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

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

Biljana Kakaraskoska Boceska  1 , Tuba Vilken  2 , Basil Britto Xavier  2   3 , Tomislav Kostyanev  2   4 , Qiang Lin  2 , Christine Lammens  2 , Sally Ellis  5 , Seamus O'Brien  5 , Renata Maria Augusto da Costa  5 , Aislinn Cook  6 , Neal Russell  6 , Julia Bielicki  6   7 , Amy Riddell  6 , Wolfgang Stohr  8 , Ann Sarah Walker  8 , Eitan Naaman Berezin  9 , Emmanuel Roilides  10 , Maia De Luca  11 , Lorenza Romani  11 , Daynia Ballot  12 , Angela Dramowski  13 , Jeannette Wadula  14 , Sorasak Lochindarat  15 , Suppawat Boonkasidecha  15 , Flavia Namiiro  16 , Hoang Thi Bich Ngoc  17 , Minh Dien Tran  17 , Tim R Cressey  18 , Kanchana Preedisripipat  19 , James A Berkley  20   21   22 , Robert Musyimi  23 , Charalampos Zarras  24 , Trusha Nana  25 , Andrew Whitelaw  26   27 , Cely Barreto da Silva  28 , Prenika Jaglal  14 , Willy Ssengooba  29 , Samir K Saha  30 , Mohammad Shahidul Islam  30 , Marisa Marcia Mussi-Pinhata  31 , Cristina Gardonyi Carvalheiro  31 , Laura J V Piddock  5 , Paul T Heath  6 , Surbhi Malhotra-Kumar  2 , Michael Sharland  6 , Youri Glupczynski  32 , Herman Goossens  2
Affiliations

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

Biljana Kakaraskoska Boceska et al. Nat Commun. .

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.

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Conflict of interest statement

The authors declare the following competing interests: J.A.B.: Research grant support to the university from Wellcome, NIHR, MRC, and the Bill & Melinda Gates Foundation who had no role in any aspect of the study or decision to publish. A.S.W. is an NIHR Senior Investigator supported by the NIHR Biomedical Research Center Oxford and core support to the MRC Clinical Trials Unit [MC_UU_00004/05]. J.B. is an NIHR Advanced Fellow and Chief Investigator supported by grant NIHR302554 and H2020 Agreement number 965328. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Distribution of the total number (indicated next to the bars) of the five most common GNB species analyzed by site.
n = 309, one isolate per species per patient only, following removal of duplicates. Number of isolates correlates with the number of neonates, except for the following sites: TH13 (13 neonates–14 isolates), SA12 (46 neonates–51 isolates), SA11 (51 neonates–56 isolates), SA10 (75 neonates–77 isolates) and BR2 (5 neonates–6 isolates).* VI Vietnam, UG Uganda, TH Thailand, SA South Africa, KE Kenya, IT Italy, GR Greece, BR Brazil, BA Bangladesh. The numbers following the country keys refer to the site number (see Table 1). Source data are provided as a Source Data file.
Fig. 2
Fig. 2. Minimum spanning tree of cgMLST analysis of MDR clones of K. pneumoniae (n = 79) showing specific local site clustering.
STs with three or more isolates are presented. A ST based clustering. B Site based clustering. VI Vietnam, UG Uganda, TH Thailand, SA South Africa, KE Kenya, GR Greece, BR Brazil, BA Bangladesh. The numbers following the country keys refer to the site number. Source data are provided as a Source Data file.
Fig. 3
Fig. 3. Distribution of ESBL genes of K. pneumoniae isolates (n = 135) by site.
(n) = total number of K. pneumoniae isolates per site. *VI Vietnam, UG Uganda, TH Thailand, SA South Africa, KE Kenya, IT Italy, BR Brazil, BA Bangladesh. The numbers following the country keys refer to the site number. Source data are provided as a Source Data file.
Fig. 4
Fig. 4. Distribution of carbapenem resistance genes of K. pneumoniae isolates (n = 135) by site.
(n) = total number of K. pneumoniae isolates per site. Sites that collected K. pneumoniae isolates lacking any carbapenem resistance genes are not shown in this figure (UG15 n = 5, GR4 n = 4, KE9 n = 4, IT8 n = 3, BR3 n = 3 and TH14 n = 2). *VI Vietnam, UG Uganda, TH Thailand, SA South Africa, KE Kenya, IT Italy, GR Greece, BR Brazil, BA Bangladesh. The numbers following the country keys refer to the site number. Source data are provided as a Source Data file.
Fig. 5
Fig. 5. Minimum spanning tree from A. baumannii genomes (n = 80) by cgMLST sequence types (STs).
A ST based clustering. B Site based clustering. VI Vietnam, UG Uganda, TH Thailand, SA South Africa, KE Kenya, BA Bangladesh. The numbers following the country keys refer to the site number. Source data are provided as a Source Data file.
Fig. 6
Fig. 6. Distribution of carbapenem resistance genes in A. baumannii isolates (n = 80) by site.
Site UG15 (n = 1) not represented in the chart since one unique A. baumannii isolate lacking any acquired carbapenemase producing genes. *VI Vietnam, UG Uganda, TH Thailand, SA South Africa, KE Kenya, IT Italy, GR Greece, BR Brazil, BA Bangladesh. The numbers following the country keys refer to the site number. Source data are provided as a Source Data file.
Fig. 7
Fig. 7. Isolates flow diagram.
The flow diagram provides an overview of the total number of isolates received at the laboratory of the University of Antwerp during the NeoOBS study and subsequent selection to the final number of isolates included in this study. GNB gram-negative bacteria, GPB gram-positive bacteria, MIC minimum inhibitory concentration.
See this image and copyright information in PMC

References

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