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

Nat Commun. 2024 May 10;15(1):3947. doi: 10.1038/s41467-024-48296-z.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinetobacter baumannii* / drug effects
  • Acinetobacter baumannii* / genetics
  • Acinetobacter baumannii* / isolation & purification
  • Amikacin / pharmacology
  • Amikacin / therapeutic use
  • Anti-Bacterial Agents* / pharmacology
  • Anti-Bacterial Agents* / therapeutic use
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Developing Countries
  • Drug Resistance, Multiple, Bacterial / genetics
  • Drug Therapy, Combination
  • Enterobacter cloacae / drug effects
  • Enterobacter cloacae / genetics
  • Enterobacter cloacae / isolation & purification
  • Escherichia coli / drug effects
  • Escherichia coli / genetics
  • Escherichia coli / isolation & purification
  • Fosfomycin / pharmacology
  • Fosfomycin / therapeutic use
  • Gram-Negative Bacteria* / drug effects
  • Gram-Negative Bacteria* / genetics
  • Gram-Negative Bacteria* / isolation & purification
  • Gram-Negative Bacterial Infections* / drug therapy
  • Gram-Negative Bacterial Infections* / microbiology
  • Humans
  • Infant, Newborn
  • Klebsiella pneumoniae* / drug effects
  • Klebsiella pneumoniae* / genetics
  • Klebsiella pneumoniae* / isolation & purification
  • Microbial Sensitivity Tests*
  • Neonatal Sepsis* / drug therapy
  • Neonatal Sepsis* / microbiology
  • Serratia marcescens / drug effects
  • Serratia marcescens / genetics
  • Serratia marcescens / isolation & purification
  • beta-Lactamases / genetics
  • beta-Lactamases / metabolism

Substances

  • Anti-Bacterial Agents
  • Amikacin
  • Fosfomycin
  • beta-Lactamases
  • Bacterial Proteins
  • carbapenemase