Impact of intra-partum azithromycin on carriage of group A streptococcus in the Gambia: a posthoc analysis of a double-blind randomized placebo-controlled trial

Abstract

Background: Group A Streptococcus (GAS) is a major human pathogen and an important cause of maternal and neonatal sepsis. Asymptomatic bacterial colonization is considered a necessary step towards sepsis. Intra-partum azithromycin may reduce GAS carriage.

Methods: A posthoc analysis of a double-blind, placebo-controlled randomized-trial was performed to determine the impact of 2 g oral dose of intra-partum azithromycin on maternal and neonatal GAS carriage and antibiotic resistance. Following screening, 829 mothers were randomized who delivered 843 babies. GAS was determined by obtaining samples from the maternal and newborn nasopharynx, maternal vaginal tract and breastmilk. Whole Genome Sequencing (WGS) of GAS isolates was performed using the Illumina Miseq platform.

Results: GAS carriage was lower in the nasopharynx of both mothers and babies and breast milk among participants in the azithromycin arm. No differences in GAS carriage were found between groups in the vaginal tract. The occurrence of azithromycin-resistant GAS was similar in both arms, except for a higher prevalence in the vaginal tract among women in the azithromycin arm. WGS revealed all macrolide-resistant vaginal tract isolates from the azithromycin arm were Streptococcus dysgalactiae subspecies equisimilis expressing Lancefield group A carbohydrate (SDSE(A)) harbouring macrolide resistant genes msr(D) and mef(A). Ten of the 45 GAS isolates (22.2%) were SDSE(A).

Conclusions: Oral intra-partum azithromycin reduced GAS carriage among Gambian mothers and neonates however carriage in the maternal vaginal tract was not affected by the intervention due to azithromycin resistant SDSE(A). SDSE(A) resistance must be closely monitored to fully assess the public health impact of intrapartum azithromycin on GAS. Trial registration ClinicalTrials.gov Identifier NCT01800942.

Keywords: Azithromycin; Bacterial carriage; Group A streptococcus; Streptococcus dysgalactiae subspecies equisimilis; Sub-Saharan Africa.

Fig. 1

Trial Profile. ¹All deaths were child deaths, there were no maternal deaths in the trial. ²All withdrawals involved a mother-pair (including twins). ³Mother/baby pair with ≥ 1 missing sample

Fig. 2

Maternal and neonatal carriage of GAS at different body sites and timepoints. A i. maternal nasopharyngeal carriage and ii. Breastmilk carriage of GAS at days 0, 3, 6, 14 and 28 post-delivery in the azithromycin and placebo arms. B Neonatal nasopharyngeal carriage of GAS at days 0, 3, 6, 14 and 28 after birth in the azithromycin and placebo arms

Fig. 3

Midpoint rooted maximum likelihood core-genome phylogenetic analysis using RAxML GTRCAT model with 1000 bootstrap replicates. Circle symbols indicate > 99% bootstrap support. A Core-genome (1299 genes) phylogenetic analysis of 35 S. pyogenes isolates from the study cohort. B International contextualization (based on core genome of 1221 genes) of 10 S. dysgalactiae subspecies equisimilis isolates with individual core-genome (upper clade: 2106 genes, lower clade: 2078 genes) phylogenetic analysis of the two distinct clades in the study cohort. (Annotation key: country of origin; black = the Gambia, yellow = USA, dark green = UK, light green = Germany, pink = Japan, white = unknown, symbols; filled = present, unfilled = absent, no symbol = unknown; study participant ID (unique study identifier for mother/baby units); M = mother, B = newborn, NPS = nasopharyngeal swab, VS = vaginal swab, BM = breast milk, AMR = antimicrobial resistance)