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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

by 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, and Herman Goossens

Posted: October 24, 2023
Server: medRxiv
DOI: 10.1101/2023.10.20.23296805

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) andEnterobacter cloacaecomplex (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. pneumoniaeisolates and 13 (38%)E. coli, as well as in 6 (18%) and 10 (37%)S. marcescensand ECC isolates, respectively. Carbapenem resistance genes were present in 41 (30%)K. pneumoniae,while 73 (91%) ofA. baumanniiisolates were predicted to be MDR based on carbapenem resistance genes. Apart fromA. 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% ofK. pneumoniaeisolates were resistant to gentamicin and 85% to cefotaxime;E. coliisolates 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-producingK. pneumoniaeandE. coliisolates were highly susceptible to the three new antibiotic combination regimens planned to be evaluated in the currently recruiting GARDP-sponsored NeoSep1 trial.

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