Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries

Biljana Kakaraskoska Boceska (), Tuba Vilken, Basil Britto Xavier, Tomislav Kostyanev, Qiang Lin, Christine Lammens, Sally Ellis, Seamus O’Brien, Renata Maria Augusto Costa, Aislinn Cook, Neal Russell, Julia Bielicki, Amy Riddell, Wolfgang Stohr, Ann Sarah Walker, Eitan Naaman Berezin, Emmanuel Roilides, Maia Luca, Lorenza Romani, Daynia Ballot, Angela Dramowski, Jeannette Wadula, Sorasak Lochindarat, Suppawat Boonkasidecha, Flavia Namiiro, Hoang Thi Bich Ngoc, Minh Dien Tran, Tim R. Cressey, Kanchana Preedisripipat, James A. Berkley, Robert Musyimi, Charalampos Zarras, Trusha Nana, Andrew Whitelaw, Cely Barreto Silva, Prenika Jaglal, Willy Ssengooba, Samir K. Saha, Mohammad Shahidul Islam, Marisa Marcia Mussi-Pinhata, Cristina Gardonyi Carvalheiro, Laura J. V. Piddock, Paul T. Heath, Surbhi Malhotra-Kumar, Michael Sharland, Youri Glupczynski () and Herman Goossens
Additional contact information
Biljana Kakaraskoska Boceska: University of Antwerp
Tuba Vilken: University of Antwerp
Basil Britto Xavier: University of Antwerp
Tomislav Kostyanev: University of Antwerp
Qiang Lin: University of Antwerp
Christine Lammens: University of Antwerp
Sally Ellis: Global Antibiotic Research and Development Partnership (GARDP)
Seamus O’Brien: Global Antibiotic Research and Development Partnership (GARDP)
Renata Maria Augusto Costa: Global Antibiotic Research and Development Partnership (GARDP)
Aislinn Cook: St. George’s University of London
Neal Russell: St. George’s University of London
Julia Bielicki: St. George’s University of London
Amy Riddell: St. George’s University of London
Wolfgang Stohr: University College London
Ann Sarah Walker: University College London
Eitan Naaman Berezin: Santa Casa de Sao Paulo
Emmanuel Roilides: Aristotle University and Hippokration General Hospital
Maia Luca: Bambino Gesu Children’s Hospital
Lorenza Romani: Bambino Gesu Children’s Hospital
Daynia Ballot: University of the Witwatersrand
Angela Dramowski: Stellenbosch University
Jeannette Wadula: University of Witwatersrand
Sorasak Lochindarat: Queen Sirikit National Institute of Child Health
Suppawat Boonkasidecha: Queen Sirikit National Institute of Child Health
Flavia Namiiro: Mulago Specialized Women’s and Neonatal Hospital
Hoang Thi Bich Ngoc: Vietnam National Children’s Hospital
Minh Dien Tran: Vietnam National Children’s Hospital
Tim R. Cressey: Faculty of Associated Medical Sciences
Kanchana Preedisripipat: Chiangrai Prachanukroh Hospital
James A. Berkley: KEMRI-Wellcome Trust Research Programme
Robert Musyimi: KEMRI-Wellcome Trust Research Programme
Charalampos Zarras: Hippokration General Hospital
Trusha Nana: University of the Witwatersrand
Andrew Whitelaw: Stellenbosch University
Cely Barreto Silva: Santa Casa de Sao Paulo
Prenika Jaglal: University of Witwatersrand
Willy Ssengooba: Department of Medical Microbiology
Samir K. Saha: Child Health Research Foundation (CHRF)
Mohammad Shahidul Islam: Child Health Research Foundation (CHRF)
Marisa Marcia Mussi-Pinhata: University of Sao Paulo
Cristina Gardonyi Carvalheiro: University of Sao Paulo
Laura J. V. Piddock: Global Antibiotic Research and Development Partnership (GARDP)
Paul T. Heath: St. George’s University of London
Surbhi Malhotra-Kumar: University of Antwerp
Michael Sharland: St. George’s University of London
Youri Glupczynski: University of Antwerp
Herman Goossens: University of Antwerp

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.

Date: 2024
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DOI: 10.1038/s41467-024-48296-z

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