Identification of potential novel combination antibiotic regimens based on drug-susceptibility and genetic diversity of Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries
Year: 2023
Type: preprint
Abstract: Objectives Several recent studies highlight the high prevalence of resistance to multiple antibiotic classes used in current treatment regimens for neonatal sepsis and new treatment options are urgently needed. We aimed to identify potential new combination antibiotic treatment regimens by investigating the drug-resistance and genetic profiles of the most frequently isolated Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries (LMICs) in the NeoOBS study. Material and methods Gram-negative bacteria isolated from neonates with culture-confirmed sepsis from 13 clinical sites in nine countries, mainly LMICs, were analyzed. Culture-based identification was followed by whole-genome sequencing (WGS). Minimal inhibitory concentrations (MICs) for 8 antibiotics were determined for a representative subset of 108 isolates. Results Five bacterial species, Klebsiella pneumoniae (n=135), Acinetobacter baumannii (n=80), Escherichia coli (n=34), Serratia marcescens (n=33) and Enterobacter cloacae complex (ECC) (n=27) accounted for most Gram-negative bacterial isolates received (309/420, 74%). Extended-spectrum β-lactamases (ESBL) genes mostly belonging to CTX-M-15 were found in 107 (79%) K. pneumoniae isolates and 13 (38%) E. coli , as well as in 6 (18%) and 10 (37%) S. marcescens and ECC isolates, respectively. Carbapenem resistance genes were present in 41 (30%) K. pneumoniae, while 73 (91%) of A. baumannii isolates were predicted to be MDR based on carbapenem resistance genes. Apart from A. baumannii, in which two major pandemic lineages predominated, a wide genetic diversity occurred at the intraspecies level with different MDR clones occurring at the different sites. Phenotypic testing showed resistance to the WHO first- and second- line recommended treatment regimens: 74% of K. pneumoniae isolates were resistant to gentamicin and 85% to cefotaxime; E. coli isolates showed resistance to ampicillin, gentamicin and cefotaxime in 90%, 38% and 47%, respectively. For the novel antibiotic regimens involving different combinations of flomoxef, fosfomycin and amikacin, the overall predicted MIC-determined susceptibility for Enterobacterales isolates was 71% (n=77) to flomoxef-amikacin, 76% (n=82) to flomoxef-fosfomycin and 79% (n=85) to fosfomycin-amikacin combinations, compared to 31% and 22% isolates susceptible to ampicillin-gentamicin and cefotaxime, respectively. ESBL-producing Enterobacterales isolates were 100% susceptible both to flomoxef-fosfomycin and flomoxef-amikacin and 92% to fosfomycin-amikacin. Conclusion Enterobacterales carried multiple resistance genes to cephalosporins, carbapenems and aminoglycosides. ESBL-producing K. pneumoniae and E. coli isolates were highly susceptible to the three new antibiotic combination regimens planned to be evaluated in the currently recruiting GARDP-sponsored NeoSep1 trial.
Source: medRxiv
Authors: Biljana Kakaraskoska Boceska, Tuba Vilken, Basil Britto Xavier, Christine Lammens, Sally Ellis, Seamus O’Brien, Renata Maria Augusto da Costa, Aislinn Cook, Neal Russell, Julia Bielicki, Eitan Naaman Berezin, Emmanual Roilides, Maia De Luca, Lorenza Romani, Daynia Ballot, Angela Dramowski, Jeannette Wadula, Sorasak Lochindarat, Suppawat Boonkasidecha, Flavia Namiiro, Hoang Thi Bich Ngoc, Tran Minh Dien, Tim R. Cressey, Kanchana Preedisripipat, James A. Berkley, Robert Musyimi, Charalampos Zarras, Trusha Nana, Andrew Whitelaw, Cely Barreto da Silva, Prenika Jaglal, Willy Ssengooba, Samir K. Saha, Mohammad Shahidul Islam, Marisa Marcia Mussi-Pinhata, Cristina Gardony Carvalheiro, Laura Piddock, Surbhi Malhotra-Kumar, Michael Sharland, Youri Glupczynski, Herman Goossens
Institutions: University of Antwerp, Instituut voor Tropische Geneeskunde, Global Antibiotic Research & Development Partnership, St George's, University of London, Aristotle University of Thessaloniki, Ippokrateio General Hospital of Thessaloniki, Bambino Gesù Children's Hospital, University of the Witwatersrand, Tygerberg Hospital, National Health Laboratory Service, Chris Hani Baragwanath Hospital, Queen Sirikit National Institute of Child Health, Mulago Hospital, Vietnam National Children's Hospital, Chiang Mai University, ChiangRai Prachanukroh Hospital, Kenya Medical Research Institute, University of Oxford, The Childhood Acute Illness and Nutrition Network, KEMRI-Wellcome Trust Research Programme, Johannesburg Hospital, University of Bristol, Irmandade da Santa Casa de Misericórdia de São Paulo, University of KwaZulu-Natal, Makerere University, Bangladesh Shishu (Children) Hospital & Institute, Child Health Research Foundation, Universidade de São Paulo
Language: English
Subfield: Microbiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4387908686