Impact of Intrapartum Oral Azithromycin on Staphylococcus aureus Colonisation and Staphylococcal Antibiotic Resistance Among Women and Their Babies in The Gambia

Bojang, Abdoulie (2020). Impact of Intrapartum Oral Azithromycin on Staphylococcus aureus Colonisation and Staphylococcal Antibiotic Resistance Among Women and Their Babies in The Gambia. PhD thesis The Open University.

Abstract

Maternal and neonatal infections are a major public health problem leading to high morbidity and mortality in middle and low-income countries. There is a need for effective interventions suitable for these countries to reduce the high burden of disease.

Intrapartum azithromycin is a potential intervention to reduce maternal and neonatal infections and their associated deaths. PregnAnZI-1, the first intrapartum oral azithromycin trial was a Phase III, double-blind, placebo controlled randomized clinical trial in which 829 women in labour were randomized to receive either a single dose of 2g of oral azithromycin or placebo (ratio 1:1). The trial was conceived as a pilot study to determine the impact of the intervention on maternal and neonatal bacterial colonization, as a necessary step towards sepsis. Nasopharyngeal swabs (NPS), breast milk (BM) and vaginal swabs (VS) were collected from study women and /or their babies during the first 4 weeks of follow-up (day 0, day 3, day 6, day 8, day 14 and day 28). Additionally, NPS were also collected from study children in a survey conducted 12 months following the trial. During the trial follow up period (birth to day 28), prevalence of carriage of S. aureus, S. pneumoniae and group B Streptococci decreased significantly in the intervention arm, whilst prevalence of azithromycin resistant S. aureus increased among mothers or their babies exposed to azithromycin compared to the placebo group.

The aims of my PhD investigations are to determine the long-term impact of such intervention on S. aureus colonisation and antimicrobial resistance; molecular epidemiology of azithromycin resistant S. aureus and the prevalence of nasopharyngeal macrolide resistance genes following intrapartum oral azithromycin intervention.

In the survey conducted 12 months following the main trial, a total of 461 NPS were screened for prevalence of carriage and azithromycin resistance for S. aureus and S. pneumoniae. As expected there was no difference in the prevalence of nasopharyngeal carriage of S. pneumoniae or S. aureus between children whose mothers had been exposed to azithromycin during labour and those whose mothers had not (85.0% vs 82.1%; odds ratio [OR], 1.23 [95% confidence interval, .73-2.08] for S. pneumoniae and 21.7% vs 21.3%; OR, 1.02 [95% CI, .64-1.64] for S. aureus). Also, prevalence of azithromycin-resistant S. pneumoniae (1.8% vs 0.9% p= 0.384) and S. aureus (3.1% vs 2.6% p= 0.724) were not different between children from the azithromycin and placebo arms, respectively. The intervention did not induce antibiotic resistance to other antibiotics commonly used in Africa for these two bacteria.

A random selection of 7 mothers and 10 babies from both arms of the trial, who carried S. aureus resistant to azithromycin in the nasopharynx at day 3 and day 28 post-intervention were included in the second investigation undertaken as part of this PhD. A total of 66 S. aureus isolates underwent genomic investigation. Seven S. aureus sequence types (STs) were identified. ST5 predominated in the placebo arm (73.0% versus 49.0%, p = 0.039) and ST15 in the azithromycin arm (27.0% versus 6.0%, p = 0.022). Among azithromycin-resistant isolates, msr(A) gene was the main macrolide resistance gene (n = 36, 80%) and was found to be located on a multidrug resistant (MDR) plasmid. The intervention appeared to select for the ermC gene as 36% of resistant S. aureus isolates from mothers and babies exposed to antibiotic carried the gene as oppose to 0% in the placebo arm (p< 0.001).

Having established that the genetic determinants for S. aureus macrolide resistance were predominantly msr(A) and 7ermC, I assessed the effect of intrapartum oral azithromycin on these genes in my final PhD investigation as they were found to be located on mobile genetic elements that can transfer horizontally between bacteria. PCRs were performed on 936 NPS from 312 children at three different time points (birth, day 28 and 12 months). At birth, prevalence of msr(A) gene was similar in both arms, higher in the azithromycin arm by day 28 (60.7% vs. 29.9% in the azithromycin and placebo arms, respectively; OR, 3.61 [95% CI, 2.20-5.93]) and again similar between arms at 12 months. Prevalence of ermC followed a similar pattern, with differences between arms only apparent at day 28 (63.9% vs. 45.9% in the azithromycin and placebo arms, respectively; OR, 2.09 [95% CI, 1.29-3.37]).

In conclusion, the effectiveness of intrapartum oral azithromycin prophylaxis in decreasing carriage of bacteria associated with both maternal and neonatal infections had been established. Emergence of azithromycin resistant S. aureus shortly (28 days) following oral azithromycin exposure was of concern. However, in the long term (12 months), neither the increased azithromycin resistant S. aureus nor the increased nasopharyngeal macrolide resistance genes observed shortly following the intervention persisted among mothers or their new-borns. Hence, supporting the use of intrapartum oral azithromycin prophylaxis as a means to reduce maternal and neonatal infections in The Gambia and potentially other developing countries worldwide.

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