1. Using Azithromycin in Labour to Prevent Transmission of Pathogenic Bacteria
Christian Bottomley

2. Intervention
One oral dose of azithromycin (2g) given during labour
PregnAnZI-1 (completed)
Primary endpoint - nasopharyngeal carriage (GBS, S. pneumoniae, S. aureus)
PregnAnZI-2 (ongoing)
Primary endpoint – neonatal mortality

3. - Rates are ‘per 1000 live births’ for neonatal and infant mortality; and ‘per 1000 children surviving to exact age 1’ for child mortality
-Between 1/3 deaths in The Gambia occur in the neonatal period (2012 Unicef)
Jasseh et al. TMIH 2011

5. Leach et al. 1999

6. US Incidence of Invasive Group B Streptococcal Disease
-Early onset (1-6 days), Late onset (7 days-3 months)
-No effect on late onset disease perhaps because greater proportion attributable to transmission on HCW or perhaps because prophylaxis delays presentation of early infection
-CDC 1996 guidelines recommend either screening and using prophylactic antibiotics in labour among women who test positive
-These CDC 1996 guidelines recommend the use of a risk-based or screening-based approach to identify candidates for intrapartum prophylaxis. According
to the risk-based approach, women who present at the time of labor with risk factors for disease
transmission (fever, prolonged rupture of the membranes, or imminent preterm delivery) are offered intrapartum
chemoprophylaxis. According to the screening-based approach, all women are screened for
carriage of group B streptococci between 35 and 37 weeks of gestation, and intrapartum chemoprophylaxisis offered to carriers.
-Revised guidelines in 2002 recommend universal screening
-Universal screening not adopted in UK
-Treatment involves giving intravenous penicillin G is the preferred antibiotic
Adapted by CDC from Jordan et al. Pediatr Infect Dis J 2008

7. MORDOR trial results Keenan et al. NEJM 2018
-CRT (villages randomised)
-Twice yearly MDA for children <5yrs
-Consistent with Ethiopian CRT (Porco et al. 2009) which found 49% mortality reduction
-In contrast trial of SMC+AZM (Chandramohan et al. ) found no effect.
Keenan et al. NEJM 2018

8. PregnAnZI-1 Intervention:
One oral dose of azithromycin (2g) given during labour
Design:
Double-blind placebo controlled randomized clinical trial
829 women randomised (419 intervention control)
Primary outcome:
Nasopharyngeal carriage (GBS, S. pneumoniae, S. aureus) at day 6

9. Day 0 Day 3 & 6 Day 8 Wk 2 & 4 NPS VS NPS BM VS NPS BM Home visits
Sensitisation
& Consent
Randomisation
(Health Facility)
Home visits
Post-natal visit
(Health facility)
NPS nasopharyngeal swab
VS vaginal swab
BM breast milk sample
Day 0
Day 3 & 6
Day 8
Wk 2 & 4
NPS VS
NPS BM VS
NPS BM

11. Bacterial carriage in Mothers
Nasopharynx
Breast Milk
Roca et al. Clin Microbiol Infect 2016

12. Bacterial carriage (nasopharynx) in infants
Primary endpoint

13. Azithromycin in breast milk
-Dose in first week=3.5mg/L*0.75L*7=18mg
-Baby dose per kg 18mg/3kg=6mg/kg
-Mother dose per kg 2g/60kg=33mg/Kg
-Recommended dose AZI in children: 10mg/kg/day

14. 60% reduction maternal infections 24% reduction neonatal infections
-Maternal infections – mastitis, infection of the genital tract (puerperal sepsis), urinary tract infection, pelvic inflammatory disease, endometritis, episiotomy discharge, and septic surgical wound
-Neonatal infections – skin infections, conjunctivitis, otitis, umbilical, oral, sepsis, pneumonia
-Gastroenteritis not included among neonatal infections (rare in neonates)
72% reduction bacterial conjunctivitis

15. Anthropometry at 12 months
No difference in mean height, weight, WAZ, HWZ, MUAC
MUAC<-2SD: 6.3% in placebo grp versus 1.3% in AZI grp
Roca et al. PLoS One 2018

16. Prevalence of S. aureus isolates resistant to azithromycin
Day 28
1 year
AZI
16.7%
3.1%
Placebo
4.5%
2.6%
Roca et al. Clin Microbiol Infect 2016, Bojang et al. CID 2018
-No difference in prevalence of resistant S. pneumonia or resistant GBS at day 28
-Other studies of resistance which have shown that prevalence increases immediately after MDA but then decreases over time, presumably reflecting a fitness cost to resistance.
(e.g. S. pneumonia: Leach 1997, E. coli: Seidman 2014, S. aureus: Bojang 2017)
-S. aureus carriage at day 28 was 33% in placebo arm and 25% in AZM arm and at 1 year it was 22% in both arms combined.

17. PregnAnZI-2
Double-blind placebo controlled randomized clinical trial
Countries: The Gambia and Burkina Faso
Target sample size: 12,500
End recruitment: 2020

18. Primary outcome
Neonatal mortality excluding VLBW, severe birth asphyxia & major congenital malformations
Secondary outcomes
Clinical
-Neonatal sepsis & infection
-Maternal sepsis & infection
-Infant growth (n=1,000)
Microbiome (n=250)
-Bacterial colonisation in gut and nasopharynx
-Resistance
Other
-Cost effectiveness
-Acceptability
-Recruiting at 8 rural sites in BF (Nanoro and Yako districts)
-In The Gambia recruiting at Jameh Foundation for Peace Health Centre (now called Bundung Maternal and Neonatal Hospital) and Serrekunda Health Centre

19. Carriage sub-study
- Oropharyngeal swabs taken primarily for detection of GAS and GBS

20. 1 Congenital malformation 8 Severe birth asphyxia 1 VLBW
The Gambia
N=3,114
Deaths
19 (0.6%) primary endpoint
1 Congenital malformation
8 Severe birth asphyxia
1 VLBW
25 Stillbirths
Burkina Faso
N=1,671
Deaths
10 (0.6%) primary endpoint
0 Congenital malformation
3 Severe birth asphyxia
2 VLBW
21 Stillbirths
-In sample size calc we assumed 1.4% in control group and RR=0.6

21. The PregnAnZI team
PI Anna Roca