scholarly journals Modelling tuberculosis drug resistance amplification rates in high-burden settings

2021 ◽  
Author(s):  
Malancha Karmakar ◽  
Romain Ragonnet ◽  
David B. Ascher ◽  
James M. Trauer ◽  
Justin T. Denholm
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
Bacterial Genome ◽  
Multidrug Resistant ◽  
Transmission Risk ◽  
Transmission Model ◽  
Viet Nam ◽  
Primary Resistance ◽  
Mdr Tb ◽  
Using Data

AbstractBackgroundAntimicrobial resistance develops following the accrual of mutations in the bacterial genome, and may variably impact organism fitness and hence, transmission risk. Classical representation of tuberculosis (TB) dynamics using a single or two strain (DS/MDR-TB) model typically does not capture elements of this important aspect of TB epidemiology. To understand and estimate the likelihood of resistance spreading in high drug-resistant TB incidence settings, we used molecular understanding to develop a compartmental epidemiological model of Mycobacterium tuberculosis (Mtb) transmission.MethodsA four-strain (drug-susceptible (DS), isoniazid mono-resistant (INH-R), rifampicin mono-resistant (RIF-R) and multidrug-resistant (MDR)) compartmental deterministic Mtb transmission model was developed to explore the progression from DS-to MDR-TB. The model incorporated strain-specific fitness costs and was calibrated using data from national tuberculosis prevalence surveys and drug resistance surveys from Philippines and Viet Nam. Using an adaptive Metropolis algorithm, we estimated drug resistance amplification and transmission rates.ResultsThe posterior estimates for the proportion of isoniazid mono-resistant amplification among treatment failure was 0.75 (0.64 – 0.85) for Philippines and 0.55 (0.39 – 0.63) for Viet Nam. The proportion of rifampicin mono-resistant amplification among treatment failure was 0.05 (0.04 – 0.06) for Philippines and 0.011 (0.010 – 0.012) for Viet Nam. In Philippines, the estimated proportion of primary resistance resulting from transmission was 56% (42 – 68) for INH-R, 48% (34 – 62) for RIF-R and 42% (34 – 50) for MDR-TB. For Viet Nam, the estimated proportion of drug resistance due to transmission was 79% (70 – 86) for INH-R, 68% (58 – 75) for RIF-R and 50% (45 – 53) for MDR-TB.DiscussionRIF-R strains were more likely to be transmitted than acquired through amplification, while both mechanisms of acquisition were important contributors in the case of INH-R. These findings highlight the complexity of drug resistance dynamics in high-incidence settings, and emphasize the importance of prioritizing testing algorithms which also allow for early detection of INH-R.

scholarly journals Analysis of drug resistance and mutation profiles in Mycobacterium tuberculosis isolates in a surveillance site in Beijing, China

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098493
Author(s):  
Jie Zhang ◽  
Yixuan Ren ◽  
Liping Pan ◽  
Junli Yi ◽  
Tong Guan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Drug Testing ◽  
Multidrug Resistant ◽  
High Rate ◽  
Drug Resistant ◽  
Surveillance Site ◽  
Mdr Tb ◽  
Previously Treated Patients ◽  
Beijing China

Objective This study analyzed drug resistance and mutations profiles in Mycobacterium tuberculosis isolates in a surveillance site in Huairou District, Beijing, China. Methods The proportion method was used to assess drug resistance profiles for four first-line and seven second-line anti-tuberculosis (TB) drugs. Molecular line probe assays were used for the rapid detection of resistance to rifampicin (RIF) and isoniazid (INH). Results Among 235 strains of M. tuberculosis, 79 (33.6%) isolates were resistant to one or more drugs. The isolates included 18 monoresistant (7.7%), 19 polyresistant (8.1%), 28 RIF-resistant (11.9%), 24 multidrug-resistant (MDR) (10.2%), 7 pre-extensively drug-resistant (XDR, 3.0%), and 2 XDR strains (0.9%). A higher rate of MDR-TB was detected among previously treated patients than among patients with newly diagnosed TB (34.5% vs. 6.8%). The majority (62.5%) of RIF-resistant isolates exhibited a mutation at S531L in the DNA-dependent RNA polymerase gene. Meanwhile, 62.9% of INH-resistant isolates carried a mutation at S315T1 in the katG gene. Conclusion Our results confirmed the high rate of drug-resistant TB, especially MDR-TB, in Huairou District, Beijing, China. Therefore, detailed drug testing is crucial in the evaluation of MDR-TB treatment.

scholarly journals Increasing prevalence of resistance to second-line drugs among multidrug-resistant Mycobacterium tuberculosis isolates in Kuwait

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Noura M. Al-Mutairi ◽  
Suhail Ahmad ◽  
Eiman Mokaddas
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Mutation Detection ◽  
Susceptibility Testing ◽  
Multidrug Resistant ◽  
Genetic Mutations ◽  
Second Line ◽  
Injectable Drugs ◽  
Mdr Tb ◽  
Phenotypic Susceptibility

AbstractMolecular methods detect genetic mutations associated with drug resistance. This study detected resistance-conferring mutations in gyrA/gyrB for fluoroquinolones and rrs/eis genes for second-line injectable drugs (SLIDs) among multidrug-resistant Mycobacterium tuberculosis (MDR-TB) isolates in Kuwait. Fifty pansusceptible M. tuberculosis and 102 MDR-TB strains were tested. Phenotypic susceptibility testing was performed by MGIT 960 system using SIRE drug kit. GenoType MTBDRsl version 1 (gMTBDRslv1) and GenoType MTBDRsl version 2 (gMTBDRslv2) tests were used for mutation detection. Results were validated by PCR-sequencing of respective genes. Fingerprinting was performed by spoligotyping. No mutations were detected in pansusceptible isolates. gMTBDRslv1 detected gyrA mutations in 12 and rrs mutations in 8 MDR-TB isolates. gMTBDRsl2 additionally detected gyrB mutations in 2 and eis mutation in 1 isolate. Mutations in both gyrA/gyrB and rrs/eis were not detected. gMTBDRslv1 also detected ethambutol resistance-conferring embB mutations in 59 isolates. Although XDR-TB was not detected, frequency of resistance-conferring mutations for fluoroquinolones or SLIDs was significantly higher among isolates collected during 2013–2019 versus 2006–2012. Application of both tests is warranted for proper management of MDR-TB patients in Kuwait as gMTBDRslv2 detected resistance to fluoroquinolones and/or SLIDs in 3 additional isolates while gMTBDRslv1 additionally detected resistance to ethambutol in 58% of MDR-TB isolates.

Exploring the Contribution of Mycobacteria Characteristics in Their Interaction with Human Macrophages

2013 ◽  
Vol 19 (5) ◽  
pp. 1159-1169 ◽  
Author(s):  
Carla Silva ◽  
Joao Perdigao ◽  
Elsa Alverca ◽  
António P. Alves de Matos ◽  
Patricia A. Carvalho ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Envelope ◽  
Treatment Strategies ◽  
Human Monocyte ◽  
Selective Advantage ◽  
Multidrug Resistant ◽  
Structural Features ◽  
Major Health Problem ◽  
Transmission Electron ◽  
Mdr Tb

AbstractTuberculosis (TB) is a major health problem. The emergence of multidrug resistant (MDR)Mycobacterium tuberculosis(Mtb) isolates confounds treatment strategies. In Portugal, cases of MDR-TB are reported annually with an increased incidence noted in Lisbon. The majority of these MDR-TB cases are due to closely related mycobacteria known collectively as theLisboafamily and Q1 cluster. Genetic determinants linked to drug resistance have been exhaustively studied resulting in the identification of family and cluster specific mutations. Nevertheless, little is known about other factors involved in development of mycobacteria drug resistance. Here, we complement genetic analysis with the study of morphological and structural features of theLisboafamily and Q1 cluster isolates by using scanning and transmission electron microscopy. This analysis allowed the identification of structural differences, such as cell envelope thickness, between Mtb clinical isolates that are correlated with antibiotic resistance. The infection of human monocyte derived macrophages allowed us to document the relative selective advantage of theLisboafamily isolates over other circulating Mtb isolates.

scholarly journals Constraints of Drug Resistance in Mycobacterium tuberculosis - Prospects for Pharmacological Reversion of Susceptibility to Antibiotics

2017 ◽  
Vol 8 (1) ◽  
pp. 33-43 ◽  
Author(s):  
Aleksandr I. Ilin ◽  
Murat E. Kulmanov ◽  
Ilya S. Korotetskiy ◽  
Marina V. Lankina ◽  
Gulshara K. Akhmetova ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Genetic Heterogeneity ◽  
Multidrug Resistant ◽  
Resistance Mutations ◽  
General Increase ◽  
Drug Induced ◽  
Mdr Tb ◽  
Resistant Strains

Emergence of multidrug resistant strains ofMycobacterium tuberculosis(MDR-TB) threatens humanity. This problem was complicated by the crisis in development of new anti-tuberculosis antibiotics. Induced reversion of drug resistance seems promising to overcome the problem. Successful clinical trial of a new anti-tuberculosis nanomolecular complex FS-1 has demonstrated prospectively of this approach in combating MDR-TB. Several clinical MDR-TB cultures were isolated from sputum samples prior and in the process of the clinical trial. Every isolate was tested for susceptibility to antibiotics and then they were sequenced for comparative genomics. It was found that the treatment with FS-1 caused an increase in the number of antibiotic susceptible strains among Mtb isolates that was associated with a general increase of genetic heterogeneity of the isolates. Observed impairing of phthiocerol dimycocerosate biosynthesis by disruptive mutations inppsACDsubunits indicated a possible virulence remission for the sake of persistence. It was hypothesized that the FS-1 treatment eradicated the most drug resistant Mtb variants from the population by aggravating the fitness cost of drug resistance mutations. Analysis of distribution of these mutations in the global Mtb population revealed that many of them were incompatible with each other and dependent on allelic states of many other polymorphic loci. The latter discovery may explain the negative correlation between the genetic heterogeneity of the population and the level of drug tolerance. To the best of our knowledge, this work was the first experimental confirmation of the drug induced antibiotic resistance reversion by the induced synergy mechanism that previously was predicted theoretically.

Hand Hygiene, Cohorting, or Antibiotic Restriction to Control Outbreaks of Multidrug-Resistant Enterobacteriaceae

2015 ◽  
Vol 37 (3) ◽  
pp. 272-280 ◽  
Author(s):  
Camille Pelat ◽  
Lidia Kardaś-Słoma ◽  
Gabriel Birgand ◽  
Etienne Ruppé ◽  
Michaël Schwarzinger ◽  
...  
Keyword(s):  
Hand Hygiene ◽  
Multidrug Resistant ◽  
Transmission Model ◽  
Patient Contact ◽  
Hand Hygiene Improvement ◽  
Single Carrier ◽  
Before And After ◽  
Hygiene Compliance ◽  
Using Data ◽  
Improvement Intervention

BACKGROUNDThe best strategy for controlling extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) transmission in intensive care units (ICUs) remains elusive.OBJECTIVEWe developed a stochastic transmission model to quantify the effectiveness of interventions aimed at reducing the spread of ESBL-PE in an ICU.METHODSWe modeled the evolution of an outbreak caused by the admission of a single carrier in a 10-bed ICU free of ESBL-PE. Using data obtained from recent muticenter studies, we studied 26 strategies combining different levels of the following 3 interventions: (1) increasing healthcare worker compliance with hand hygiene before and after contact with a patient; (2) cohorting; (3) reducing antibiotic prevalence at admission with or without reducing antibiotherapy duration.RESULTSImproving hand hygiene compliance from 55% before patient contact and 60% after patient contact to 80% before and 80% after patient contact reduced the nosocomial incidence rate of ESBL-PE colonization by 91% at 90 days. Adding cohorting to hand hygiene improvement intervention decreased the proportion of ESBL-PE acquisitions by an additional 7%. Antibiotic restriction had the lowest impact on the epidemic. When combined with other interventions, it only marginally improved effectiveness, despite strong hypotheses regarding antibiotic impact on transmission.CONCLUSIONOur results suggest that hand hygiene is the most effective intervention to control ESBL-PE transmission in an ICU.Infect. Control Hosp. Epidemiol. 2016;37(3):272–280

scholarly journals Drug-resistant Mycobacterium tuberculosis and its genotypes isolated from an outbreak in western Thailand

2020 ◽  
Author(s):  
Janisara Rudeeaneksin ◽  
Benjawan Phetsuksiri ◽  
Chie Nakajima ◽  
Supranee Bunchoo ◽  
Krairerk Suthum ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Variable Number Tandem Repeat ◽  
Multidrug Resistant ◽  
Variable Number ◽  
Drug Resistant ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Extensively Drug Resistant ◽  
Mdr Tb ◽  
Vntr Analysis

Abstract Background Multidrug-resistant TB (MDR-TB) outbreaks have occurred in the Thamaka district, Kanchanaburi province in Thailand. Methods Seventy-two isolates, which included 7% mono-, 30.6% MDR and extensively drug-resistant TB (XDR-TB), were genotyped by spoligotyping, mycobacterial interspersed repetitive unit-variable-number tandem repeat (MIRU-VNTR) and single nucleotide polymorphism genotyping, and their drug resistance was analysed. Results The spoligotyping results showed that Beijing spoligo-international type (SIT)1 was predominant (n=38; 52.8%) while the remaining were non-Beijing sublineages (n=34). The MIRU-VNTR analysis showed that Beijing isolates, most of which belonged to the modern type (n=37), formed 5 clusters and 13 individual patterns. In katG, only mutation Ser315Thr was identified. In rpoB, Ser531Leu was predominant, except for His526Arg and Leu533Pro, which were found in two isolates. A cluster of 14 Beijing strains contained these common mutations and shared the MIRU-VNTR genotype with isolates in the Thamaka district that had spread previously. Two U SIT523 isolates contained the mutations A1400G in rrs and Asp94Gly in gyrA genes, indicating a spread of XDR-TB. Conclusions Most mutations were associated with drug resistance and the specific MDR Beijing and XDR-TB in U SIT523 isolates remain. This genotyping is a key tool for tracking TB transmission in the Thamaka district of Thailand.

scholarly journals Prevalence of Extensively Drug Resistant Tuberculosis among Archived Multidrug Resistant Tuberculosis Isolates in Zimbabwe

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Tichaona Sagonda ◽  
Lucy Mupfumi ◽  
Rumbidzai Manzou ◽  
Beauty Makamure ◽  
Mqondisi Tshabalala ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Multidrug Resistant ◽  
Cross Sectional Study ◽  
Second Line ◽  
Cross Sectional ◽  
Resistant Tuberculosis ◽  
Resistance Patterns ◽  
Mdr Tb ◽  
Definition Of

We conducted a cross-sectional study of second line drug resistance patterns and genetic diversity of MDR-TB isolates archived at the BRTI-TB Laboratory, Harare, between January 2007 and December 2011. DSTs were performed for second line antituberculosis drugs. XDR-TB strains were defined as MDR-TB strains with resistance to either kanamycin and ofloxacin or capreomycin and ofloxacin. Strain types were identified by spoligotyping. No resistance to any second line drugs was shown in 73% of the isolates, with 23% resistant to one or two drugs but not meeting the definition of XDR-TB. A total of 26 shared types were identified, and 18 (69%) matched preexisting shared types in the current published spoligotype databases. Of the 11 out of 18 clustered SITs, 4 predominant (>6 isolates per shared type) were identified. The most and least abundant types were SIT 1468 (LAM 11-ZWE) with 12 (18%) isolates and SIT 53 (T1) with 6 (9%) isolates, respectively. XDR-TB strains are rare in Zimbabwe, but the high proportion of “pre-XDR-TB” strains and treatment failure cases is of concern. The genetic diversity of the MDR-TB strains showed no significant association between SITs and drug resistance.

scholarly journals Rifampicin and isoniazid drug resistance among patients diagnosed with pulmonary tuberculosis in southwestern Uganda

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0259221
Author(s):  
Lisa Nkatha Micheni ◽  
Kennedy Kassaza ◽  
Hellen Kinyi ◽  
Ibrahim Ntulume ◽  
Joel Bazira
Keyword(s):  
Drug Resistance ◽  
Pulmonary Tuberculosis ◽  
Multidrug Resistant ◽  
Bivariate Analysis ◽  
Newly Diagnosed ◽  
High Resolution Melt ◽  
Significant Control ◽  
Mdr Tb ◽  
Previously Treated ◽  
Southwestern Uganda

Multidrug-resistant tuberculosis (MDR-TB) has become a major threat to the control of tuberculosis globally. Uganda is among the countries with a relatively high prevalence of tuberculosis despite significant control efforts. In this study, the drug resistance of Mycobacterium tuberculosis to rifampicin (RIF) and isoniazid (INH) was investigated among patients diagnosed with pulmonary tuberculosis in Southwestern Uganda. A total of 283 sputum samples (266 from newly diagnosed and 17 from previously treated patients), collected between May 2018 and April 2019 at four different TB diagnostic centres, were assessed for RIF and INH resistance using high-resolution melt curve analysis. The overall prevalence of monoresistance to INH and RIF was 8.5% and 11% respectively, while the prevalence of MDR-TB was 6.7%. Bivariate analysis showed that patients aged 25 to 44 years were at a higher risk of developing MDR-TB (cOR 0.253). Furthermore, among the newly diagnosed patients, the prevalence of monoresistance to INH, RIF and MDR-TB was 8.6%, 10.2% and 6.4% respectively; while among the previously treated cases, these prevalence rates were 5.9%, 23.5% and 11.8%. These rates are higher than those reported previously indicating a rise in MTB drug resistance and may call for measures used to prevent a further rise in drug resistance. There is also a need to conduct frequent drug resistance surveys, to monitor and curtail the development and spread of drug-resistant TB.

scholarly journals Effectiveness of Shorter Treatment Regimen in Multidrug-Resistant Tuberculosis Patients in Pakistan: A Multicenter Retrospective Record Review

2021 ◽  
Author(s):  
Abudl Wahid ◽  
Nafees Ahmad ◽  
Abdul Ghafoor ◽  
Abdullah Latif ◽  
Fahad Saleem ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Success Rate ◽  
Treatment Success ◽  
Multidrug Resistant ◽  
Retrospective Record Review ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Record Review

In Pakistan, the treatment of multidrug-resistant tuberculosis (MDR-TB) with a shorter treatment regimen (STR), that is, 4–6 months of amikacin, moxifloxacin (Mfx), ethionamide, clofazimine (Cfz), pyrazinamide (Z), ethambutol (E), and high-dose isoniazid, followed by 5 months of Mfx, Cfz, Z, and E, was initiated in 2018. However, there is a lack of information about its effectiveness in Pakistani healthcare settings. Therefore, this retrospective record review of MDR-TB patients treated with STR at eight treatment sites in Pakistan aimed to fill this gap. Data were analyzed using SPSS 23. Multivariate binary logistic regression (MVBLR) analysis was conducted to find factors associated with death and treatment failure, and lost to follow-up (LTFU). A P-value < 0.05 was considered statistically significant. Of 912 MDR-TB patients enrolled at the study sites, only 313 (34.3%) eligible patients were treated with STR and included in the current study. Of them, a total of 250 (79.9%) were cured, 12 (3.8%) completed treated, 31 (9.9%) died, 16 (5.1%) were LTFU, and four (1.3%) were declared as treatment failures. The overall treatment success rate was 83.7%. In MVBLR analysis, patients’ age of 41–60 (odds ratio [OR] = 4.9, P-value = 0.020) and > 60 years (OR = 3.6, P-value = 0.035), being underweight (OR = 2.7, P-value = 0.042), and previous TB treatment (OR = 0.4, P-value = 0.042) had statistically significant association with death and treatment failure, whereas patients’ age of > 60 years (OR = 5.4, P-value = 0.040) and previous TB treatment (OR = 0.2, P-value = 0.008) had statistically significant association with LTFU. The treatment success rate of STR was encouraging. However, to further improve the treatment outcomes, special attention should be paid to the patients with identified risk factors.

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