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Randomized Controlled Trial
. 2026 Apr 17;21(4):e0346174.
doi: 10.1371/journal.pone.0346174. eCollection 2026.

Impact of prophylactic oral azithromycin during labor on Azithromycin Resistance (AMR) in nasal Staphylococcus aureus and Streptococcus pneumoniae in women and infants in the multi-country Azithromycin Prevention in Labor Use Study (A-PLUS)

Patricia L Hibberd  1 , Jean H Kim  2 , Marissa Trotta  2 , Sixto M Leal  3 , Anna Aceituno  2 , Doyle V Ward  4 , Archana Patel  5   6 , Akila Subramaniam  3 , Waldemar A Carlo  3 , Imran Ahmed  7 , Sarah Saleem  7 , Sk Masum Billah  8   9 , Rashidun Haque  8 , Manolo Mazariegos  10 , Fabian Esamai  11 , Manjunath S Somannavar  12 , Shivaprasad S Goudar  12 , Elwyn Chomba  13 , Muska Mwenchanya  13 , Adrien Lokangaka  14 , Antoinette Tshefu  14 , Robert L Goldenberg  15 , Melissa Bauserman  16 , Nancy F Krebs  17 , Sherri Bucher  18 , Richard J Derman  19 , William A Petri  20 , Marion Koso-Thomas  21 , Denise C Babineau  2 , Elizabeth M McClure  2 , Alan T N Tita  3
Affiliations
Randomized Controlled Trial

Impact of prophylactic oral azithromycin during labor on Azithromycin Resistance (AMR) in nasal Staphylococcus aureus and Streptococcus pneumoniae in women and infants in the multi-country Azithromycin Prevention in Labor Use Study (A-PLUS)

Patricia L Hibberd et al. PLoS One. .

Abstract

Background: Prophylactic oral azithromycin vs. placebo reduced maternal, but not neonatal, mortality/sepsis in the A-PLUS Randomized Trial. While prophylactic intrapartum azithromycin reduces maternal mortality/sepsis, it may promote antimicrobial resistance (AMR) in commensal bacteria,.

Methods: Randomly selected women and their infants participating in A-PLUS were enrolled in a longitudinal cross-sectional sub-study to assess the presence of azithromycin resistance in selected bacteria in nasal cultures. Staphylococcus aureus and Streptococcus pneumoniae were cultured on selective agar, then azithromycin-containing agar to select for azithromycin resistant bacteria, identified biochemically. Azithromycin susceptibility was assessed by E-test. Nasal cultures were collected from women and infants between August 11, 2021 and September 18, 2023 during labor/day 1, day 7, 6 weeks, and 3, 6 and 12 months after delivery.

Results: The study enrolled 911 women and 915 liveborn infants at 8 sites in 7 countries. Azithromycin resistance in S aureus was higher and azithromycin susceptibility was lower in women receiving azithromycin compared with those receiving placebo on day 7 (P < 0.001), 6 weeks (P < 0.001) and 3 months (P = 0.009) after delivery. Azithromycin resistance in S aureus was also higher and azithromycin susceptibility was lower 6 weeks after delivery (P < 0.001) in infants born to women receiving azithromycin, Azithromycin resistance in S. pneumoniae was too sparse to interpret.

Conclusions: There was an increase in prevalence of azithromycin resistance (or reduction in azithromycin susceptibility) in commensal nasal S. aureus between day 7, 6 weeks and 3 months in women exposed to azithromycin vs. placebo and only at 6 weeks in infants exposed to azithromycin vs. placebo. These differences between the azithromycin and placebo groups were no longer detected at 6 and 12 months post-partum in the women and after 6 weeks through 12 months in the infants.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. A-PLUS and the AMR Sub-Study Profile.
Fig 2
Fig 2. Specimen collection, Laboratory Flow and Classification of S aureus or S pneumoniae Culture Results and Azithromycin Susceptibility at each Study Time-point.
Fig 3
Fig 3. Prevalence of Azithromycin Resistance in S. aureus in Nasal Cultures Across Study Sites: Women.
Fig 4
Fig 4. Prevalence of Azithromycin Resistance in S. aureus in Nasal Cultures Across Study Sites: Infants.
See this image and copyright information in PMC

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