Antimicrobial resistance in neonatal sepsis is rising, yet mechanisms of resistance that often spread between species via mobile genetic elements, ultimately limiting treatments in low- and middle-income countries (LMICs), are poorly characterized. The Burden of Antibiotic Resistance in Neonates from Developing Societies (BARNARDS) network was initiated to characterize the cause and burden of antimicrobial resistance in neonatal sepsis for seven LMICs in Africa and South Asia. A total of 36,285 neonates were enrolled in the BARNARDS study between November 2015 and December 2017, of whom 2,483 were diagnosed with culture-confirmed sepsis. Klebsiella pneumoniae (n = 258) was the main cause of neonatal sepsis, with Serratia marcescens (n = 151), Klebsiella michiganensis (n = 117), Escherichia coli (n = 75) and Enterobacter cloacae complex (n = 57) also detected. We present whole-genome sequencing, antimicrobial susceptibility and clinical data for 916 out of 1,038 neonatal sepsis isolates (97 isolates were not recovered from initial isolation at local sites). Enterobacterales (K. pneumoniae, E. coli and E. cloacae) harboured multiple cephalosporin and carbapenem resistance genes. All isolated pathogens were resistant to multiple antibiotic classes, including those used to treat neonatal sepsis. Intraspecies diversity of K. pneumoniae and E. coli indicated that multiple antibiotic-resistant lineages cause neonatal sepsis. Our results will underpin research towards better treatments for neonatal sepsis in LMICs.
Background Sepsis is a major contributor to neonatal mortality, particularly in low-income and middle-income countries (LMICs). WHO advocates ampicillin-gentamicin as first-line therapy for the management of neonatal sepsis. In the BARNARDS observational cohort study of neonatal sepsis and antimicrobial resistance in LMICs, common sepsis pathogens were characterised via whole genome sequencing (WGS) and antimicrobial resistance profiles. In this substudy of BARNARDS, we aimed to assess the use and efficacy of empirical antibiotic therapies commonly used in LMICs for neonatal sepsis.Methods In BARNARDS, consenting mother-neonates aged 0-60 days dyads were enrolled on delivery or neonatal presentation with suspected sepsis at 12 BARNARDS clinical sites in
To investigate the mobilizable elements associated with bla in Enterobacteriaceae isolated from septicaemic neonates at a NICU in India, during December, 2008-2011. An attempt was also made to understand whether there was a pattern in the temporal acquisition of bla within the unit. Transferability of carbapenem resistance was tested by conjugation and transformation. Plasmid types and addiction systems were analysed. The genetic background of bla and association with class 1 integron were evaluated by PCR mapping. RFLP was carried out to discriminate plasmids of same incompatibility group. Transfer of carbapenem resistance was successful in 13/15 cases. bla was associated with different plasmid scaffolds (IncFII, IncL/M, IncN, IncR, IncHIB-M/FIB-M), IncF type being the prevalent one. Addiction systems ccdAB and hok/sok were associated with transferable plasmids. Genetic structures surrounding bla showed its association with at least a remnant of ISAba125 at its 5'-end. The spread of NDM-1 was not related to class 1 integron which possessed resistance determinants against trimethoprim (dfrA12, dfrA1, dfrA5), streptomycin (aadA2, aacA4), and rifampicin (arr-3). RFLP showed that three isolates possessed the same FII/FIIs plasmid; two of these three isolates were from a single neonate, implying interspecies transfer of bla The predominance of FII plasmids and ISAba125 along with bla was noted, but no specific pattern in the temporal acquisition of mobile genetic elements could be identified. To the best of our knowledge, this report is the first to inform the in-vivo interspecies plasmid transfer event of bla in a neonate.
Background The bla NDM-1 (New Delhi Metallo-β-lactamase-1) gene has disseminated around the globe. NDM-1 producers are found to co-harbour resistance genes against many antimicrobials, including fluoroquinolones. The spread of large plasmids, carrying both bla NDM and plasmid-mediated fluoroquinolone resistance (PMQR) markers, is one of the main reasons for the failure of these essential antimicrobials. Methods Enterobacteriaceae ( n = 73) isolated from the blood of septicaemic neonates, admitted at a neonatal intensive care unit (NICU) in Kolkata, India, were identified followed by PFGE, antibiotic susceptibility testing and determination of MIC values for meropenem and ciprofloxacin. Metallo-β-lactamases and PMQRs were identified by PCR. NDM-positive isolates were studied for mutations in GyrA & ParC and for co-transmission of bla NDM and PMQR genes ( aac(6′)-Ib-cr, qnrB, qnrS ) through conjugation or transformation. Plasmid types, integrons, plasmid addiction systems, and genetic environment of the bla NDM gene in NDM-positive isolates and their transconjugants/ transformants were studied. Results Isolated Enterobacteriaceae comprised of Klebsiella pneumoniae ( n = 55), Escherichia coli ( n = 16), Enterobacter cloacae ( n = 1) and Enterobacter aerogenes ( n = 1). The rates of ciprofloxacin (90%) and meropenem (49%) non-susceptibility were high. NDM was the only metallo-β-lactamase found in this study. NDM-1 was the predominant metallo-β-lactamase but NDM-5, NDM-7, and NDM-15 were also found. There was no significant difference in ciprofloxacin non-susceptibility (97% vs 85%) and the prevalence of PMQRs (85% vs 77%) between NDM-positive and NDM-negative isolates. Among the PMQRs, aac(6′)-Ib-cr was predominant followed by qnrB1 and qnrS1. Twenty-nine isolates (40%) co-harboured PMQRs and bla NDM , of which 12 co-transferred PMQRs along with bla NDM in large plasmids of IncFIIK, IncA/C, and IncN types. Eighty-two percent of NDM-positive isolates possessed GyrA and/or ParC mutations. Plasmids carrying only bla NDM were of IncHIB-M type predominantly. Most of the isolates had IS Aba125 in the upstream region of the bla NDM gene. Conclusion We hypothesize that the spread ...
This study investigates susceptibility toward three fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), multiple fluoroquinolone-resistance mechanisms, and epidemiological relationship of neonatal septicaemic Acinetobacter baumannii. Previous studies on fluoroquinolone resistance in A. baumannii focused primarily on ciprofloxacin susceptibility and assessed a particular mechanism of resistance; a more holistic approach was taken here. Epidemiological relationship was evaluated by Multi Locus Sequence Typing. Minimum Inhibitory Concentrations of fluoroquinolones was determined with and without efflux pump inhibitors. Overexpression of efflux pumps, resistance-nodulation-cell-division (RND)-type, and multidrug and toxic compound extrusion (MATE)-type efflux pumps were evaluated by reverse transcriptase-qPCR. Mutations within regulatory proteins (AdeRS, AdeN, and AdeL) of RND-pumps were examined. Chromosomal mutations, presence of qnr and aac(6′)-Ib-cr were investigated. A. baumannii were highly diverse as 24 sequence-types with seven novel STs (ST-1440/ST-1441/ST-1481/ST-1482/ST-1483/ST-1484/ST-1486) were identified among 47 A. baumannii. High resistance to ciprofloxacin (96%), levofloxacin (92%), and particularly moxifloxacin (90%) was observed, with multiple mechanisms being active. Resistance to 4th generation fluoroquinolone (moxifloxacin) in neonatal isolates is worrisome. Mutations within GyrA (S83L) and ParC (S80L) were detected in more than 90% of fluoroquinolone-resistant A. baumannii (FQRAB) spread across 10 different clonal complexes (CC1/CC2/CC10/CC25/CC32/CC126/CC149/CC216/CC218/CC513). Efflux-based FQ resistance was found in 65% of FQRAB with ≥2 different active pumps in 38% of strains. Overexpression of adeB was highest (2.2−34-folds) followed by adeJ, adeG, and abeM. Amino acid changes in the regulators (AdeRS/AdeN/AdeL) either as single or multiple substitutions substantiated the overexpression of the pumps. Diverse mutations within AdeRS were detected among different CCs whereas mutations within AdeN linked to CC10 and CC32. Chromosomal mutations and active efflux pumps were detected simultaneously among 64% of FQRAB. Presence of aac(6′)-Ib-cr was also high (74% of FQRAB) but qnrS were absent. As most FQRABs had chromosomal mutations, this was considered predominant, however, isolates where pumps were also active had higher MIC values, establishing the critical role of the efflux pumps. The high variability of FQ susceptibility among FQRAB, possessing the same set of mutations in gyrA, parC, and efflux pump regulators, was also noted. This reveals the complexity of interpreting the interplay of multiple resistance mechanisms in A. baumannii.
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