Prevalence of nasopharyngeal Streptococcus pneumoniae carriage and resistance to macrolides in the setting of azithromycin mass drug administration: analysis from a cluster-randomised controlled trial in Malawi, 2015–17

Abstract

Background Azithromycin mass drug administration (MDA) could reduce child mortality. However, macrolide resistance, which has generally been reported to develop after whole-community MDA for trachoma control, is a concern, and it has less commonly been studied in the context of treating children to reduce mortality. Here, we report on macrolide resistance after biannual azithromycin MDA at the Malawi site of the MORDOR study. MethodsIn the MORDOR cluster-randomised trial in Malawi, 30 communities in Mangochi District were randomly selected. Communities were randomly assigned to receive azithromycin or placebo by simple randomisation without stratification. Children aged 1-59 months were administered azithromycin 20 mg/kg or placebo as an oral suspension biannually for a total of four treatments in 2015-17. 1200 children (40 children per community) were randomly selected for nasopharyngeal swabs at baseline, 12 months (6 months after the second treatment visit), and 24 months (6 months after the fourth treatment visit). Samples were processed to culture Streptococcus pneumoniae. The primary outcome was the proportion of S pneumoniae isolates exhibiting macrolide resistance at 12 months and 24 months, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02048007. Findings At baseline, 3467 (76%) of 4541 eligible children in the azithromycin group and 3107 (72%) of 4308 eligible children in the placebo group were treated. 564 nasopharyngeal swabs were taken from the azithromycin group and 563 from the placebo group, with similar numbers of swabs taken at 12 months and 24 months. In both groups at baseline, carriage of S pneumoniae was greater than 85% and the proportion of strains resistant to macrolides was 28%. At the 12-month follow-up, macrolide resistance was higher in the azithromycin group (36•9%, 95% CI 32•5-41•2) than in the placebo group (21•6%, 17•7-25•4; OR 2•26, 95% CI 1•46-3•49; p=0•0002). At 24 months, macrolide resistance remained higher in the azithromycin group (43•9%, 39•2-48•5) compared with placebo (32•8%, 28•5-37•1; OR 1•66, 1•15-2•40; p=0•0069). Interpretation These findings support previous evidence from trachoma MDA programmes and suggest that monitoring of macrolide resistance should remain a key component of azithromycin interventions for reducing child mortality. Funding Bill & Melinda Gates Foundation.

Trends inStreptococcus pneumoniaeAntimicrobial Resistance in US Children: A Multicenter Evaluation

“…Although noninvasive PD cases are generally less severe, they contribute to widespread antibiotic use [ 18–20 ] and exert a heavy burden on the healthcare system, including an estimated 382 182 pneumonia hospitalizations and 93 million office visits for otitis media in US children between 1997 and 2019 [ 2 ]. It is likely that the observed resistance in pediatric noninvasive PD isolates is related to high levels of antibiotic use for outpatient respiratory infections, as has been suggested by some studies [ 21 , 22 ]. We also found higher resistance rates in children under the age of 2 compared with older age groups for total and noninvasive PD isolates.…”

The Impact of Antenatal Azithromycin and Monthly Sulfadoxine-Pyrimethamine on Maternal Malaria during Pregnancy and Fetal Growth: A Randomized Controlled Trial

“…40 , 41 Also, the possible SP resistance of P. falciparum and spreading antibiotic resistance should be considered. 42 – 46 Although the results from our sample suggest that azithromycin combined with monthly SP would provide benefits in birth outcomes compared with the monthly SP alone, the policy changes and increased SP and antibiotic resistance might modify its impact on one or more outcomes.…”

Effect of Biannual Azithromycin to Children under 5 Years on the Carriage of Respiratory Pathogens among Children Aged 7–11 Years

“…In the Malawi site of MORDOR, a subset of the younger children were tested for S. pneumoniae by nasopharyngeal culture at similar time points after biannual azithromycin and 10-20% were positive (reduced from a pretreatment baseline of 40-50%). 12,13 The 80% prevalence of pneumococcal carriage we detected in older children is higher, but reasonably expected because we used qPCR, which is generally more sensitive than culture. 14 The prevalence was also higher than that observed in other studies in the region, which ranged from 20% to 65%.…”