the efficacy of Azithromycin over placebo in infants &lt;24 months with acute bronchiolitis. Data extraction was guided by a predetermined checklist. Using RevMan 5 software, the mean length of hospital stay and duration of oxygen administration were pooled from the selected studies. The fixed-effect model was used to compare the length of hospital stay and the duration of oxygen administration in the Azithromycin and placebo group. Data analyses were performed in July 2023. The primary outcome was a comparison of the length of hospital stay in infants with Bronchiolitis receiving either azithromycin (intervention) or placebo (control). The secondary outcome was the assessment of the duration of oxygen requirement in both intervention and control groups.The initial search yielded 601 records of which 68 articles underwent full-text evaluation, which identified four articles and a total of 571 patients that were included. The findings did not favor the usage of azithromycin antibiotic in treatment of acute bronchiolitis (Mean deviation = 1.21, 95% CI 0.53–2.78, P = 0.80). An insignificant Q statistic (P = 0.001) indicated the absence of heterogeneity (I2 = 0%). Length of hospital stay showed an overall insignificant effect as the length of stay is almost similar in both drugs (OR = 1.04 95% CI 0.49–2.23, P = 1.00). An insignificant Q statistic (P = 1.00) indicated the absence of heterogeneity (I2 = 0%).

Intrapartum azithromycin to prevent maternal and neonatal sepsis and deaths: A systematic review with meta-analysis.

A systematic review with met-analysis was performed to summarise the evidence on the effect of intrapartum azithromycin on maternal and neonatal infections and deaths. PubMed, Scopus and Web of Science databases were searched in March 2023. Randomised controlled trials comparing intrapartum single-dose of azithromycin with placebo. Maternal infections, maternal mortality, neonatal sepsis, neonatal mortality. We used the random-effects Mantel-Haenszel method to calculate risk ratios (RR) with 95% confidence intervals (95% CI). We assessed risk of bias of the included studies and estimated the evidence certainty using the GRADE approach. After screening 410 abstracts, five studies with 44 190 women and 44 565 neonates were included. The risk of bias was low in four and had some concerns in one of the studies. The risk of endometritis was 1.5% in the azithromycin group and 2.3% in the placebo group (RR 0.64, 95% CI 0.55-0.75), and the evidence certainty was high. The respective risk for chorioamnionitis was 0.05% and 0.1% (RR 0.50, 95% CI 0.22-1.18; evidence certainty moderate). The wound infection rate was lower in the azithromycin group (1.6%) than in the placebo group (2.5%), RR 0.52 (95% CI 0.30-0.89; moderate certainty evidence). The maternal sepsis rate was 1.1% in the azithromycin group and 1.7% in the placebo group (RR 0.66, 95% CI 0.56-0.77; evidence certainty high). Mortality rates did not show evidence of a difference (0.09% versus 0.08%; RR 1.26, 95% CI 0.65-2.42; moderate certainty evidence). The neonatal mortality rate was 0.7% in the azithromycin group and 0.8% in the placebo group (RR 0.94, 95% CI 0.76-1.16; moderate certainty evidence). The neonatal sepsis rate was 7.6% in the azithromycin group and 7.4% in the placebo group (RR 1.02, 95% CI 0.96-1.09; moderate certainty evidence). Intrapartum administration of azithromycin to the mother reduces maternal postpartum infections, including sepsis. Impact on maternal mortality remains undecided. Azithromycin does not reduce neonatal sepsis or mortality rates.

Antenatal, intrapartum and infant azithromycin to prevent stillbirths and infant deaths: study protocol for SANTE, a 2×2 factorial randomised controlled trial in Mali

IntroductionIn high mortality settings, prophylactic azithromycin has been shown to improve birth weight and gestational age at birth when administered antenatally, to reduce the incidence of neonatal infections when administered...