A major multi-country study has found that WHO-recommended first-line antibiotics for neonatal sepsis are likely to be effective in only a quarter of infections in low- and middle-income countries (LMICs). The findings presented today at ESCMID Global 2026 highlight the growing impact of antimicrobial resistance (AMR).
Neonatal sepsis, a life-threatening infection within the first month of life, remains a leading cause of neonatal death worldwide. The World Health Organization (WHO) currently recommends ampicillin plus gentamicin as first-line empirical antibiotic therapy – treatment is initiated before the causative organism and its antibiotic sensitivity are known. However, these recommendations are largely based on data from high-income settings.
To assess how these recommendations work in LMIC hospital settings, researchers from the University of Oxford and an international network of partner hospitals and research institutes conducted the Barnards II study in 13 tertiary neonatal units in Pakistan, Bangladesh and Nigeria between February 2024 and October 2025.
The study included 14,259 newborns treated with empirical antibiotics for suspected sepsis, with initial treatment regimens varying widely and typically consisting of one to three antimicrobials. Two-drug regimens were most common, most often amikacin plus cefotaxime, while only 40 neonates received the WHO-recommended first-line combination of ampicillin and gentamicin.
Of a total of 5,012 culture-confirmed cases, a subgroup of 2,821 had both pathogen identification from blood cultures and available antibiotic susceptibility data. High levels of AMR were observed. The combination of ampicillin and gentamicin recommended by WHO would have been active against only 25.0% of identified pathogens (including fungal).
“What was most worrying was the identification of high rates of antimicrobial resistance,” said lead author Dr Katherine Thomson of the University of Oxford. “The substantial AMR burden makes it extremely challenging to identify consistently effective empiric antibiotic regimens. In these settings, ampicillin and gentamicin may have provided limited coverage against locally prevalent, highly resistant pathogens.”
Dr. Thomson added, “In our group, the limited expected effectiveness of WHO-recommended first-line therapy makes deviations from these guidelines clinically understandable. Rather than reflecting poor adherence to guidelines, it likely represents the challenges of adapting to local resistance patterns and implementing global treatment recommendations in these environments.”
Overall, 1,039 of 2,821 newborns (36.8%) received appropriate empirical therapy during the study period, defined as initial treatment in which at least one of the antibiotics given was active against the pathogen identified by blood culture.
In contrast, inappropriate empiric therapy – seen in 1,783 of the same 2,821 newborns – was associated with two times higher mortality (32.1% vs. 17.9%) in unadjusted analyses. However, this association was not maintained after adjustment for key clinical factors, particularly gestational age.
Dr. Thomson explained, “Gestational age has emerged as the strongest predictor of mortality. This does not mean that the choice of antibiotic is unimportant – prompt and appropriate therapy remains important in neonatal sepsis. Rather, underlying clinical vulnerability plays a major role and may influence the relationship between treatment and outcomes.”
Reflecting on the implications of the study, Professor Tim Walsh, principal investigator of the Barnards study, said, “Our results show that a one-size-fits-all approach to empirical antibiotic guidelines is unlikely to be effective globally. Even across the countries included in this study, we observed significant differences in both the pathogens responsible for infection and their resistance profiles.”
Professor Walsh concluded, “Improving outcomes for newborns will ultimately require locally informed empirical treatment strategies, improved diagnostics, continuous AMR surveillance, antimicrobial stewardship and sustainable access to effective antibiotics supported by long-term policy commitment and investment.”
