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Epidemiology of Extended-Spectrum Beta-Lactamase and Carbapenemase-Producing Enterobacterales in the Greater Mekong Subregion: A Systematic-Review and Meta-Analysis of Risk Factors Associated With Extended-Spectrum Beta-Lactamase and Carbapenemase Isolation.

ABSTRACT: Background: Despite the rapid spread of extended-spectrum beta-lactamase (ESBL) producing-Enterobacterales (ESBL-E) and carbapenemase-producing Enterobacterales (CPE), little is known about the extent of their prevalence in the Greater Mekong Subregion (GMS). In this systematic review, we aimed to determine the epidemiology of ESBL-E and CPE in clinically significant Enterobacterales: Escherichia coli and Klebsiella pneumoniae from the GMS (comprising of Cambodia, Laos, Myanmar, Thailand, Vietnam and Yunnan province and Guangxi Zhuang region of China). Methods: Following a list of search terms adapted to subject headings, we systematically searched databases: Medline, EMBASE, Scopus and Web of Science for articles published on and before October 20th, 2020. The search string consisted of the bacterial names, methods involved in detecting drug-resistance phenotype and genotype, GMS countries, and ESBL and carbapenemase detection as the outcomes. Meta-analyses of the association between the isolation of ESBL from human clinical and non-clinical specimens were performed using the "METAN" function in STATA 14. Results: One hundred and thirty-nine studies were included from a total of 1,513 identified studies. Despite the heterogeneity in study methods, analyzing the prevalence proportions on log-linear model scale for ESBL producing-E. coli showed a trend that increased by 13.2% (95%CI: 6.1-20.2) in clinical blood specimens, 8.1% (95%CI: 1.7-14.4) in all clinical specimens and 17.7% (95%CI: 4.9-30.4) increase in carriage specimens. Under the log-linear model assumption, no significant trend over time was found for ESBL producing K. pneumoniae and ESBL-E specimens. CPE was reported in clinical studies and carriage studies past 2010, however a trend could not be determined because of the small dataset. Twelve studies were included in the meta-analysis of risk factors associated with isolation of ESBL. Recent antibiotic exposure was the most studied variable and showed a significant positive association with ESBL-E isolation (pooled OR: 2.9, 95%CI: 2.3-3.8) followed by chronic kidney disease (pooled OR: 4.7, 95%CI: 1.8-11.9), and other co-morbidities (pooled OR: 1.6, 95%CI: 1.2-2.9). Conclusion: Data from GMS is heterogeneous with significant data-gaps, especially in community settings from Laos, Myanmar, Cambodia and Yunnan and Guangxi provinces of China. Collaborative work standardizing the methodology of studies will aid in better monitoring, surveillance and evaluation of interventions across the GMS.

SUBMITTER: Singh SR

PROVIDER: S-EPMC8661499 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe Greater Mekong subregion is a recurrent source of antimalarial drug resistance in Plasmodium falciparum malaria. This study aimed to characterise the extent and spread of resistance across this entire region between 2007 and 2018.MethodsP falciparum isolates from Myanmar, Thailand, Laos, and Cambodia were obtained from clinical trials and epidemiological studies done between Jan 1, 2007, and Dec 31, 2018, and were genotyped for molecular markers (pfkelch, pfcrt, pfplasmepsin2, and pfmdr1) of antimalarial drug resistance. Genetic relatedness was assessed using microsatellite and single nucleotide polymorphism typing of flanking sequences around target genes.Findings10 632 isolates were genotyped. A single long pfkelch Cys580Tyr haplotype (from -50 kb to +31·5 kb) conferring artemisinin resistance (PfPailin) now dominates across the eastern Greater Mekong subregion. Piperaquine resistance associated with pfplasmepsin2 gene amplification and mutations in pfcrt downstream of the Lys76Thr chloroquine resistance locus has also developed. On the Thailand-Myanmar border a different pfkelch Cys580Tyr lineage rose to high frequencies before it was eliminated. Elsewhere in Myanmar the Cys580Tyr allele remains widespread at low allele frequencies. Meanwhile a single artemisinin-resistant pfkelch Phe446Ile haplotype has spread across Myanmar. Despite intense use of dihydroartemisinin-piperaquine in Kayin state, eastern Myanmar, both in treatment and mass drug administrations, no selection of piperaquine resistance markers was observed. pfmdr1 amplification, a marker of resistance to mefloquine, remains at low prevalence across the entire region.InterpretationArtemisinin resistance in P falciparum is now prevalent across the Greater Mekong subregion. In the eastern Greater Mekong subregion a multidrug resistant P falciparum lineage (PfPailin) dominates. In Myanmar a long pfkelch Phe446Ile haplotype has spread widely but, by contrast with the eastern Greater Mekong subregion, there is no indication of artemisinin combination therapy (ACT) partner drug resistance from genotyping known markers, and no evidence of spread of ACT resistant P falciparum from the east to the west. There is still a window of opportunity to prevent global spread of ACT resistance.FundingThailand Science Research and Innovation, Initiative 5%, Expertise France, Wellcome Trust.

Project description:Extended-spectrum β-lactamases (ESBLs) are a growing public health threat, and one key human exposure point is through livestock and the food supply. Understanding microbiome factors associated with fecal ESBL carriage can help detect and ideally assist with controlling and preventing ESBL dissemination among livestock. The objective of this study was to investigate the diversity and composition of the heifer fecal microbiota in ESBL-producing Enterobacterales (ESBL-PE) carriers and noncarriers. A total of 59 fecal samples were collected from replacement heifers between 12 and 18 months old from eight dairy farms in central Israel. Genomic DNA was extracted, and 16S rRNA amplicon sequencing was performed (Illumina short reads), focusing on a comparison between 33 ESBL-PE carriers (55.9%) and 26 (44.1%) noncarriers. Samples were analyzed and compared using QIIME2 (DADA2 pipeline and taxonomic assignment with SILVA database) and associated R packages for alpha and beta diversity and taxonomic abundances. Alpha diversity (Shannon diversity) and beta diversity (unweighted UniFrac) showed no significant difference between ESBL-PE carriers and noncarriers. Heifers from farms feeding calves with pooled colostrum had higher ESBL-PE carriage rates than heifers from farms feeding with individual mother colostrum (p < 0.001). Taxonomical abundance analysis revealed that the most common bacterial phyla were Bacteroidetes (44%) and Firmicutes (38%). There was no significant difference in taxonomic composition between ESBL-PE carriers and noncarriers at the phylum and genus levels. However, LEfSe biomarker discovery analysis identified several genera which were significantly different between carriers and noncarriers. For example, Prevotellacaea, Bacteroides, Rikenellaceae, and uncultured Bacteroidales were more abundant in ESBL carriers than noncarriers. Some aspects of microbiota composition differ between ESBL carriers and noncarriers in dairy heifers, specifically the abundance of certain genera. Feeding with pooled colostrum may play a role in that assembly. These could potentially serve as markers of ESBL-PE carriage. However, further research is needed to determine whether these observed differences have a significant impact on colonization with ESBL-PE.

Project description:Antimicrobial-resistant (AMR) infections pose a serious risk to human and animal health. A major factor contributing to this global crisis is the sharing of resistance genes between different bacteria via plasmids. The WHO lists Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae, producing extended-spectrum β-lactamases (ESBL) and carbapenemases as "critical" priorities for new drug development. These resistance genes are most often shared via plasmid transfer. However, finding methods to prevent resistance gene sharing has been hampered by the lack of screening systems for medium-/high-throughput approaches. Here, we have used an ESBL-producing plasmid, pCT, and a carbapenemase-producing plasmid, pKpQIL, in two different Gram-negative bacteria, E. coli and K. pneumoniae Using these critical resistance-pathogen combinations, we developed an assay using fluorescent proteins, flow cytometry, and confocal microscopy to assess plasmid transmission inhibition within bacterial populations in a medium-throughput manner. Three compounds with some reports of antiplasmid properties were tested; chlorpromazine reduced transmission of both plasmids and linoleic acid reduced transmission of pCT. We screened the Prestwick library of over 1,200 FDA-approved drugs/compounds. From this, we found two nucleoside analogue drugs used to treat HIV, abacavir and azidothymidine (AZT), which reduced plasmid transmission (AZT, e.g., at 0.25 μg/ml reduced pCT transmission in E. coli by 83.3% and pKpQIL transmission in K. pneumoniae by 80.8% compared to untreated controls). Plasmid transmission was reduced by concentrations of the drugs which are below peak serum concentrations and are achievable in the gastrointestinal tract. These drugs could be used to decolonize humans, animals, or the environment from AMR plasmids.IMPORTANCE More and more bacterial infections are becoming resistant to antibiotics. This has made treatment of many infections very difficult. One of the reasons this is such a large problem is that bacteria are able to share their genetic material with other bacteria, and these shared genes often include resistance to a variety of antibiotics, including some of our drugs of last resort. We are addressing this problem by using a fluorescence-based system to search for drugs that will stop bacteria from sharing resistance genes. We uncovered a new role for two drugs used to treat HIV and show that they are able to prevent the sharing of two different types of resistance genes in two unique bacterial strains. This work lays the foundation for future work to reduce the prevalence of resistant infections.

Project description:We validate and evaluate a new phenotypic assay, named the direct β-lactam inactivation method (dBLIM), for the rapid and simultaneous detection of carbapenemase or extended-spectrum-cephalosporinase activity directly from Enterobacterales (EB)-positive blood cultures (BCs). It originates from the carbapenem inactivation method (CIM), an inexpensive and highly sensitive assay for carbapenemase activity detection. dBLIM cutoff values to detect extended-spectrum β-lactamase (ESBL) and carbapenemase activities resulted in diameters of ≤12 mm for a 5-μg-cefotaxime disk and for a 10-μg-meropenem disk. dBLIM assessment was determined with both aerobic and anaerobic BC bottles spiked with 422 characterized EB strains, classifiable into the following 4 phenotypic groups: (i) ESBL/AmpC-type β-lactamase (ACBL)/carbapenemase (CARB)-nonproducing (np-ESBL/ACBL/CARB) EB (n = 116), (ii) ESBL-producing EB (n = 111), (iii) AmpC-β-lactamase-producing EB (n = 33), and (iv) carbapenemase-producing EB (n = 162). No false-positive results were obtained in any of the np-ESBL/ACBL/CARB EB, ESBL, and AmpC groups, demonstrating an overall assay specificity of 100%. There were no significant discrepancies in dBLIM performance between aerobic and anaerobic BCs across all groups, except with VIM-type carbapenemase-expressing EB. Interestingly, among BCs spiked with blaVIM-harboring EB, the sensitivity rates of the assay in anaerobic and aerobic bottles were 53.6% and 100%, respectively. In contrast, dBLIM performance was deemed excellent for the KPC, OXA-48, and NDM carbapenemase producers regardless of the type of bottle being tested, with a sensitivity rate ranging between 99% and 100%. Concerning the detection of the extended-spectrum cephalosporinases of the ESBL-producing and AmpC types, dBLIM sensitivities was 100% and 84 to 87%, respectively. dBLIM may be a cost-effective and highly robust phenotypic screening method for the reliable detection of carbapenemases or extended-spectrum cephalosporinases directly from BCs on the same day of bottle positivity detection.

Project description:BackgroundEvidence suggests that the PfKelch13 mutations that confer artemisinin resistance in falciparum malaria have multiple independent origins across the Greater Mekong subregion, which has motivated a regional malaria elimination agenda. We aimed to use molecular genotyping to assess antimalarial drug resistance selection and spread in the Greater Mekong subregion.MethodsIn this observational study, we tested Plasmodium falciparum isolates from Myanmar, northeastern Thailand, southern Laos, and western Cambodia for PfKelch13 mutations and for Pfplasmepsin2 gene amplification (indicating piperaquine resistance). We collected blood spots from patients with microscopy or rapid test confirmed uncomplicated falciparum malaria. We used microsatellite genotyping to assess genetic relatedness.FindingsAs part of studies on the epidemiology of artemisinin-resistant malaria between Jan 1, 2008, and Dec 31, 2015, we collected 434 isolates. In 2014-15, a single long PfKelch13 C580Y haplotype (-50 to +31·5 kb) lineage, which emerged in western Cambodia in 2008, was detected in 65 of 88 isolates from northeastern Thailand, 86 of 111 isolates from southern Laos, and 14 of 14 isolates from western Cambodia, signifying a hard transnational selective sweep. Pfplasmepsin2 amplification occurred only within this lineage, and by 2015 these closely related parasites were found in ten of the 14 isolates from Cambodia and 15 of 15 isolates from northeastern Thailand. C580Y mutated parasites from Myanmar had a different genetic origin.InterpretationOur results suggest that the dominant artemisinin-resistant P falciparum C580Y lineage probably arose in western Cambodia and then spread to Thailand and Laos, outcompeting other parasites and acquiring piperaquine resistance. The emergence and spread of fit artemisinin-resistant P falciparum parasite lineages, which then acquire partner drug resistance across the Greater Mekong subregion, threatens regional malaria control and elimination goals. Elimination of falciparum malaria from this region should be accelerated while available antimalarial drugs still remain effective.FundingThe Wellcome Trust and the Bill and Melinda Gates Foundation.

Dataset Information

Epidemiology of Extended-Spectrum Beta-Lactamase and Carbapenemase-Producing Enterobacterales in the Greater Mekong Subregion: A Systematic-Review and Meta-Analysis of Risk Factors Associated With Extended-Spectrum Beta-Lactamase and Carbapenemase Isolation.

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