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1.
Indian J Tuberc ; 68(1): 106-113, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33641829

RESUMEN

Tuberculosis is currently an anticipated driver of pandemic diseases. It remains an imminent issue accounting for about 1.4 million deaths annually across the world. Since the evolution of human entity drug susceptible tuberculosis was managed through potent first line therapies. Unfortunately, the emergence of newer multitude strains refractory amongst available drugs in Drug resistant TB has led to an emergence MDR-TB and XDR-TB. Moreover, the increasing incidence of drug susceptible TB in developing countries paved way to development of new guidelines for treating various form of tuberculosis. Furthermore, newer regimens are warranted to combat resistance that preferably cause a reduction in mortality. Until now, various ongoing trials are being carried in order to potentially evaluate the suitable novel drug candidates, repurposed drugs and host directed therapies that will optimistically be safe, easy to tolerate, cost effective and non-toxic that will modify the prospects for treating drug resistant TB and latent TB. In context, the current scenario seems to impose a significant challenge on health care researchers in the field of drug discovery owing to complexities, prolong treatment duration, and is cumbersome. Pretomanid is a novel drug with potent bactericidal properties emerging a key advancement used in combination along with other drug therapies This review details the role of pretomanid in treating tuberculosis and the clinical trials in adultsd.

2.
Indian J Tuberc ; 68(1): 154-156, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33641840
3.
Jpn J Infect Dis ; 2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33642430

RESUMEN

Various mechanisms underlying antimicrobial resistance in Acinetobacter baumannii have been reported. There exists controversy regarding the relationships between efflux pump activity, biofilm formation, and antimicrobial resistance in A. baumannii. In this study, we investigated the relative expression of RND efflux pump genes, H33342 efflux activity, and biofilm-forming activity in 120 A. baumannii clinical isolates, examined their potential relationships with one another, and then statistically analyzed their effects on antibiotic resistance. High adeB expression and high H33342 efflux activity were correlated with low biofilm-forming activity. High adeB expression was significantly correlated with resistance to tigecycline and cefotaxime, but not with the multidrug resistance (MDR) phenotype. Importantly, only high adeJ expression was significantly correlated with the MDR phenotype, and was observed to be correlated with resistance to various antibiotics. However, we found no significant correlation between adeJ expression and biofilm-forming activity. Further, adeG expression was found to not be correlated with antibiotic resistance and biofilm-forming activity. The results of multivariate analysis showed that adeB overexpression and high H33342 efflux activity are related to biofilm-forming activity, and only adeJ overexpression is significantly associated with the MDR phenotype, highlighting the importance of adeJ overexpression.

4.
J Toxicol Sci ; 46(3): 131-142, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33642519

RESUMEN

Pluripotent stem cells (PSCs) possess unique characteristics that distinguish them from other cell types. Human embryonic stem (ES) cells are recently gaining attention as a powerful tool for human toxicity assessment without the use of experimental animals, and an embryonic stem cell test (EST) was introduced for this purpose. However, human PSCs have not been thoroughly investigated in terms of drug resistance or compared with other cell types or cell states, such as naïve state, to date. Aiming to close this gap in research knowledge, we assessed and compared several human PSC lines for their resistance to drug exposure. Firstly, we report that RIKEN-2A human induced pluripotent stem (iPS) cells possessed approximately the same sensitivity to selected drugs as KhES-3 human ES cells. Secondly, both ES and iPS cells were several times less resistant to drug exposure than other non-pluripotent cell types. Finally, we showed that iPS cells subjected to naïve-state induction procedures exhibited a sharp increase in drug sensitivity. Upon passage of these naïve-like cells in non-naïve PSC culture medium, their sensitivity to drug exposure decreased. We thus revealed differences in sensitivity to drug exposure among different types or states of PSCs and, importantly, indicated that naïve-state induction could increase this sensitivity.

5.
Exp Mol Med ; 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33642573

RESUMEN

The concept of the antibiotic resistome was introduced just over a decade ago, and since then, active resistome studies have been conducted. In the present study, we describe the previously established concept of the resistome, which encompasses all types of antibiotic resistance genes (ARGs), and the important findings from each One-Health sector considering this concept, thereby emphasizing the significance of the One-Health approach in understanding ARG transmission. Cutting-edge research methodologies are essential for deciphering the complex resistome structure in the microbiomes of humans, animals, and the environment. Based on the recent achievements of resistome studies in multiple One-Health sectors, future directions for resistome research have been suggested to improve the understanding and control of ARG transmission: (1) ranking the critical ARGs and their hosts; (2) understanding ARG transmission at the interfaces of One-Health sectors; (3) identifying selective pressures affecting the emergence, transmission, and evolution of ARGs; and (4) elucidating the mechanisms that allow an organism to overcome taxonomic barriers in ARG transmission.

6.
World J Gastroenterol ; 27(6): 487-500, 2021 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-33642823

RESUMEN

BACKGROUND: Gastric cancer (GC) is a prevalent malignancy, leading to a high incidence of cancer-associated death. Cisplatin (DDP)-based chemotherapy is the principal therapy for clinical GC treatment, but DDP resistance is a severe clinical challenge and the mechanism remains poorly understood. Circular RNAs (circRNAs) have been identified to play crucial roles in modulating the chemoresistance of gastric cancer cells. AIM: To explore the effect of circVAPA on chemotherapy resistance during GC progression. METHODS: The effect of circVAPA on GC progression and chemotherapy resistance was analyzed by MTT assay, colony formation assay, Transwell assay, wound healing assay, and flow cytometry analysis in GC cells and DDP resistant GC cell lines, and tumorigenicity analysis in nude mice in vivo. The mechanism was investigated by luciferase reporter assay, quantitative real-time PCR, and Western blot analysis. RESULTS: CircVAPA expression was up-regulated in clinical GC tissues compared with normal samples. CircVAPA depletion inhibited proliferation, migration, and invasion and increased apoptosis of GC cells. The expression of circVAPA, STAT3, and STAT3 downstream genes was elevated in DDP resistant SGC7901/DDP cell lines. CircVAPA knockdown attenuated the DDP resistance of GC cells. Mechanically, circVAPA was able to sponge miR-125b-5p, and miR-125b-5p could target STAT3 in the GC cells. MiR-125b-5p inhibitor reversed circVAPA depletion-enhanced inhibitory effect of DDP on GC cells, and STAT3 knockdown blocked circVAPA overexpression-induced proliferation of DDP-treated SGC7901/DDP cells. The depletion of STAT3 and miR-125b-5p inhibitor reversed circVAPA depletion-induced GC cell apoptosis. Functionally, circVAPA contributed to the tumor growth of SGC7901/DDP cells in vivo. CONCLUSION: CircVAPA promotes chemotherapy resistance and malignant progression in GC by miR-125b-5p/STAT3 signaling. Our findings present novel insights into the mechanism by which circVAPA regulates chemotherapy resistance of GC cells. CircVAPA and miR-125b-5p may be considered as the potential targets for GC therapy.

7.
J Chemother ; : 1-6, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33645447

RESUMEN

Ceftolozane/tazobactam (C/T), a cephalosporin/beta-lactamase inhibitor combination, was evaluated in vitro vs. 10 comparators against 299 pediatric extended-spectrum-cephalosporin-resistant or carbapenem-resistant (ESC-R/CR) Gram-negative Enterobacteriaceae from three freestanding pediatric centers. Isolates were from urine or other sterile sites of children and adolescents through 21 years of age. Susceptibilities were assayed by microbroth dilution via custom Sensititre plates (Thermo Fisher Scientific). Susceptibility was determined using the Sensititre Vizion® system (Thermo Fisher Scientific). Susceptibility breakpoint criteria were those of the Clinical and Laboratory Standards Institute (CLSI) for 2017, except for colistin (EUCAST 2019). Overall, 87.5% isolates were C/T susceptible (MIC ≤2 µg/ml; MIC50/90, 0.25/4 µg/ml). Susceptibility to C/T was detected more frequently as compared to all other antimicrobials tested except for colistin (95.4%) and meropenem (97.4%). Percent susceptibility to C/T was high for E. coli (91%) and Klebsiella spp. (73.3%). C/T demonstrated good in-vitro activity and high potency against most beta-lactam resistant pediatric Enterobacteriaceae from three geographically diverse U.S. regions.

8.
Rev Esp Quimioter ; 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33645948

RESUMEN

OBJECTIVE: To analyse the susceptibility to ceftolozane-tazobactam and comparators in Enterobacterales and Pseudomonas aeruginosa isolates recovered from intraabdominal (IAI), urinary (UTI), respiratory (RTI) and bloodstream infection (BSI) in the SMART (Study for Monitoring Antimicrobial Resistance Trends) study. METHODS: The susceptibility of 5,351 isolates collected in 11 Spanish hospitals (2016-2018) were analysed (EUCAST-2020 criteria) by broth microdilution and were phenotypically studied for the presence of extended-spectrum beta-lactamases (ESBL). Ceftolozane-tazobactam and/or carbapenem resistant isolates were genetically characterized for ESBL and carbapenemases. RESULTS: Escherichia coli was the most frequent pathogen (49.3% IAI, 54.9% UTI, 16.7% RTI and 50% BSI), followed by Klebsiella pneumoniae (11.9%, 19.1%, 13.1% and 15.4%, respectively). P. aeruginosa was isolated in 9.3%, 5.6%, 32% and 9%, respectively. The frequency of isolates with ESBLs (2016-2017) was: 30.5% K. pneumoniae, 8.6% E. coli, 2.3% Klebsiella oxytoca and 0.7% Proteus mirabilis. Ceftolozane-tazobactam was very active against non-ESBL-(99.3% susceptible) and ESBL-(95.2%) producing E. coli being less active against K. pneumoniae (98% and 43.1%, respectively) isolates. CTX-M-15 was the most prevalent ESBL in E. coli (27.5%) and K. pneumoniae (51.9%) frequently associated with OXA-48-like carbapenemase. Overall, 93% of P. aeruginosa isolates were susceptible to ceftolozane-tazobactam, preserving this activity (>75%) in isolates resistant to other beta-lactams except in those resistant to meropenen or ceftazidime-avibactam. GES-5, PER-1, VIM-1/2 were the most prevalent enzymes in isolates resistant to ceftolozane-tazobactam. CONCLUSIONS: Ceftolozane-tazobactam showed high activity rates against isolates recovered in the SMART study although it was affected in K. pneumoniae and P. aeruginosa isolates with ESBL and/or carbapenemases.

9.
Bull Math Biol ; 83(4): 36, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33646415

RESUMEN

The ecological and human health impact of antibiotic use and the related antimicrobial resistance (AMR) in animal husbandry is poorly understood. In many countries, there has been considerable pressure to reduce overall antibiotic use in agriculture or to cease or minimise use of human critical antibiotics. However, a more nuanced approach would consider the differential impact of use of different antibiotic classes; for example, it is not known whether reduced use of bacteriostatic or bacteriolytic classes of antibiotics would be of greater value. We have developed an ordinary differential equation model to investigate the effects of farm practice on the spread and persistence of AMR in the dairy slurry tank environment. We model the chemical fate of bacteriolytic and bacteriostatic antibiotics within the slurry and their effect on a population of bacteria, which are capable of resistance to both types of antibiotic. Through our analysis, we find that changing the rate at which a slurry tank is emptied may delay the proliferation of multidrug-resistant bacteria by up to five years depending on conditions. This finding has implications for farming practice and the policies that influence waste management practices. We also find that, within our model, the development of multidrug resistance is particularly sensitive to the use of bacteriolytic antibiotics, rather than bacteriostatic antibiotics, and this may be cause for controlling the usage of bacteriolytic antibiotics in agriculture.

10.
Int J Med Microbiol ; 311(2): 151477, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33524636

RESUMEN

OBJECTIVE: We aim to describe the epidemiological, clinical and microbiological characteristics of the linezolid- and vancomycin- resistant Enterococcus faecium (LVRE) in a tertiary care hospital in Germany. METHODS: We conducted a retrospective analysis of 196 LVRE cases observed from 1st January 2012 to 31th December 2018. Patients' medical charts were reviewed and available LVRE (n = 102) were subjected to whole-genome-sequencing. Antibiotic consumption was measured in defined daily dose (DDD)/100 bed-days (BD). RESULTS: The prevalence of LVRE isolates among VRE was 6.3 % in 2018. Most patients had an onco-hematological disease (134/196, 68.4 %). From 2012-2018 an increase of +356.7 % of linezolid defined daily dose/100 bed-days was observed. In 71.4 % (90/126, 70 missing values) of the patients, linezolid was prescribed in the previous 6 months. The median exposure to linezolid was 15 days (Interquartile, IQR 9-23). 42/196 (21.4 %) patients had an LVRE-related infection with an overall 30-day mortality rate of 33 %. In 121/196 (61.7 %) patients, linezolid-susceptible VREfm were isolated before LVRE, suggesting secondary acquisition of linezolid resistance. Genetic analysis revealed that most isolates belonged to ST117 (64/102 available isolates, 62.7 %). The G2576T 23S rDNA mutation was identified as the most common resistance mechanism (96/102, 94.1 %). poxtA was identified in two isolates, while cfr, and optrA were not detected. CONCLUSIONS: Incidence of LVRE related to 23S rDNA mutations is rising and probably associated with antibiotic consumption. Restrictions in the use of linezolid may be needed in order to retain therapeutic options in VRE.


Asunto(s)
Farmacorresistencia Bacteriana , Enterococcus faecium/efectos de los fármacos , Infecciones por Bacterias Grampositivas , Linezolid/farmacología , Resistencia a la Vancomicina , Antibacterianos/farmacología , Enterococcus faecium/genética , Alemania/epidemiología , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/epidemiología , Humanos , Pruebas de Sensibilidad Microbiana , ARN Ribosómico 23S/genética , Estudios Retrospectivos , Vancomicina
11.
Microbiol Immunol ; 2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33527392

RESUMEN

The wide occurrence of antimicrobial-resistant (AMR) bacteria in various environments is of great concern. Here, we examined the prevalence and antimicrobial susceptibility of Enterobacteriaceae isolated from 88 wild arthropods, collected in Gifu city, Japan. In total, 168 isolates of Enterobacteriaceae were obtained from 61 arthropods. All isolates were susceptible to all the antimicrobial agents tested, except colistin (31 isolates) and kanamycin (one isolate). The aph(3')-Ia gene, responsible for kanamycin resistance, was detected in Klebsiella oxytoca. Although synanthropic arthropods (houseflies and cockroaches) serve as vectors for AMR Enterobacteriaceae, other wild arthropods are not crucial carriers of Enterobacteriaceae resistant to antimicrobial agents.

12.
Biomaterials ; 270: 120649, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33588139

RESUMEN

High intracellular glutathione (GSH) levels play an important role in multidrug resistance (MDR) in cancer cells. It remains challenging to develop a drug delivery system that is simultaneously capable of GSH depletion and drug activation for multidrug resistance reversal. Herein, we designed a polyprodrug (denoted as PSSD) based on poly(disulfide) conjugated with doxorubicin (DOX) on the polymer side chains that exhibits GSH depletion and cascade DOX activation for drug resistance reversal. The poly(disulfide) backbone with a high disulfide density depletes intracellular antioxidant GSH via the disulfide-thiol exchange reaction to disrupt intracellular redox homeostasis in cells. Simultaneously, DOX can be activated through a cascade reaction, and degradation of the poly(disulfide) backbone further facilitates its drug release. Therefore, poly(disulfide) can be used as a GSH scavenger to reverse MDR as well as a prodrug backbone to target high intracellular GSH levels in cancer cells, providing a general strategy for drug resistance reversal.

13.
Artículo en Inglés | MEDLINE | ID: mdl-33626417

RESUMEN

OBJECTIVES: With the continued spread of antimicrobial resistance in animals, it is important to assess its occurrence throughout a microbiome quantitatively in order to evaluate significantly affecting factors e.g. antimicrobial usage. Metagenomics methods makes it possible to measure the abundance of antimicrobial resistance genes in complex samples such as pooled faeces samples from batches of slaughter pigs. This study was performed to determine; the random error in antimicrobial resistance in pooled samples from batches pigs at slaughter, and the measurement error from the metagenomics processes. METHODS: In four farms, two pooled samples were obtained from a batch of slaughter pigs by two individual samplers, each pooled sample was hereafter processed twice. Hierarchically clustered heatmaps were applied to evaluate dissimilarities between samples. The coefficient of variation was used to calculate the percentage difference between samples from the same farm. RESULTS: The results of the analysis revealed that it was not possible to quantitatively separate the variation arising from sampling and metagenomics processes. They both contributed to the overall measurement error of antimicrobial resistance in batches of slaughter pigs. CONCLUSIONS: Sampling of single pigs in 30 randomly selected pig pens within the farms provides a composition representative for frequently occurring antimicrobial resistance genes present within the farms, while rare genes were not dispersed in a similar manner. Aggregating the resistance abundance at gene family or antimicrobial class level will reduce the apparent variation originating from errors in sampling and metagenomics processing.

14.
Int J Food Microbiol ; 342: 109044, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33529874

RESUMEN

Antimicrobial resistance (AMR) in non-typhoidal Salmonella from poultry is a public health concern. Injudicious use of antibiotics in humans and agriculture fuels the emergence of resistance. The objective of this study was to characterize the prevalence, antibiotic susceptibility profiles and genetic resistance mechanisms of Salmonella isolated from US retail poultry meat samples with and without antibiotic-related claims. We reviewed data from 46,937 poultry meat samples collected from 2008 to 2017 through the FDA NARMS retail meat program. Antibiotic usage claims on the poultry packaging were used to categorize the sample as 'conventionally raised' or 'reduced or no antibiotic use'. The results show that the prevalence of Salmonella in conventional poultry samples (8.6%) was higher than reduced or no antibiotic use poultry samples (5.1%). The odds of resistance to three or more antimicrobial classes (multi-drug resistant) were 2.61 times higher for Salmonella isolates from conventional samples, compared to isolates from reduced antibiotic use samples. The frequency of the aminoglycoside resistance gene, strB, and the beta-lactam resistant gene, blaCMY-2, were higher in isolates from conventional meat. This study suggests that conventionally raised poultry meat was more likely to be contaminated with multi-drug resistant Salmonella, and those Salmonella are more likely to carry genes for antibiotics resistance.

15.
Microbiome ; 9(1): 49, 2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33597026

RESUMEN

BACKGROUND: Pathogenic microorganisms cause disease by invading, colonizing, and damaging their host. Virulence factors including bacterial toxins contribute to pathogenicity. Additionally, antimicrobial resistance genes allow pathogens to evade otherwise curative treatments. To understand causal relationships between microbiome compositions, functioning, and disease, it is essential to identify virulence factors and antimicrobial resistance genes in situ. At present, there is a clear lack of computational approaches to simultaneously identify these factors in metagenomic datasets. RESULTS: Here, we present PathoFact, a tool for the contextualized prediction of virulence factors, bacterial toxins, and antimicrobial resistance genes with high accuracy (0.921, 0.832 and 0.979, respectively) and specificity (0.957, 0.989 and 0.994). We evaluate the performance of PathoFact on simulated metagenomic datasets and perform a comparison to two other general workflows for the analysis of metagenomic data. PathoFact outperforms all existing workflows in predicting virulence factors and toxin genes. It performs comparably to one pipeline regarding the prediction of antimicrobial resistance while outperforming the others. We further demonstrate the performance of PathoFact on three publicly available case-control metagenomic datasets representing an actual infection as well as chronic diseases in which either pathogenic potential or bacterial toxins are hypothesized to play a role. In each case, we identify virulence factors and AMR genes which differentiated between the case and control groups, thereby revealing novel gene associations with the studied diseases. CONCLUSION: PathoFact is an easy-to-use, modular, and reproducible pipeline for the identification of virulence factors, bacterial toxins, and antimicrobial resistance genes in metagenomic data. Additionally, our tool combines the prediction of these pathogenicity factors with the identification of mobile genetic elements. This provides further depth to the analysis by considering the genomic context of the pertinent genes. Furthermore, PathoFact's modules for virulence factors, toxins, and antimicrobial resistance genes can be applied independently, thereby making it a flexible and versatile tool. PathoFact, its models, and databases are freely available at https://pathofact.lcsb.uni.lu . Video abstract.

16.
BMC Vet Res ; 17(1): 86, 2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602222

RESUMEN

BACKGROUND: The discovery of the superbug mcr-1-positive Escherichia coli (MCRPEC) has drew greet attention. Swine-origin multi-drug resistant MCRPEC has been a potential threat to public health and safety. However, there were few detailed studies have been reported on swine MCRPEC in Guangxi, South China. RESULTS: In this study, thirty-three MCRPEC strains were detected from 142 E. coli strains from 116 samples in Guangxi in 2018. Which could be classified into eight unique STs and a total of six incompatibility plasmid groups (IncFI, IncHI1, IncY, IncN, IncI1 and IncX1). After that, the susceptibility of MCRPEC isolates to 27 antimicrobial agents belonging to 17 antimicrobial categories was tested. There were nineteen E. coli resistant to 3rd and 4th generation cephalosporins and twelve E. coli resistant to carbapenem resistan. Importantly, the MCRPEC showed high resistance highly resistance for imipenem and meropenem, which were forbidden to use in livestock production. Three MCRPEC strains were further proved to be extensively drug-resistant (XDR), and the other isolates were multi-drug-resistant (MDR). Furthermore, we found that the plasmid-carrying resistance genes coexisted with the mcr-1 gene of the MCRPEC isolates. Which were listed as follows: ß-lactamase antimicrobial resistance genes e.g. ESBL genes (blaCTX-M14, blaCTX-M24, blaCTX-M123, blaOXA-1), plasmid-mediated AmpC (pAmpC) gene (blaCMY-2), the carbapenem resistance gene (blaNDM-5), and non-ß-lactamase antimicrobial resistance genes (qnrA, qnrB, qnrS, aac (6')-Ib-cr, tetA, tetB, sul1, sul2, floR, aadA). CONCLUSION: Thirty-three mcr-1-positive E. coli isolates in Guangxi displayed a wide profile of antimicrobial resistance. Plasmid-carrying resistance genes might be the main cause of MCRPEC multidrug resistance. This study highlighted the necessity for long-term surveillance of mcr-1-positive E. coli in pigs.

17.
Open Vet J ; 10(4): 452-456, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33614441

RESUMEN

Background: Methicillin-resistant staphylococci (MRS) are an emerging global problem with serious public health concern. Aims: This study investigated the prevalence and antimicrobial susceptibility of commensal Staphylococcus species isolated from healthy and clinical cats and dogs. Methods: Nasal swab samples were collected from animals and processed using selective and semi-selective mediums. Presumptive isolates were subjected to biochemical testing and analyzed using the Phoenix automated identification and susceptibility testing system. PCRs protocols were used to screen for mecA and pvl genes. Results: In total, 151 pets (103 cats and 48 dogs) were enrolled, of which 14 dogs (29%) and 24 cats (23%) were colonized with various Staphylococcus species mainly originated from healthy animals. A total of 38 staphylococci isolates were collected and distributed between 24 coagulase-negative and 14 coagulase-positive staphylococci. Only 13 staphylococci strains were identified as MRS, out of which only five isolates expressed that the mecA gene exclusively originated from healthy pets. Conclusion: This is the first study reporting the prevalence and colonization status of staphylococci species and MRS strains isolated from cats and dogs in Libya. The study reports important information of medical and clinical importance on antimicrobial and multidrug resistance of different staphylococci strains, particularly the coagulase negative species.

18.
Artículo en Inglés | MEDLINE | ID: mdl-33599270

RESUMEN

OBJECTIVES: WHO guidelines on ART define the HIV-1 viral load (VL) threshold for treatment failure at 1000 copies/mL. The Switch Either near Suppression Or THOusand (SESOTHO) trial, conducted in Lesotho from 2017 to 2020, found that patients with persistent viraemia below this threshold (100-999 copies/mL) benefit from switching to second-line ART. This pre-planned nested study assesses the prevalence of resistance-associated mutations (RAMs) in SESOTHO trial participants. METHODS: The SESOTHO trial [registered at ClinicalTrials.gov (NCT03088241)] enrolled 80 persons taking NNRTI-based first-line ART with low-level HIV-1 viraemia (100-999 copies/mL) and randomized them (1:1) to switch to a PI-based second-line regimen (switch) or continue on first-line therapy (control). We sequenced relevant regions of the viral pol gene using plasma samples obtained at enrolment and 36 weeks. RAMs were classified with the Stanford HIV Drug Resistance Database. RESULTS: Sequencing data were obtained for 37/80 (46%) participants at baseline and 26/48 (54%) participants without viral suppression to <50 copies/mL at 36 weeks (21 control participants and 5 switch participants). At baseline, 31/37 (84%) participants harboured high-level resistance to at least two drugs of their current regimen. At 36 weeks, 17/21 (81%) control participants harboured resistance to at least two drugs of their current regimen, while no PI-associated resistance was detected in the 5 switch participants with ongoing viraemia. CONCLUSIONS: Among persons with low-level viraemia while taking NNRTI-based first-line ART enrolled in the SESOTHO trial, the majority harboured HIV-1 with RAMs that necessitate ART modification. These findings support lowering the VL threshold triggering a switch to second-line ART in future WHO guidelines.

19.
Turk J Med Sci ; 2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33600098

RESUMEN

BACKGROUND/AIM: In up to 20% of epilepsy patients, seizures may not be controlled despite the use of antiepileptic drugs, either singly or in combination. These individuals are considered to have drug resistant epilepsy. Drug-resistant epilepsy is usually associated with intellectual disability, psychiatric comorbidity, physical injury, sudden unexpected death, and low life quality. Early detection and prediction of drug resistant epilepsy are essential in determining the patient's most appropriate treatment option. This retrospective study aimed to determine the clinical, electroencephalographic, and radiological factors associated with medically intractable childhood seizures. MATERIALS AND METHODS: Data regarding 177 patients diagnosed with drug resistant epilepsy were compared with 281 patients with drug responsive epilepsy. RESULTS: Univariate analysis showed that age at seizure onset, having mixed seizure types, history of status epilepticus, history of neonatal seizures, history of both having febrile and afebrile seizures, daily seizures at the onset, abnormality on the first electroencephalogram, generalized epileptic abnormality on electroencephalogram, abnormal neurodevelopmental status, abnormal neuroimaging, having symptomatic etiology were significant risk factors for the development of drug resistant epilepsy (P < 0.05). In multivariable analysis, having mixed seizure types, history of status epilepticus, having multiple seizures in a day, intellectual disability, symptomatic etiology, and MRI abnormality remained significant predictors for developing drug resistant epilepsy. CONCLUSIONS: In the course of childhood epilepsy, some clinical features may predict the outcome. Early identification of patients with high risk for drug resistant epilepsy will help plan the appropriate treatment option. Further prospective studies should confirm these findings.

20.
Ann Clin Microbiol Antimicrob ; 20(1): 13, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33588850

RESUMEN

BACKGROUND: Klebsiella pneumoniae is a common cause of nosocomial infections. Antibiotic resistance and ability to form biofilm, as two key virulence factors of K. pneumoniae, are involved in the persistence of infections. The purpose of this study was to investigate the correlation between antimicrobial resistance and biofilm formation capability among K. pneumoniae strains isolated from hospitalized patients in Iran. METHODS: Over a 10-month period, a total of 100 non-duplicate K. pneumoniae strains were collected. Antibiotic susceptibility was determined by Kirby-Bauer disk diffusion method according to CLSI. Biofilm production was assessed by tissue culture plate method. Finally, polymerase chain reaction was conducted to detect four families of carbapenemase: blaIMP, blaVIM, blaNDM, blaOXA-48; biofilm formation associated genes: treC, wza, luxS; and K. pneumoniae confirming gene: rpoB. RESULTS: Most of the isolates were resistant to trimethoprim-sulfamethoxazole (52 %), cefotaxime (51 %), cefepime (43 %), and ceftriaxone (43 %). Among all the 100 isolates, 67 were multidrug-resistant (MDR), and 11 were extensively drug-resistant (XDR). The prevalence of the blaVIM, blaIMP, blaNDM, and blaOXA-48 genes were 7 , 11 , 5 , and 28 %, respectively. The results of biofilm formation in the tissue culture plate assay indicated that 75 (75 %) strains could produce biofilm and only 25 (25 %) isolates were not able to form biofilm. Among these isolates, 25 % formed fully established biofilms, 19 % were categorized as moderately biofilm-producing, 31 % formed weak biofilms, and 25 % were non-biofilm-producers. The antimicrobial resistance among biofilm former strains was found to be significantly higher than that of non-biofilm former strains (p < 0.05). Molecular distribution of biofilm formation genes revealed that 98 , 96 , and 34 % of the isolates carried luxS, treC, and wza genes, respectively. CONCLUSIONS: The rise of antibiotic resistance among biofilm-producer strains demonstrates a serious concern about limited treatment options in the hospital settings. All of the data suggest that fundamental actions and introduction of novel strategies for controlling of K. pneumoniae biofilm-related infections is essential.

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