Prevention of bacterial infections in the newborn by pre-delivery administration of azithromycin: Study protocol of a randomized efficacy trial

Anna Roca, Claire Oluwalana, Bully Camara, Abdoulie Bojang, Sarah Burr, Timothy M E Davis, Robin Bailey, Beate Kampmann, Jenny Mueller, Christian Bottomley, Umberto D'Alessandro, Anna Roca, Claire Oluwalana, Bully Camara, Abdoulie Bojang, Sarah Burr, Timothy M E Davis, Robin Bailey, Beate Kampmann, Jenny Mueller, Christian Bottomley, Umberto D'Alessandro

Abstract

Background: Neonatal deaths, estimated at approximately 4 million annually, now account for almost 40% of global mortality in children aged under-five. Bacterial sepsis is a leading cause of neonatal mortality. Assuming the mother is the main source for bacterial transmission to newborns, the primary objective of the trial is to determine the impact of one oral dose of azithromycin, given to women in labour, on the newborn's bacterial carriage in the nasopharynx. Secondary objectives include the impact of the intervention on bacterial colonization in the baby and the mother during the first month of life.

Methods/design: This is a Phase III, double -blind, placebo controlled randomized clinical trial in which 830 women in labour were randomized to either a single dose of 2 g oral azithromycin or placebo (ratio 1:1). The trial included pregnant women in labour aged 18 to 45 years attending study health centres in the Western Gambia. A post-natal check of the mother and baby was conducted at the health centre by study clinicians before discharge and 8-10 days after delivery. Home follow up visits were conducted daily during the first week and then weekly until week 8 after delivery. Vaginal swabs and breast milk samples were collected from the mothers, and the pathogens Streptococcus pneumoniae, Group B Streptococcus (GBS) and Staphylococcus aureus were isolated from the study samples. For bacterial isolates, susceptibility pattern to azithromycin was determined using disk diffusion and E-test. Eye swabs were collected from newborns with eye discharge during the follow up period, and Chlamydial infection was assessed using molecular methods.

Discussion: This is a proof-of-concept study to assess the impact of antibiotic preventive treatment of women during labour on bacterial infections in the newborn. If the trial confirms this hypothesis, the next step will be to assess the impact of this intervention on neonatal sepsis. The proposed intervention should be easily implementable in developing countries.

Trial registration: ClinicalTrials.gov Identifier--NCT01800942--First received: February 26, 2013.

Figures

Fig. 1
Fig. 1
Study site
Fig. 2
Fig. 2
Sensitisation and Informed Consent Understanding Tool Process
Fig. 3
Fig. 3
Overall study approach

References

    1. Hill K, You D, Inoue M, Oestergaard MZ. Child mortality estimation: accelerated progress in reducing global child mortality, 1990–2010. PLoS Med. 2012;9:e1001303. doi: 10.1371/journal.pmed.1001303.
    1. Jasseh M, Webb EL, Jaffar S, Howie S, Townend J, Smith PG, et al. Reaching millennium development goal 4 - the Gambia. Trop Med Int Health. 2011;16:1314–1325. doi: 10.1111/j.1365-3156.2011.02809.x.
    1. Lawn JE, Cousens S, Zupan J. 4 million neonatal deaths: when? Where? Why? Lancet. 2005;365:891–900. doi: 10.1016/S0140-6736(05)71048-5.
    1. Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE, et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet. 2012;379:2151–2161. doi: 10.1016/S0140-6736(12)60560-1.
    1. Seale AC, Mwaniki M, Newton CR, Berkley JA. Maternal and early onset neonatal bacterial sepsis: burden and strategies for prevention in sub-Saharan Africa. Lancet Infect Dis. 2009;9:428–438. doi: 10.1016/S1473-3099(09)70172-0.
    1. Waters D, Jawad I, Ahmad A, Luksic I, Nair H, Zgaga L, et al. Aetiology of community-acquired neonatal sepsis in low and middle income countries. J Glob Health. 2011;1:154–170.
    1. Schrag SJ, Cutland CL, Zell ER, Kuwanda L, Buchmann EJ, Velaphi SC, et al. Risk factors for neonatal sepsis and perinatal death among infants enrolled in the prevention of perinatal sepsis trial, Soweto, South Africa. Pediatr Infect Dis J. 2012;31:821–826. doi: 10.1097/INF.0b013e31825c4b5a.
    1. Chatzakis E, Scoulica E, Papageorgiou N, Maraki S, Samonis G, Galanakis E. Infant colonization by Staphylococcus aureus: role of maternal carriage. Eur J Clin Microbiol Infect Dis. 2011;30:1111–1117. doi: 10.1007/s10096-011-1199-9.
    1. Rudan I, Theodoratou E, Nair H, Marusic A, Campbell H. Reducing the burden of maternal and neonatal infections in low income settings. J Glob Health. 2011;1:106–109.
    1. Suara RO, Adegbola RA, Baker CJ, Secka O, Mulholland EK, Greenwood BM. Carriage of group B Streptococci in pregnant Gambian mothers and their infants. J Infect Dis. 1994;170:1316–1319. doi: 10.1093/infdis/170.5.1316.
    1. Drew RH, Gallis HA. Azithromycin--spectrum of activity, pharmacokinetics, and clinical applications. Pharmacotherapy. 1992;12:161–173.
    1. Nosten F, McGready R, D’Alessandro U, Bonell A, Verhoeff F, Menendez C, et al. Antimalarial drugs in pregnancy: a review. Curr Drug Saf. 2006;1:1–15. doi: 10.2174/157488606775252584.
    1. Orton LC, Omari AA. Drugs for treating uncomplicated malaria in pregnant women.Cochrane Database Syst Rev. 2008. CD004912.
    1. Chico RM, Hack BB, Newport MJ, Ngulube E, Chandramohan D. On the pathway to better birth outcomes? A systematic review of azithromycin and curable sexually transmitted infections. Expert Rev Anti Infect Ther. 2013;11:1303–1332. doi: 10.1586/14787210.2013.851601.
    1. Kalilani L, Mofolo I, Chaponda M, Rogerson SJ, Alker AP, Kwiek JJ, et al. A randomized controlled pilot trial of azithromycin or artesunate added to sulfadoxine-pyrimethamine as treatment for malaria in pregnant women. PLoS One. 2007;2:e1166. doi: 10.1371/journal.pone.0001166.
    1. Luntamo M, Kulmala T, Mbewe B, Cheung YB, Maleta K, Ashorn P. Effect of repeated treatment of pregnant women with sulfadoxine-pyrimethamine and azithromycin on preterm delivery in Malawi: a randomized controlled trial. Am J Trop Med Hyg. 2010;83:1212–1220. doi: 10.4269/ajtmh.2010.10-0264.
    1. Friedman DS, Curtis CR, Schauer SL, Salvi S, Klapholz H, Treadwell T, et al. Surveillance for transmission and antibiotic adverse events among neonates and adults exposed to a healthcare worker with pertussis. Infect Control Hosp Epidemiol. 2004;25:967–973. doi: 10.1086/502328.
    1. Kelsey JJ, Moser LR, Jennings JC, Munger MA. Presence of azithromycin breast milk concentrations: a case report. Am J Obstet Gynecol. 1994;170:1375–1376. doi: 10.1016/S0002-9378(13)90469-5.
    1. Ballard HO, Shook LA, Bernard P, Anstead MI, Kuhn R, Whitehead V, et al. Use of azithromycin for the prevention of bronchopulmonary dysplasia in preterm infants: a randomized, double-blind, placebo controlled trial. Pediatr Pulmonol. 2011;46:111–118. doi: 10.1002/ppul.21352.
    1. Chang AB, Grimwood K, White AV, Maclennan C, Sloots TP, Sive A, et al. Randomized placebo-controlled trial on azithromycin to reduce the morbidity of bronchiolitis in Indigenous Australian infants: rationale and protocol. Trials. 2011;12:94. doi: 10.1186/1745-6215-12-94.
    1. Salman S, Rogerson SJ, Kose K, Griffin S, Gomorai S, Baiwog F, et al. Pharmacokinetic properties of azithromycin in pregnancy. Antimicrob Agents Chemother. 2010;54:360–366. doi: 10.1128/AAC.00771-09.
    1. Fry AM, Jha HC, Lietman TM, Chaudhary JS, Bhatta RC, Elliott J, et al. Adverse and beneficial secondary effects of mass treatment with azithromycin to eliminate blindness due to trachoma in Nepal. Clin Infect Dis. 2002;35:395–402. doi: 10.1086/341414.
    1. Leach AJ, Shelby-James TM, Mayo M, Gratten M, Laming AC, Currie BJ, et al. A prospective study of the impact of community-based azithromycin treatment of trachoma on carriage and resistance of Streptococcus pneumoniae. Clin Infect Dis. 1997;24:356–362. doi: 10.1093/clinids/24.3.356.
    1. Harding-Esch EM, Edwards T, Mkocha H, Munoz B, Holland MJ, Burr SE, et al. Trachoma prevalence and associated risk factors in the gambia and Tanzania: baseline results of a cluster randomised controlled trial. PLoS Negl Trop Dis. 2010;4:e861. doi: 10.1371/journal.pntd.0000861.
    1. Burr SE, Milne S, Jafali J, Bojang E, Rajasekhar M, Hart J, et al. Mass administration of azithromycin and Streptococcus pneumoniae carriage: cross-sectional surveys in the Gambia. Bull World Health Organ. 2014;92:490–498. doi: 10.2471/BLT.13.133462.
    1. Porco TC, Gebre T, Ayele B, House J. Keenan J, Zhou Z, et al. Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial. JAMA. 2009;302:962–968. doi: 10.1001/jama.2009.1266.
    1. Tramper-Stranders GA, van der Ent CK, Gerritsen SA, Fleer A, Kimpen JL, Wolfs TF. Macrolide-resistant Staphylococcus aureus colonization in cystic fibrosis patients: is there transmission to household contacts? J Antimicrob Chemother. 2007;60:665–668. doi: 10.1093/jac/dkm235.
    1. O’Brien KL, Nohynek H. Report from a WHO working group: standard method for detecting upper respiratory carriage of Streptococcus pneumoniae. Pediatr Infect Dis J. 2003;22:133–140.
    1. Roca A, Bottomley C, Hill PC, Bojang A, Egere U, Antonio M, et al. Effect of age and vaccination with a pneumococcal conjugate vaccine on the density of pneumococcal nasopharyngeal carriage. Clin Infect Dis. 2012;55:816–824. doi: 10.1093/cid/cis554.
    1. Brueggemann AB, Pai R, Crook DW, Beall B. Vaccine escape recombinants emerge after pneumococcal vaccination in the United States. PLoS Pathog. 2007;3:e168. doi: 10.1371/journal.ppat.0030168.
    1. Roberts CH, Last A, Molina-Gonzalez S, Cassama E, Butcher R, Nabicassa M, et al. Development and evaluation of a next-generation digital PCR diagnostic assay for ocular Chlamydia trachomatis infections. J Clin Microbiol. 2013;51:2195–2203. doi: 10.1128/JCM.00622-13.
    1. Bottomley C, Bojang A, Smith PG, Darboe O, Antonio M, Foster-Nyarko E et al.. The impact of childhood vaccines on bacterial carriage in the nasopharynx: a longitudinal study. under review. 2013. Ref Type: Generic
    1. Schrag SJ, Verani JR. Intrapartum antibiotic prophylaxis for the prevention of perinatal group B streptococcal disease: experience in the United States and implications for a potential group B streptococcal vaccine. Vaccine. 2013;31(Suppl 4):D20–D26. doi: 10.1016/j.vaccine.2012.11.056.
    1. Neal AH, P. Jaon C, Micael AG, Donald SG, Steve K, S. Michael M, et al. Revised guidelines for prevention of early-onset group B streptococcal (GBS) infection. American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn. Pediatrics.1997;99:489–496.
    1. Sigauque B, Roca A, Mandomando I, Morais L, Quinto L, Sacarlal J, et al. Community-acquired bacteremia among children admitted to a rural hospital in Mozambique. Pediatr Infect Dis J. 2009;28:108–113. doi: 10.1097/INF.0b013e318187a87d.
    1. Onalo R, Ogala WN, Ogunrinde GO, Olayinka AT, Adama SA, Ega BA. Predisposing factors to neonatal septicaemia at ahmadu bello university teaching hospital, zaria Nigeria. Niger Postgrad Med J. 2011;18:20–25.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe