Rozprawy doktorskie: „EXtremely Drug Resistant Tuberculosis”

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Smith, Louise. "Resilience of the partners of long term hospitalised patients with multidrug-resistant (MDR) and extreme drug-resistant (XDR) tuberculosis (TB)". Thesis, Nelson Mandela Metropolitan University, 2013. http://hdl.handle.net/10948/d1020913.

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Patients diagnosed with Multidrug-resistant(MDR) and Extreme drug-resistant (XDR) tuberculosis (TB) have to be hospitalised for a period of six to twelve months, according to the MDR/XDR Policy Guidelines on the treatment of drug-resistant TB – until the patient recovers, and is no longer infectious. There are factors associated with both the patients’ and their partners’ (spouses) resistance to long-term hospitalisation. This has resulted in several acts of violence against the hospital property and members of the health-care team. However, there are a small number of partners who assist the health-care team – by ensuring compliance from the patients and providing their continued support to the patient – despite their own risk of being infected with MDR and XDR TB. This qualitative study was aimed at exploring and describing the resilience factors that have been observed amongst a small number of partners of patients with MDR and XDR TB at an in-patient treatment centre in Port Elizabeth. The research design was exploratory, descriptive and contextual in nature; and the researcher interviewed eight spouses or live-in partners of patientsfor this study, until data saturation was achieved. The data were collected through semi-structured interviews; and the data analysis was conducted, according to the eight steps proposed by Tesch model of data analysis (in Creswell, 1998).Guba’smodel of trustworthiness was used to assess the data collected during the interviews. The findings from this study will inform the health-care team on methods of how the support of the patients’ partners could be mobilised in the holistic treatment plan of MDR and XDR TB patients in an in-patient treatment centre.

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Seddon, James Alexander. "Drug-resistant tuberculosis in children". Thesis, London School of Hygiene and Tropical Medicine (University of London), 2012. http://researchonline.lshtm.ac.uk/4646555/.

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The number of children globally who develop drug-resistant tuberculosis is unclear, in part due to diagnostic challenges and limited resistance testing, and in part because recording and reporting is not comprehensive. Large numbers of children, however, are exposed to drug resistant bacilli each year and it is clear that the very young and those immune-compromised are vulnerable to developing disease. Few studies have looked at the progression from exposure to infection or from infection to disease in the child contacts of adults with drug-resistant tuberculosis. It is uncertain which factors influence this progression and also whether any interventions can prevent it. Finally, few studies have analysed the presentation, treatment and outcome of children with disease. This thesis starts by reviewing what is published regarding drug-resistant tuberculosis in children. This includes systematic reviews of the management of children exposed to drug resistant tuberculosis as well as the management of those with multi drug-resistant tuberculosis disease. It reviews what is known regarding the second-line tuberculosis drugs in children and then clarifies the definitions that are used throughout the rest of the work. The thesis then systematically examines each of the stages from infection to disease with a series of inter-related studies. The first study attempts to quantify the burden of drug resistance in the context that the work is carried out. The following study investigates the risk factors for infection and prevalent disease in children exposed to a multi drug-resistant tuberculosis source case. This is followed by two studies which explore the transmission of drug-resistant bacilli from adults to children. The identification and referral patterns and obstacles to referral for exposed children are examined through operational studies that include qualitative and quantitative components. A descriptive cohort study assesses the toxicity and efficacy of a standardised preventive treatment regimen given to child contacts. The final part of the thesis includes a series of studies to investigate the treatment of drug resistant tuberculosis disease in children and the adverse effects of the second-line medications.

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Patel, Fadheela. "Development of a cost-effective drug sensitivity test for multi-drug resistant and extensively drug-resistant tuberculosis". Thesis, Cape Peninsula University of Technology, 2010. http://hdl.handle.net/20.500.11838/1496.

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Thesis (MTech (Biomedical Technology))--Cape Peninsula University of Technology, 2010
The World Health Organisation estimates that nine million people are infected with tuberculosis (TB) every year of which ninety-five percent live in developing countries. Africa has one of the highest incidences of TB in the world. but few of its countries are equipped to diagnose drug-resistant TB. This study aimed to develop a robust. yet simple and cost-effective assay. which would require minimal sophisticated instrumentation and specialised personnel that would make drug sensitivity screening for multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) accessible to resource-poor high-burden settings. A four-quadrant colorimetric agar plate method was developed which showed good specificity (97.3%-100%) and sensitivity (77.8%-100%) compared to the polymerase chain reaction (PCR) method used as gold standard. Agreement between the methods. using Simple Kappa Coefficients. ranged between very good and excellent. all with high statistical significance (P < 0.0001). The currently used BACTEC MGIT SIREN sensitivity assay coupled with the E-test® strip method. as routinely used in the TB reference laboratory. was compared and showed excellent comparison with the newlydeveloped plate method. for each antibiotic tested. as well as the resultant monoresistant, MDR- or XDR-TB diagnoses. Moreover. the new method was found to be extremely cost-effective. priced at half the cost of a peR assay. These four quadrant plates. with a colorimetric indicator and selected antibiotics. can be considered as an economic altemative or a complimentary method for laboratories wishing to reduce the cost and complexity for TB drug sensitivity testing. Routine diagnostic testing would thus be made more accessible and affordable to laboratories that are not presently diagnosing drug resistant TB. therefore enhancing case detection and treatment in the resource-poor settings hardest hit by this curable disease.

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Krüüner, Annika. "Drug-resistant Mycobacterium tuberculosis in Estonia /". Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-455-0/.

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Dubiniecki, Christine. "Drug resistant tuberculosis in Montreal 1992-1995". Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33751.

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Objective. Since the 1980's the incidence of tuberculosis (TB) in Montreal has remained at 11 cases per 100,000. In order to improve TB prevention and control programs, we sought to identify predictors of tuberculosis drug-resistance and to describe the epidemiology of TB drug resistance on the island of Montreal.
Study design. Retrospective descriptive analysis Study population. All culture proven TB patients reported to the Montreal Regional Health Board aged 0--49 for 1992--1994 and 0--18 years for 1995.
Results. Drug resistant TB was found in 18.3% of culture-proven TB cases. The rate of INH resistance in our study cohort was 10.6%. Two percent of TB cases were found to have MDR-TB. Only 3 TB cases (0.9%) in our study cohort developed acquired drug resistance over the study period. Previous history of TB was associated with a 3.9 times greater risk of drug resistant TB.
Conclusions. Drug resistance is a significant problem in Montreal that continues to hinder TB treatment and control. Previous history of tuberculosis is a strong predictor of drug resistance. In addition, immigration from individual countries was not associated with an increase in the rate of drug resistance. Nonetheless, country-specific drug resistance rates may serve to predict the likelihood of drug resistant TB among the foreign-born in Canada.

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Ford, Christopher Burton. "The Evolution of Drug Resistant Mycobacterium Tuberculosis". Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10596.

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Mycobacterium tuberculosis (Mtb) poses a global health catastrophe that has been compounded by the emergence of highly drug resistant Mtb strains. We used whole genome sequencing (WGS) to directly compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent and early reactivation disease. Based on the distribution of single nucleotide polymorphisms (SNPs) observed, we calculated the mutation rates for these disease states. Our data suggest that during latency, Mtb acquires a similar number of chromosomal mutations as would be expected to emerge in a logarithmically growing culture over the same period of time despite reduced bacterial replication during latent infection. The pattern of polymorphisms suggests that the mutational burden in vivo is due to oxidative DNA damage. We next sought to determine why some strains of Mtb are preferentially associated with high-level drug resistance. We demonstrate that Mtb strains from the East Asian lineage acquire drug resistances in vitro more quickly than Mtb strains from the Euro-American lineage. Their higher drug resistance rate in vitro reflects a higher basal mutation. Moreover, the in vitro mutation rate correlates well with the bacterial mutation rate in humans as determined by whole genome sequencing of clinical isolates. Finally, using an agent-based model, we show that the observed differences in mutation rate predict a significantly higher probability of multi-drug resistance in patients infected with East Asian lineage strains of Mtb. Lastly, we sought to determine the mechanisms Mtb uses to proofread nascently polymerized DNA. Through fluctuation analysis of deletion mutants of two potential $polIII\epsilon$ homologs, we demonstrate that neither is responsible for the maintenance of DNA replication fidelity. To explore the possibility that one of these homologs, Rv3711c, participates in an unknown redundant pathway, we used transposon capture and sequence (TraCS) to identify genes conditionally essential in an Rv3711c deletion mutant. Our analysis suggests that while Rv3711c does not participate in proofreading, it may act in an alternative novel DNA repair pathway. Taken together, our fluctuation analysis and TraCS data suggest that mycobacteria do not use canonical methods of proofreading to maintain genomic fidelity.

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Shean, Karen Penelope. "Extensively drug resistant tuberculosis in South Africa". Master's thesis, University of Cape Town, 2011. http://hdl.handle.net/11427/11620.

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Includes abstract.
Includes bibliographical references (leaves 161-168).
There are few data for treatment-related outcomes in patients with XDR tuberculosis in settings with high HIV prevalence. We reviewed the case records of 227 consecutively diagnosed South African patients with XDR-TB between 2002 and 2008, and analysed the records of another 115 patients, retrospectively, for adverse drug reactions (ADRs). It was found that a significant proportion of XDR-TB patients are HIV unrelated, and prognosis, regardless of HIV status, poor. Nevertheless, survival in HIV infected patients is better than previously reported, and treatment with HAART improves outcomes. The frequency of ADR’s with XDR-TB treatment regimens is high, often severe, and negatively impacts on culture conversion outcomes. These data have implications for the formulation of recommendations for control programmes in resource-poor settings.

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Al-Shammaa, Zaid. "Targeting Drug-Resistant Tuberculosis Using SMART Nanotechnology Approach". University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439310613.

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Stoffels, Karolien. "Contribution to the research on drug resistant Mycobacterium tuberculosis". Doctoral thesis, Universite Libre de Bruxelles, 2014. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209194.

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Tuberculosis (TB) is a potentially fatal contagious disease that can affect almost any part of the body but is mainly an infection of the lungs. It is caused by micro-organisms of the Mycobacterium tuberculosis complex. It is the second greatest killer worldwide due to a single infectious agent, after the Human Immunodeficiency Virus (HIV). Without treatment, fatality is 50% in immune competent persons. TB remains the leading cause of death among HIV positive persons, causing one fifth of the deaths. The World Health Organization estimates that one third of the world population is infected by this micro-organism but only 5 to 10% develop TB disease. Nevertheless, this enormous reservoir leads to around 1.4 millions deaths annually. Standard curative treatment lasts at least 6 months and includes 4 different drugs. Toxicity of the drugs leading to (severe) adverse events and the long duration of the daily administration challenges patient’s compliance. Subinhibitory concentration of the drugs (due to poor adherence) can induce resistance of the mycobacteria to the provided drugs. Unlike most bacteria where resistance is acquired by plasmids, drug resistance of mycobacteria is obtained by genomic mutations. “Multi drug-resistant tuberculosis (MDR-TB)” is strictly defined as TB resistant to specifically isoniazid and rifampicin, the two main first line drugs. “Extensively drug resistance (XDR)” is defined as MDR-TB with additional resistance to any of the fluoroquinolones (such as ofloxacin or moxifloxacin) and to at least one of three injectable second-line drugs (amikacin, capreomycin or kanamycin). The increase of MDR-TB represents an enormous challenge to Public Health globally. This research examined different aspects of tuberculosis resistance performed in the Belgian National Reference Center, a clinical laboratory setting.

First of all, a profound analysis of the MDR-TB situation in Belgium was conducted. It is the first retrospective population-based survey of MDR-TB in Belgium, covering a 15-year period (1994-2008). It comprises 174 patients representing more than 80% of the culture positive MDR-TB patients reported to the Belgian register, thus this study is considered of national relevance. It includes bacteriological and molecular data on the isolates as well as clinical aspects of the patients and treatment results. Considering only the patient’s first MDR-TB isolate, an increase over time was observed in the number of isolates resistant to a second-line drug as well as the total number of drugs each isolate was resistant to. XDR-TB was detected since 2002 and panresistant TB (resistant to every available antituberculosis drug) since 2009. Overall, a successful treatment outcome was obtained for 67.8% of the MDR-TB cases. Drug susceptibility testing (DST) of Mycobacterium tuberculosis to first line drugs (isoniazid, rifampicin, ethambutol and pyrazinamide) in liquid culture medium has a turn around time of at least two weeks, after identification of the positive culture (obtained after 2 to 4 weeks) from the patient’s clinical isolate. In order to provide the clinician with valuable information about the isolated mycobacteria leading to patient adapted therapy before bacteriological DST results are available, resistance is predicted by detection of mutations in certain genes of the mycobacteria. It is common practice for rifampicin (rpoB gene) and isoniazid (katG gene and/or inhA promoter region). In this MDR-TB collection, rifampicin resistant related mutations were found in 97.1% (168/173) of the clinical isolates and isoniazid resistant related mutations in 94.1% (160/170). The pncA, embB and gyrA genes have been sequenced to identify possible mutations because of their possible involvement with resistance to pyrazinamide, ethambutol and the fluoroquinolones respectively. However, little is known about the resistance prediction value of the mutations in these genes.

The study is also the first study on the molecular epidemiology of MDR-TB in the country. DNA fingerprinting showed a large diversity of strains (67% of the patients were infected by a strain with a unique pattern) and further epidemiological examination revealed limited local transmission of MDR-TB in Belgium.

The second part investigated the pncA gene and its association with pyrazinamide resistance in MDR-TB isolates from Belgium and in vitro cultured spontaneous mutants. The genetic analysis showed that 98.3% (59/60) of the Belgian clinical MDR pyrazinamide resistant (PZAR) isolates present a mutation in the pncA gene. We found 1.7% (1/60) of the PZAR MDR-isolates encoding wild type pncA and flank. A total (PZAR and PZAS) of 41 different amino acid changes, 3 protein truncations and 5 frameshifts were observed including eight novel mutations: 8Asp>Ala, 13Phe>Leu, 64Tyr>Ser, 107Glu>stop, 143Ala>Pro, 172Leu>Arg and frameshifts starting in codon 55 and 82. Analysis of all observed mutations (i.e. in clinical isolates as well as spontaneous mutants) revealed that they are not always associated with drug resistance and that they are not scattered randomly throughout the gene, but occur rather at preferential sites such as in codons with amino acids associated with either iron or substrate binding and catalytic active sites. The frequency of in vitro mutagenesis to pyrazinamide at pH 6.0 was determined and found to be relatively high at 10-5 CFU/ml.

Finally, the in vitro activity of tobramycin and clarithromycin (with unclear efficacy against M. tuberculosis) was evaluated on 25 M. tuberculosis clinical isolates with various resistance profiles. The effect of the drugs administered together was examined for possible synergistic effect. The median minimum inhibitory concentration (MIC) of 8 µg/ml obtained for both drugs in this study is rather high but are beyond the concentrations obtained in lung tissues. This suggests that both drugs should be investigated further as potential adjuncts to the treatment of resistant TB when other alternatives have failed; in particularly through new drug delivery systems such as the Dry Power Inhaler which allows local drug deposition with high drug concentrations in the lungs but low toxicity due to limited systemic absorption. In addition, for 36% of the tested isolates a decrease of the MIC of clarithromycin by a single or twofold dilution was observed in the presence of a subinhibitory concentration of tobramycin and no antagonistic effect was seen for the remaining isolates.

This research illustrates different (laboratory) aspects in the fight against drug resistant TB, all using the Belgian TB collection: characterisation of the Belgian MDR-TB situation on bacteriological, molecular and epidemiological level; profound analysis of genomic mutations and their possible association with drug resistance; and investigation of synergistic activity of drugs with low efficacy against M. tuberculosis.

Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished

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Kwong, Tsz-ching, i 鄺芷晴. "The role of molecular diagnosis of drug resistant tuberculosis". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2015. http://hdl.handle.net/10722/208588.

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Emerging multidrug-resistant tuberculosis (MDR-TB) is one of the most urgent global public health issues. Recent advances in molecular techniques should enable the development of different rapid detection tests for drug-resistant TB. Large-scale comparative studies on the diagnostic accuracy and turn-around-time (TAT) of these novel assays may promote their smooth implementation as routine tests for TB in diagnostic laboratories. In a pilot evaluation of 30 clinical isolates and 202 sputum specimens, diagnostic performance of a novel in-house assay for MTB identification (IS6110 qPCR) was compared to a commercial COBAS TaqMan MTB test (Roche Diagnostics). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of IS6110 qPCR were 100%, 94.6%, 85.2% and 100%, respectively, compared to 94.7%, 100%, 100% and 98.6% for COBAS TaqMan MTB. Large-scale validation using 2,350 sputum specimens revealed the optimal cut-off crossing point (Cp) value of IS6110 qPCR was 29.61 with 97.3% sensitivity and 98.3% specificity determined by receiver operating characteristics (ROC) curve analysis. The median TAT for IS6110 qPCR and COBAS TaqMan MTB test to the reporting of results was 0.9 and 1.2 days, respectively. Among the IS6110 qPCR-positive specimens in the large-scale validation, 287 samples were tested in-house by katG MAS-PCR and rpoB PCR sequencing assays and 159 samples were tested by GenoType® MTBDRplus assay (Hain LifeScience). The sensitivity and specificity of katG MAS-PCR for isoniazid (INH) resistance detection were 71.4% and 99.5%, respectively. The sensitivity and specificity of rpoB PCR sequencing for rifampicin (RIF) resistance detection were 100% and 99.6%, respectively. Commercial GenoType® MTBDRplus assay reached 100% sensitivity for both INH and RIF resistance detection at a specificity of 99.3% and 100%, respectively. The median TAT for the in-house assays and GenoType® MTBDRplus assay to the reporting of the results was 4.7 and 1.4 days, respectively. The findings from this study provide different implementation strategies for diagnostic test combinations. The most cost-effective drug-resistant TB diagnosis cascade was IS6110 qPCR followed by GenoType® MTBDRplus assay. The TAT for results is 2.3 days at a cost of US$49.7. Despite an additional cost of US$24.6, COBAS TaqMan MTB test should replace IS6110 qPCR in populations with high prevalence of IS6110-negative strains. The in-house katG MAS-PCR and rpoB PCR sequencing assays should be used in developing countries instead of the expensive GenoType® MTBDRplus assay. Subsequently, accurate diagnosis of drug-resistant tuberculosis can be achieved in 4.5 days with a reasonable reagent cost of US$9.3. In conclusion, excellent diagnostic accuracy and shorter TAT of the molecular diagnostic cascade for drug-resistant TB, in particular IS6110 qPCR, can serve to guide physicians in the prompt choice of chemotherapy. This leads to timely delivery of anti-TB treatments to patients and holds the promise of easing the MDR-TB burden.
published_or_final_version
Microbiology
Master
Master of Philosophy

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Hayes, Cindy. "Prevalence and resistance gene mutations of multi-drug resistant and extensively drug resistant mycobacterium tuberculosis in the Eastern Cape". Thesis, Nelson Mandela Metropolitan University, 2014. http://hdl.handle.net/10948/d1020374.

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The emergence and spread of multi-drug resistant (MDR-TB) and extensively drugresistant tuberculosis (XDR-TB) are a major medical and public problem threatening the global health. The objectives of this study were to (i) determine the prevalence of MDR-TB and XDR-TB in the Eastern Cape; (ii) analyze patterns of gene mutations in MDR-TB and (iii) identify gene mutations associated with resistance to second line injectable drugs in XDR-TB isolates. A total of 1520 routine sputum specimens sequentially received within a period of 12 months i.e. February 2012 to February 2013 from all MDR-TB and XDR-TB patients treated by Hospitals and clinics in the Eastern Cape were included in this study, of which 1004 had interpretable results. Samples were analyzed with the Genotype MTBDRplus VER 2.0 assay kit (Hain Lifescience) for detection of resistance to Rifampicin and Isoniazid while solid and liquid culture drug susceptibility tests were used for ethambutol, streptomycin, ethionamide, ofloxacin, capreomycin and amikacin. PCR and sequence analysis of short regions of target genes gyrA, (encode subunit of DNA topoisomerase gyrase), rrs (16S rRNA) and tlyA (encodes a 2’-O-methyltransferase) were performed on 20 XDR-TB isolates. MTBDRplus kit results and drug susceptibility tests identified 462 MDR-TB, 284 pre-XDR and 258 XDR-TB isolates from 267 clinics and 25 hospitals in the Eastern Cape. There was a high frequency of resistance to streptomycin, ethionamide, amikacin, ofloxacin and capreomycin. Mutation patterns indicated differences between the health districts as well as differences between the facilities within the health districts. The most common mutation patterns observed were: (i) ΔWT3, ΔWT4, MUT1 [D516V+del515] (rpoB), ΔWT, MUT1 [S315T1] (katG), ΔWT1 [C15T] (inhA) [39 MDR, 204 XDR-TB and 214 pre XDR-TB isolates], (ii) ΔWT8, MUT3 [L533P+S531L] (rpoB), ΔWT, MUT1 [S315T1] [145 MDR, 18 pre-XDR and 3 XDR-TB solates] and (iii) ΔWT3, WT4 [D516Y+del515] (rpoB), ΔWT, MUT1 [S315T1] (katG) [75 MDR, 1 pre-XDR and 7 XDR-TB isolates]. Mutations in inhA promoter regions were strongly associated with XDR-TB isolates. Two thirds (66.6 percent (669/1004) of the isolates had inhA mutations present with 25.4 percent (170/669) found among the MDR isolates, 39.2 percent (262/669) among the pre-XDR isolates and 35.4 percent (237/669) among the XDR-TB isolates, which implies that these resistant isolates are being spread by transmission within the community and circulating in the province. There was good correlation between XDR-TB drug susceptibility test results and sequence analyses of the gyrA and rrs genes. The majority of XDR-TB isolates contained mutations at positions C269T (6/20) and 1401G (18/20) in gyrA and rrs genes respectively. Sequence analysis of short regions of gyrA and rrs genes may be useful for detection of fluoroquinolone and amikacin/ kanamycin resistance in XDR-TB isolates but the tlyA gene is not a sensitive genetic marker for capreomycin resistance. This study highlighted the urgent need for the development of rapid diagnostics for XDR-TB and raised serious concerns regarding ineffective patientmanagement resulting in ongoing transmission of extremely resistant strains of XDRTB in the Eastern Cape suggesting that the Eastern Cape could be fast becoming the epicenter for the development of Totally Drug-resistant Tuberculosis (TDR-TB) in South Africa.

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Schaaf, Hendrik Simon. "The epidemiology and management of drug-resistant tuberculosis in childhood". Thesis, Stellenbosch : Stellenbosch University, 2002. http://hdl.handle.net/10019.1/53109.

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Thesis (MD)--University of Stellenbosch, 2002.
ENGLISH ABSTRACT: Resistance to antituberculosis agents became evident soon after antituberculosis treatment was introduced for the first time. Combined drug therapy seemed to resolve this problem. Animal experimental studies, which showed that isoniazid (INH)-resistant strains of Mycobacterium tuberculosis were less infectious and pathogenic than drugsusceptible strains, gave further reassurance that drug resistance was not a major issue. Transmission of INH- and multiple-drug-resistant strains did, however, occur. Studies in children, who develop mainly primary drug resistant tuberculosis (TB), showed that drug resistance in adults was followed by a similar rise in drug-resistant (TB) in children, and that tuberculous infection rates in childhood contacts of INHresistant and drug-susceptible adult TB cases were the same. It was however, only after the significant rise in the incidence of TB and large outbreaks of multidrug-resistant (MDR) TB cases in developed countries (mainly because of the human immunodeficiency virus epidemic) in the early nineties that sufficient attention was again focussed on the problem of drug-resistant TB. Drugresistant tuberculosis, and more in particular MDR TB, posed a serious threat to global TB control programmes. Despite this renewed interest, childhood drug-resistant TB remained neglected. The incidence of drug-resistant TB among children, which could give a good indication of currently circulating strains in a community, is hardly known. The management of childhood contacts of adults with infectious MDR TB or children with MDR TB has also not been studied prospectively. All confirmed childhood TB cases from a specific geographic drainage area over a 3.5-year period were prospectively included in a drug resistance surveillance study. The incidence of drug resistance in children was comparable to the incidence of initial (primary plus undisclosed previous treatment) drug resistance documented in adults in the same area. The findings show that the incidence of drug-resistant TB in children in the Western Cape province is low, and probably reflects the level of primary drug resistance amongst organisms currently circulating in this community. The short- and long-term outcome of children <5 years of age in contact with infectious adult MDR TB cases was determined by prospective follow-up for 30 months. The initial evaluation showed an infection rate significantly higher in MDR TB contacts compared with contacts of drug susceptible cases, but the disease rate was lower. On follow-up, many more children became infected or developed disease. The finding that 90% of those who developed disease did so within the first 12 months, indicates that follow-up beyond 12 months is probably not cost-effective in resource poor countries. The results demonstrate that MDR TB is not less infectious than drug susceptible TB. Despite the fact that some children received chemoprophylaxis, 24% of the children eventually developed disease. This is not different from the expected prevalence of disease in childhood contacts <5 years of age of infectious drug-susceptible adult pulmonary TB cases. Restriction fragment length polymorphism analysis confirmed transmission from an adult source case to a child contact in 5 of 6 adult-child pairs in whom both isolates were available. If therefore an isolate of M tuberculosis for susceptibility testing cannot be obtained from a child in close contact with an infectious MDR TB case, the child should therefore be treated according to the drug susceptibility pattern of the source case's strain. Treatment of children with confirmed and probable MDR TB included 2 or 3 drugs to which the adult source case's isolate was susceptible in addition to pyrazinamide and high-dose INH. Duration of treatment ranged from 6 to 12 months depending on the severity of the disease. INH was included in the treatment regimen because low-level resistance to INH was present in about half the cases of primary INH resistance. The pharmacokinetics of INH in children confirmed that an adequate concentration and exposure time could be achieved for this purpose. Ethionamide often caused gastrointestinal adverse events, but these could be overcome in most cases by temporary dose adjustments. The fluoroquinolones, which are not generally recommended for use in children, possibly caused arthralgia in 1 of the17 children treated for ~6 months. This is in accordance with previous reports of the safety of these drugs in children for short- and medium-term treatment. TB disease occurred significantly less often in children who received appropriate chemoprophylaxis (according to the drug susceptibility pattern of the adult source case's isolate). Although this was not a randomised controlled trial, the group that received chemoprophylaxis was at higher risk for developing disease. This implies that prevention of TB in MDR contacts is possible. A prospective, randomised controlled study is necessary to evaluate the best drug combinations and the optimal duration of such chemoprophylactic regimens.
AFRIKAANSE OPSOMMING: Middelweerstandigheid het na vore gekom kort nadat antituberkulose behandeling vir die eerste keer in gebruik geneem is. Die gekombineerde gebruik van middels het klaarblyklik die probleem oorkom. Diere eksperimente wat getoon het dat isoniasied (INH)-weerstandige stamme van Mycobacterium tuberculosis minder infektief en patogenies IS as vatbare stamme, het verdere gerustelling gegee dat middelweerstandigheid nie 'n groot probleem is nie. Die oordrag van INH- en multi-middelweerstandige stamme het egter wel plaasgevind. Studies in kinders, wat hoofsaaklik primêre middelweerstandige tuberkulose (TB) ontwikkel, het getoon dat middelweerstandigheid in volwassenes gevolg is deur 'n soortgelyke toename in middelweerstandige TB in kinders en dat die voorkoms van tuberkuleuse infeksie in kinderkontakte van INH-weerstandige en middelvatbare volwasse TB gevalle dieselfde is. Dis egter eers toe daar 'n beduidende toename in die insidensie van TB en groot uitbrake van multimiddelweerstandige (MDR) TB gevalle in die ontwikkelde lande (hoofsaaklik as gevolg van die menslike immuungebrek virus epidemie) in die vroeë negentigerjare was dat daar opnuut aandag aan die probleem van weerstandige TB geskenk is. Middelweerstandige TB, en in besonder MDR TB, hou 'n ernstige bedreiging vir globale TB beheerprogramme in. Tenspyte van die nuwe belangstelling in middelweerstandige TB is die probleem in kinders steeds afgeskeep. Die insidensie van weerstandige TB in kinders is onbekend alhoewel dit 'n goeie weergawe van die huidig sirkuIerende stamme in 'n gemeenskap sou gee. Die hantering van kinderkontakte van volwassenes met infektiewe MDR TB of kinders met MDR TB is ook nog nie prospektiefbestudeer nie. Alle bevestigde kinder-TB gevalle van 'n spesifieke geografiese gebied is oor 'n 3.5 jaar tydperk prospektief in 'n middelweerstandige waarnemingstudie ingesluit. Die insidensie van middelweerstandigheid in kinders was vergelykbaar met die insidensie van inisiële (primêre weerstandigheid plus onbekende vonge behandeling) middelweerstandigheid in volwassenes van dieselfde gebied. Die bevindinge toon dat die insidensie van middelweerstandige TB in kinders in die Weskaap provinsie laag is. Dit weerspieël waarskynlik die vlak van primêre middelweerstandigheid in organismes wat tans in hierdie gemeenskap sirkuleer. Die kort- en langtermyn uitkoms van kinders <5 jaar oud wat in kontak met infektiewe volwasse MDR TB gevalle was, is prospektief tydens 'n 30-maande opvolg bepaal. Die aanvanklike evaluasie het 'n beduidend hoër infeksiekoers in die MDR TB kontakte in vergelyking met kontakte van middelvatbare gevalle getoon, maar die siektekoers was laer. Tydens die opvolgperiode het baie meer kinders infeksie of siekte ontwikkel. Aangesien 90% van dié wat siekte ontwikkel het, dit gekry het binne die eerste 12 maande, is opvolg ná 12 maande waarskynlik nie koste-effektief in hulpbronbeperkte lande nie. Die bevindinge toon dat MDR TB nie minder infektief is as middelvatbare TB nie. Tenspyte daarvan dat sommige kinders chemoprofilakse ontvang het, het 24% van die kinders uiteindelik siekte ontwikkel. Dit verskil nie van die verwagte siekte-insidensie van kinderkontakte <5 jaar oud wat in kontak met infektiewe volwasse middelvatbare pulmonale TB was nie. Restriksie fragment lengte polimorfisme analise het oordrag van volwasse brongeval na kinderkontak in 5 uit 6 volwasse-kind pare, van wie beide isolate beskikbaar was, bevestig. Indien daar dus nie 'n isolaat van M. tuberculosis vir vatbaarheidstoetse van 'n kind met nabye kontak met 'n infektiewe MDR TB geval beskikbaar is nie, behoort die kind volgens die middelvatbaarheidspatroon van die brongeval se stam behandel te word. Behandeling van kinders met bevestigde of waarskynlike MDR TB het 2 tot 3 middels waarvoor die volwasse brongeval se isolaat vatbaar was, ingesluit, tesame met pirasinamied en hoë-dosis INH. Die duur van behandeling het gewissel van 6 tot 12 maande op grond van die omvang van die siekte. INH is in die behandeling ingesluit omdat dit getoon is dat ongeveer die helfte van die gevalle met primêre INHweerstandigheid lae-vlak weerstandigheid het. Die farmakokinetika van INH in kinders het bevestig dat genoegsame vlakke en blootstellingstyd aan INH vir hierdie doel bereik kan word. Etionamied het dikwels gastrointestinale newe-effekte veroorsaak, maar dit kon in die meeste gevalle oorkom word. Die fluorokwinolone, wat nie oor die algemeen in kinders aanbeveel word nie, het moontlik artralgie veroorsaak in 1 uit 17 kinders wat vir ~6 maande behandel is, wat vorige verslae oor die veiligheid van hierdie middels in kort- en medium-termyn behandeling bevestig. TB-siekte het beduidend minder dikwels voorgekom in kinders wat toepaslike chemoprofilakse (volgens die middelvatbaarheidspatroon van die volwasse brongeval se isolaat) ontvang het. Alhoewel dit nie 'n ewekansig gekontroleerde studie was nie, het die groep wat chemoprofilakse ontvang het die hoogste risiko vir die ontwikkeling van siekte gehad. Dit dui daarop dat voorkoming van TB in MDR TB kontakte moonlik is. 'n Prospektiewe, ewekansig gekontrolleerde studie is nodig om die beste middel kombinasies en die optimale duur van so 'n chemoprofilaktiese behandeling te bepaal.

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Bahcall, Orli Gilat. "The emergence, transmission, and control of drug resistant tuberculosis epidemics". Thesis, Imperial College London, 2007. http://hdl.handle.net/10044/1/11427.

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Hoang, Thi Thanh Thuy. "An analysis of multi drug resistant tuberculosis control in Vietnam". Thesis, Open University, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.700287.

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Multi-drug resistant tuberculosis is a major global health problem. Viet Nam is 14th among 27 MDR-TB high burden countries with an estimated about 5,100 MDR-TB cases among notified TB cases per year. Management of MDR-TB in Viet Nam is one of the main objectives of the TB control programme. This thesis provides an understanding of the current situation of MDRlXDR-TB in Vietnam and its control policies focusing on case finding strategy, targeting groups for MDR-TB screening. MDR-TB contacts, one of the high risk groups recommended by the WHO is a focus of this thesis. The thesis presents screening practices of household contacts of TB patients, feasibility of TB contact investigations, and to identify challenges and solutions for a successful implementation of an efficient contact investigation among MDR -TB patients in Viet Nam. Since 2009, the programmatic management of drug resistant tuberculosis (PMDT) was piloted in Viet Nam following the development of 2009 country MDR TB guideline. A year after the WHO updated guideline was disseminated, the country revised its guideline and SOP to be in line with WHO's recommendations and contextualized to local capacity and resources. The PMDT has been rolled out and scaled up in the country. However, lack of resources, limited communication on policy changes to lower level, unable to provide screening to all risk groups, inadequate capacity to perform diagnosis of mono and poly resistant TB and second- line DST have posed significant challenges for the NTP to implement their policy. This study found that only about 30 % MDR TB cases was detected. through the PMDT system. The possible reasons we identified were: (1) delay in fully rolling out PMDT policies and limited capacity of the system, mostly due to inadequate resources, (2) operational factors, . . and (3) neglecting high risk groups during MDR- TB screening, particularly close contacts of MDR TB patients. Noteworthy, the NTP strategy relies on "passive case finding" while the proportion of household contacts of smear-positive tuberculosis patients screened for TB under the current passive screening approach of the Vietnam National TB program is very low compared with prevalence of TB among contacts in high burden countries, particularly for contacts under 5 years of age. Although screening of close contacts of MDR-TB patients is recommended by the NTP of Viet Nam, this is generally not done.

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15

Minn, Minn Soe. "Drug resistant tuberculosis in patients with AIDS at Bamrasnaradura hospital /". Abstract, 1999. http://mulinet3.li.mahidol.ac.th/thesis/2542/42E-MinnMinnSoe.pdf.

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Oo, Aung Myat Punnee Pitisuttithum. "Drug resistant tuberculosis in patients with AIDS at Bamrasnaradura hospital /". Abstract, 1999. http://mulinet3.li.mahidol.ac.th/thesis/2542/42E-AungMyatOO.pdf.

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17

Rey, Jurado Emma. "Virulence of drug-resistant Mycobacterium tuberculosis and activity of drug combinations against drug-resistant and drug-susceptible isolates in ex-vivo and in vitro models". Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/107758.

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Tuberculosis (TB) remains a global threat worldwide with nearly nine million incident cases of TB. The emergence of M. tuberculosis resistance to antituberculous drugs has led to the need for careful TB surveillance and control. Further knowledge of drug-resistant M. tuberculosis plays an important role in avoiding TB transmission as well as designing more efficient schedules of treatment. The objectives were: 1) to analyse of clinical isolates of Mycobacterium tuberculosis resistant to antituberculous drugs to penetrate and grow within murine macrophages compared with drug-susceptible isolates; 2) to determine the in vitro synergistic activity of the following combinations against clinical isolates of M. tuberculosis resistant to isoniazid (INH) compared with drug-susceptible isolates: a) INH-rifampicin (RIF)-ethambutol (EMB), b) ofloxacin (OFL)-RIF-EMB; 3) to determine the in vitro synergistic activity of the following combinations against clinical isolates of multi-drug resistant M. tuberculosis compared with drug-susceptible isolates: a) levofloxacin (LEV)-linezolid(LNZ)-amikacin(AMK), b) LEV-LNZ-EMB, c) LEV-AMK-EMB; 4) to determine the antimicrobial and the synergistic activity of drug combinations of objective 3 against multidrug-resistant (MDR) and drug-susceptible clinical isolates of M. tuberculosis in a cell culture model of human macrophages from the THP-1 cell line. In the study of murine macrophages, we found that INH-resistant and MDR isolates with mutations in the katG gene showed decreased multiplication inside murine macrophages, suggesting a lower fitness of M. tuberculosis with these resistance patterns. With the results of this thesis, the reliability of the method of the three-drug chequerboard assay has been showed. The combination including INH, RIF and EMB could be efficient to treat TB cases with low level INH resistance (MICs ≤ 0.8µg/ml) due to the synergistic effect of the combination showed. The combination including OFL, RIF and EMB shows better efficacy than that of INH, RIF and EMB, being of potential use in drug-susceptible and in INH-resistant isolates. The combinations including second-choice drugs (LEV-AMK-EMB; LEV-AMK-LNZ; LEV-EMB-LNZ) are equally effective to the combination of INH, RIF and EMB with the checkerboard assay. On the other hand, these drug combinations including second-choice drugs tested against M. tuberculosis-infected macrophages show antimicrobial activity, with the combinations including LNZ and LEV displaying an antagonistic effect.
La Tuberculosi (TB) continua sent una de les malalties més important en salut pública arreu del món. La preocupació sobre el control de la TB ha augmentat a conseqüència de l’aparició de soques resistents als fàrmacs disponibles actualment. Un millor coneixement de les soques de M. tuberculosis resistents a fàrmacs és clau per evitar la transmissió així com per dissenyar pautes de tractament més efectives contra la TB. Els objectius d’aquesta tesi van ser: 1) analitzar l’habilitat de soques clíniques de M. tuberculosis resistents a fàrmacs de penetrar i créixer dintre dels macròfags murins comparat amb soques sensibles; 2) determinar l’activitat sinèrgica in vitro de les següents combinacions davant de soques clíniques de M. tuberculosis resistents a isoniazida (INH) comparant amb soques sensibles: a) INH-rifampicina(RIF)–etambutol (EMB) i b) ofloxacin (OFL)–RIF-EMB; 3) determinar l’activitat sinèrgica in vitro de les següents combinacions davant de soques clíniques de M. tuberculosis multiresistents comparant amb soques sensibles; a) levofloxacin(LEV)-linezolid(LNZ)-amikacin(AMK), b)LEV-LNZ-EMB, c)LEV-AMK-EMB; 4) determinar l’activitat microbiana i sinèrgica de les combinacions descrites al objectiu 3 davant de soques clíniques de M. tuberculosis multiresistents i sensibles en un model de macròfags humans de la línia cel•lular THP-1. En l’estudi en macròfags murins, es va trobar que les soques resistents a INH i les multiresistents amb mutació en el gen katG van mostrar una multiplicació en l’interior dels macròfags disminuïda, suggerint una fitness disminuïda de les soques amb aquests patrons de resistència de M. tuberculosis. En aquesta tesi s’ha vist com l’adaptació del mètode de tauler d’escacs, és una tècnica fiable per l’estudi in vitro de combinacions de tres fàrmacs. La combinació incloent INH, RIF i EMB podria ser eficaç per tractar casos de TB amb una baixa resistència a INH (CIMs ≤ 0.8µg/ml) degut al efecte sinergístic de la combinació mostrat. Les combinacions de INH-RIF-EMB i la de OFL-EMB-RIF poden ser útils pel tractament tot i que la combinació que conté OFL presenta una eficàcia major, sent d’us potencial per tractar casos de soques resistents com de sensibles. In vitro, les combinacions que inclouen fàrmacs de segona línia (LEV-AMK-EMB; LEV-AMK-LNZ; LEV-EMB-LNZ) són igual de eficaces que la combinació de INH-RIF-EMB utilitzant el mètode de tauler d’escacs. En canvi, aquestes combinacions que inclouen fàrmacs de segona línia davant de macròfags humans THP-1 infectats amb M. tuberculosis mostren una activitat antimicrobiana, i un efecte antagonista de les combinacions que inclouen LEV i LNZ.

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Kosmas, Petrus Ndiiluka. "Extensively drug-resistant tuberculosis in Africa: prevalence and factors associated: a systematic review and meta-analysis". Master's thesis, Faculty of Health Sciences, 2019. http://hdl.handle.net/11427/31604.

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Background: There is a dearth of information regarding prevalence of extensively drugresistant tuberculosis (XDR-TB) in Africa. Although countries in Africa conduct national tuberculosis surveys on a regular basis, this information has not been systematically reviewed to ascertain the overall prevalence of XDR-TB in Africa. Methods: The study aimed to perform a systematic review and meta-analysis of the prevalence and factors associated with prevalence of pulmonary XDR-TB among adults in Africa. Eligible studies, published between 2006 and 2018, were sourced from various electronic databases including PubMed, Scopus, and Web of Science. Meta-analysis was performed using STATA (version 14.2) statistical software. The protocol of this review was registered with PROSPERO, reg No CRD42018117037. Result: A total of 6242 records were retrieved. Forty-eight studies were screened for eligibility and seven, which varied in terms of country setting and study design, were included. The prevalence of XDR-TB is 4% (95%CI 2-7) among participants tested for second-line anti-TB drug resistance, and 3% (95%1-6) among participants with drug resistant TB. The prevalence of XDR-TB was 7% (95%CI 1-18) among participants with MDR-TB. A few studies reported on the factors associated with the prevalence of XDR-TB. Discussion: The reported prevalence of XDR-TB among participants tested for second-line anti-TB drug resistance is low compared to WHO estimates. The systematic review underscores a dearth of studies depicting the reality regarding the prevalence of XDR-TB in Africa. Policymakers and stakeholders interested in drug-resistant TB should apply prudence when considering XDR-TB prevalence reported for Africa.

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19

Van, Rie Annelies. "Disease dynamics in patients with drug-resistant tuberculosis residing in a high incidence community". Thesis, Stellenbosch : Stellenbosch University, 2000. http://hdl.handle.net/10019.1/51732.

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Thesis (PhD)--Stellenbosch University, 2000.
ENGLISH ABSTRACT: Drug-resistant tuberculosis poses a threat to global tuberculosis control by the WHO DOTS strategy. Studies in the United States and Europe have shown (i) that drug-resistant tuberculosis is present in every country; (ii) that, by contrast to previous dogma, drug-resistant bacilli are virulent and can be transmitted, especially in institutional settings and to immunocompromised patients; and (iii) that the majority of cases arise by acquisition of drug resistance due to errors in the management of TB cases. (iv) Furthermore, it has been shown that the extremely high case fatality rates of the 1980s and early 1990s can be reduced by individualized, but costly treatment. However, the majority of drug-resistant TB cases reside in the developing world. Data on disease epidemics in less developed parts of the world are scarce. The aim of this thesis was to study the disease dynamics of drug-resistant TB in a developing country where TB is endemic. All cases of drug-resistant TB during a 5-year period in two communities with poor socioeconomic living conditions were included for this observational study. Three different methods were used: restriction fragment length polymorphism (RFLP), mutation detection analysis by dot-blot hybridisation technique and a Geographic Information System. Results of RFLP analysis and mutation detection analysis showed that community outbreaks of drug-resistant Mycobacterium tuberculosis strains occur, even without the involvement of immunocomprimised patients. Infection with a drug-resistant strain occurred in new patients (primary drug resistance) as well as in patients treated before (exogenous reinfection). Exogenous reinfection was also shown to be an important mechanism of recurrence after previous cure for drug-sensitive TB. Transmission of drug-resistant strains occurred more frequent in areas with lower socioeconomic living conditions. The relative contribution of transmission differed substantially between the group of multi drugresistant (two thirds of cases) and single-drug-resistant (no cases) cases, which probably reflects the prolonged infectiousness of multi drug-resistant cases. To stop the growing epidemic of multi drug-resistant TB, prevention of acquisition as well as transmission of drug-resistant tuberculosis will be required. This will only be possible in areas where a DOTS strategy is well functioning and with a modification of central elements of the standard DOTS mechanism: a "DOTS-plus" strategy. Early and accurate diagnosis of drug resistance is essential for effective management. Diagnosis based on two direct smear tests might have to be replaced by routine drugsusceptibility tests at diagnosis. Because the routine performance of phenotypic drugsusceptibility tests was inferior to the performance of genotypic tests, the development of an affordable commercial kit testing a limited number of mutations conferring resistance could be of great value in the global fight against multidrugresistant TB. Because of the importance of early diagnosis, selective active contact tracing for multidrug-resistant cases, additional to the routine passive contact tracing, could prove to be cost-effective. Individualized treatment regimens are effective in reducing the failure rate, mortality and probably transmission of multidrug-resistant TB. Multidrug-resistant tuberculosis is a problem confronting the efforts for global tuberculosis control. Efficient strategies to turn the tide exist, but international political commitment and financial support will be essential.
AFRIKAANSE OPSOMMING: Middel weerstandige tuberkulose hou 'n bedreiging in vir globale tuberkulose kontrole deur die WGO DOTS strategie. Studies in die Verenigde State en Europa het getoon (i) dat middel weerstandige tuberkulose in alle lande voorkom; (ii) dat, in teenstelling met vorige dogma, middel weerstandige bakterieë virulent is en oorgedra kan word, veral in inrigtings en aan immuun-onderdrukte pasiënte; en (iii) dat die meeste gevalle ontstaan deur die verwerwing van middel weerstandigheid a.g.v. die foutiewe hantering van tuberkulose gevalle. (iv) Bykomend is getoon dat die ontsettende hoë mortaliteit syfers van die 1980s verlaag kan word deur geindividualiseerde, maar duur behandeling. Die meeste middel weerstandige tuberkulose gevalle woon egter in die ontwikkelende wêreld. Data oor siekte epidemies in minder ontwikkelde dele van die wêreld is skaars. Die doel van hierdie tesis was om die siekte dinamiek van middel weerstandige tuberkulose te bestudeer in 'n ontwikkelende land waar tuberkulose endemies is. Alle gevalle van middel weerstandige tuberkulose gedurende 'n 5-jaar periode in twee lae sosio-ekonomiese gemeenskappe, is in hierdie studie ingesluit. Drie verskillende metodes is gebruik: restriksie fragment lengte polimorfisme (RFLP), mutasie analise deur dot-blot hibridisasie en 'n Geografiese Inligting Stelsel. Resultate van die RFLP analise het getoon dat uitbrake van middel weerstandige Mycobacterium tuberculosis stamme in die gemeenskap voorkom, selfs sonder die aantasting van immuun-onderdrukte pasiënte. Infeksie met middel weerstandige stamme het voorgekom in nuwe pasiënte (primêre middel weerstandigheid) en ook in pasiënte wat reeds voorheen behandel is (eksogene herinfeksie ). Daar is ook gevind dat eksogene herinfeksie 'n belangrike meganisme was van herhaalde tuberkulose na vorige genesing van middel sensitiewe tuberkulose. Die oordrag van middel weerstandige stamme het meer dikwels voorgekom in areas met laer sosioekonomiese omstandighede. Die relatiewe bydrae van oordrag het merkwaardig verskil tussen multi-middel weerstandigheid (twee derdes van gevalle) en enkelmiddel weerstandigheid (geen gevalle). Dit weerspieël waarskynlik die verlengde periode van infektiwiteit van die multi-middel weerstandige gevalle. Die bekamping van die groeiende epidemie van multi-middel weerstandige tuberkulose, vereis die voorkoming van verworwe sowel as oorgedraagde middel weerstandige tuberkulose. Dit sal slegs moontlik wees in areas waar 'n DOTS strategie reeds goed funksioneer en met 'n aanpassing van die sentrale elemente van die roetine DOTS meganisme: 'n "DOTS-plus" strategie. Vroeë en akkurate diagnose van middel weerstandigheid is essensieël vir effektiewe hantering. Diagnose gebaseer op twee direkte sputum smeer toetse mag moontlik vervang moet word deur roetine middel sensitiwiteit bepalings by diagnose. Die roetine fenotipiese middel sensitiwiteit bepaling is gevind om minderwaardig te wees in vergelyking met die genotipiese toetse. Die ontwikkeling van 'n bekostigbare toetsstelsel wat die mees algemene mutasies vir middel weerstandigheid sal opspoor, kan van groot waarde wees in die stryd teen mutimiddel weerstandige tuberkulose. Aangesien vroeë diagnose so belangrik is, kan aktiewe kontak opsporing koste-effektief wees. Ge-individualiseerde behandelingskedules is effektief om die sukses van behandeling en oorlewing te verbeter, en moontlik ook om die oordrag van multi-middel weerstandige tuberkulose te verminder. Multi-middel weerstandige tuberkulose is 'n probleem vir die globale kontrole van tuberkulose. Effektiewe strategieë om die vloed te stuit, bestaan, maar politieke verbintenis en geldelike ondersteuning sal essensieël wees.

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Santos-Lazaro, David, Ronnie G. Gavilan, Lely Solari, Aiko N. Vigo i Zully M. Puyen. "Whole genome analysis of extensively drug resistant Mycobacterium tuberculosis strains in Peru". Nature Research, 2021. http://hdl.handle.net/10757/657341.

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Peru has the highest burden of multidrug-resistant tuberculosis in the Americas region. Since 1999, the annual number of extensively drug-resistant tuberculosis (XDR-TB) Peruvian cases has been increasing, becoming a public health challenge. The objective of this study was to perform genomic characterization of Mycobacterium tuberculosis strains obtained from Peruvian patients with XDR-TB diagnosed from 2011 to 2015 in Peru. Whole genome sequencing (WGS) was performed on 68 XDR-TB strains from different regions of Peru. 58 (85.3%) strains came from the most populated districts of Lima and Callao. Concerning the lineages, 62 (91.2%) strains belonged to the Euro-American Lineage, while the remaining 6 (8.8%) strains belonged to the East-Asian Lineage. Most strains (90%) had high-confidence resistance mutations according to pre-established WHO-confident grading system. Discordant results between microbiological and molecular methodologies were caused by mutations outside the hotspot regions analysed by commercial molecular assays (rpoB I491F and inhA S94A). Cluster analysis using a cut-off ≤ 10 SNPs revealed that only 23 (34%) strains evidenced recent transmission links. This study highlights the relevance and utility of WGS as a high-resolution approach to predict drug resistance, analyse transmission of strains between groups, and determine evolutionary patterns of circulating XDR-TB strains in the country.
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21

Olayanju, Olatunde. "Efficacy and safety of novel and repurposed drugs for the treatment of drug-resistant tuberculosis". Doctoral thesis, Faculty of Health Sciences, 2020. http://hdl.handle.net/11427/32322.

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Background: There is widespread concern about the rise of drug-resistant TB because treatment outcomes of affected patients remain poor and treatment options are limited. After more than a forty-year gap without any breakthrough discovery, several new (bedaquiline and delamanid) and repurposed drugs (linezolid) are increasingly becoming available for use. However, data regarding the efficacy and safety of these drugs in drug-resistant TB patients, with or without HIV infection, from a real-life programmatic setting are lacking. This thesis aims to address that knowledge gap and provide information for management of drug-resistant TB in countries with high disease burden. Methods: A total of 326 drug resistant TB patients were prospectively followed up between January 2008 and April 2018. The efficacy and safety of two new drugs (bedaquiline and delamanid) and one repurposed drug (linezolid) was determined in these patients in three studies. In the first study, 24 months treatment outcomes and adverse event profiles were compared between extensively drug resistant (XDR) TB patients who received programmatic treatment regimens with the backbone of second line injectables and fluoroquinolones (nonbedaquiline-based) and those who received a bedaquiline- and/ or linezolid-based treatment regimen. The second study determined the frequency of system-specific adverse events associated with linezolid. The third study interrogated the safety and effectiveness of a strengthened treatment regimen containing a combination of delamanid and bedaquiline in patients with poor prognostic features compared to bedaquiline-based regimen. Results: In the first study, patients who received a bedaquiline-based treatment regimen had a significantly greater favourable outcome rate (66.2% vs 13.2%; p<0.001) ), more than a fourfold reduction in treatment failure rate (5.9% vs 26%; p<0.001 ) and less than a half of mortality rate compared to patients who received a non-bedaquiline-based regimen. The bedaquiline survival and favourable outcome effect remained significant in HIV-infected patients (p<0.001). The second study showed that linezolid interruption was common in patients receiving a bedaquiline-based treatment regimen, and that system-specific toxicity occurred within predictable time frames. It also showed that anaemia (77.3% versus 7.3%; p<0.001), peripheral neuropathy (63.6% versus 14.6%; p=0.003), and optic neuritis (18.2% versus 9.8%; p=0.34) occurred more frequently in linezolid interrupters than in non-interrupters. The third study showed that the use of delamanid-bedaquiline combination regimen was safe and efficacious in drug resistant TB patients with poor prognosis when compared with outcomes in the less sick patients who received a bedaquiline-based regimen. It also showed no significant difference in culture conversion rate at 6 months (92.5% versus 81.8%; p=0.26) or favourable treatment outcome rate (63.4% versus 67.5%; p=0.66) between the two groups. Although patients who received the combination regimen had more frequent occurrence of QTcF prolongation greater than 60 ms from baseline (p=0.001) and more episodes of QTcF greater than 450 ms during treatment (p=0.001), none of them were symptomatic or had delamanid or bedaquiline withdrawn from their regimen. Conclusion: These data demonstrated that new and repurposed drugs remarkably improved treatment outcomes in patients with drug-resistant TB. Although linezolid, which is an important component of the bedaquiline-based treatment regimen, is often associated with system-specific adverse events, these occurred at predictable time frames thereby guiding physicians to make informed management decisions. Lastly, drug resistant TB patients with poor prognosis may benefit from a regimen containing delamanid and bedaquiline which seems relatively safe from an adverse event perspective. These data, despite some limitations, make a case for a widespread and accelerated roll-out of new and repurposed drugs for the treatment of drug resistant TB.

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22

Sultana, Razvan. "High-throughput genotyping and fingerprinting of mycobacterium tuberculosis multi-drug resistant strains". Thesis, Boston University, 2012. https://hdl.handle.net/2144/31612.

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Thesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
Multiple drug resistance in Mycobacterium tuberculosis poses both significant treatment and epidemiological challenges. Measuring drug resistance in clinical settings is time consuming and prone to errors, problems that can lead to suboptimal treatments and the selection of further resistance to an increased number of antibacterial drugs. A fast and accurate genotyping assay, directed at mutations that are highly associated with drug-resistance, would improve response time and the choice of drugs used to treat multiple drug resistant tuberculosis. From an epidemiologic perspective, tracking the origin and dynamics of drug resistant strains in outbreaks is also a challenge and existing methods fall short because they lack resolution (spoligtyping) or are too expensive or labor-intensive to implement on a large scale (RFLP, MIRU-VNTR). In this work, I developed methods to adapt and expand a high throughput targeted resequencing method based on molecular inversion probes and subsequent Illumina sequencing, to cover 28 protein and rRNA-coding genes described previously as primary and secondary actors in drug resistance. I validated the method on a control set, compared it with traditional Sanger sequencing and whole-genome Illumina sequencing and applied it to a collection of 1200 drug resistant Mycobacterium tuberculosis strains from all over the world. This project was funded by the Bill and Melinda Gates Foundation and the result of our work will be freely available as a resource to the research community through a website hosted by the Broad Institute. For this project, I have written, tested and optimized algorithms for large-scale molecular inversion probe design (MIPDesigner), for next-generation sequence data processing (MIPCleaner), for SNP filtering, and for quality-control metric computation. Molecular inversion probes also provide a mechanism for rapid, high-throughput, molecular fingerprinting of Mycobacterium tuberculosis strains, that can be performed simultaneously with the detection drug resistance mutations. I used my optimized MIPs pipeline to design and test a "virtual spoligotyping" method based on the capture and sequencing of the spacers in the CRISPR locus with a molecular inversion probe. This new method expands the resolution and power of the classical spoligotyping assay and provides a mechanism for the continuous improvement of Mycobacterium tuberculosis fingerprinting.
2031-01-01

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Siu, Kit-hang, i 蕭傑恆. "Molecular characterization of multi-drug resistance mechanisms in mycobacterium tuberculosis". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B46076219.

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Azores, Molovon Jr Pasagui. "Possible Risk Factors for Multidrug-Resistant Tuberculosis Infection in the Philippines". ScholarWorks, 2017. https://scholarworks.waldenu.edu/dissertations/3551.

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Multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is a leading cause of morbidity and mortality in the Philippines. The purpose of this study was to gain knowledge about the relationship between potential risk factors and MDR-TB. Risk factors (the independent variables) for MDR-TB (the dependent variable) include previous TB treatment, infection with HIV, exposure to patients with drug-susceptible TB/MDR-TB, delays in diagnosis and treatment, employment status, smoking, imprisonment, alcohol abuse, and poor compliance with TB treatment regimens. The study was based on the epidemiological approach to causal inference work. A case-control study design was used wherein a quantitative method was applied in data analysis to assess the strength of the pre-identified possible risk factor(s) association to MDR-TB infection. Data were collected using survey questionnaires that were administered to patients (N = 172) from health centers in Leyte, San Mateo Rizal, and San Lazaro. Hypotheses were tested using chi-square analysis, Fisher's exact test, and an odd ratio. Drug-susceptible TB respondents who smoked on a daily basis were three times more likely (95% CI 1.021-13.341, OR 3.69) to develop an MDR-TB infection than were other respondents. Respondents who did not comply with the anti-TB treatment regimen were nine times more likely (95% CI 2.104-43.059, OR 9.519) to develop an MDR-TB infection than other respondents. Health care providers may be able to use study findings to develop programs to help drug-susceptible TB patients stop smoking and better comply with treatment regimens designed to prevent MDR-TB infection, resulting, potentially, in improved public health outcomes for patients.

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Ko, Wai-ting, i 高慧婷. "Molecular characterization of pyrazinamide resistance in Mycobacterium tuberculosis". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193536.

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Tuberculosis (TB) is a highly infectious disease that causes the second highest mortality rate in human worldwide. The emergence of multi-drug resistance tuberculosis (MDR-TB) leads to a major public health problem in controlling TB-caused mortality. Pyrazinamide (PZA) is an important first-line drug in the treatment of MDR-TB. However, since the challenge in performing susceptibility test on PZA, World Health Organization has not published any data on the prevalence of PZA resistance in Mycobacterium tuberculosis (M. tuberculosis). Since the occurrence of PZA resistance makes MDR-TB more difficult to treat with poor prognosis, rapid detection method in PZA resistance is urgently needed. Since pncA mutation is highly associated with up to 98% PZA resistant M. tuberculosis strains, it is worthwhile to develop rapid molecular method for detecting PZA resistance. This study aims to identify the mutations in PZA resistant M. tuberculosis strains. The first part of this study aims to characterize the pattern of pncA mutation among PZA-resistant and PZA-susceptible M. tuberculosis using Sanger sequencing method. Among all clinical isolates, 12 out of 29 cases of M. tuberculosis were resistant to PZA. All PZA-resistant M. tuberculosis strains harbored pncA mutation, whereas no known mutations were found among those PZA-susceptible strains, giving the positive predictive value to be 100%. Eight mutation patterns were found among 12 resistant isolates. Four of these pncA mutations have not been described previously by other studies. Study also characterizes the pattern of pncA mutation in 19 sputum specimens, with 2 mutation patterns found. Overall 10 mutation patterns were found in this study. Results show that the mutation of pncA gene is highly associated with PZA-resistant M. tuberculosis. Results also suggest the scattered and more extensive mutations in pncA gene that confer PZA resistance to M. tuberculosis. The second and the last part of this study aims to evaluate the possibility of using molecular method to detect PZA resistance in routine clinical laboratory. Results show that using molecular sequencing to detect PZA resistance can shorten the turnaround time to about 3-4 working days. Since mutation of pncA was scattered along the entire pncA gene, using DNA sequencing approach may be the best strategy for the rapid detection of PZA resistance in M. tuberculosis.
published_or_final_version
Medical Sciences
Master
Master of Medical Sciences

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Mkhontfo, Mandzisi Mbongeni. "An Examination of The Distribution of Diabetes Mellitus Among TB Patients with Pulmonary Tuberculosis and Drug Resistant Tuberculosis In The State Of Florida, USA". Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6325.

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Background: Pulmonary Tuberculosis (PTB) is considered a disease of the past but it remains a major cause of mortality among immune compromised patients and continues to be a significant threat to public health globally. Notably, the prevalence of diabetes mellitus (DM) has increased over the years. The biological link of TB and DM has been reported in numerous literature with DM attributed to three folds increase in the risk of TB and linked to Drug Resistant TB, especially amongst aged diabetic patients. The aim of the study was to examine the distribution of DM among TB patients and explore the risk of Drug resistant TB in Diabetics infected with TB Methods: The study employed a retrospective cross-sectional descriptive case based study involving 3638 patients diagnosed with pulmonary TB in the State of Florida, USA, 2009-2014. A comparative analysis of TB cases with DM and cases without DM adjusted for age was conducted. The risk of Drug resistant TB associated with DM was estimated through logistic regression analysis. Odds Ratios of TB/DM comorbidity were calculated and adjusted for Age using 5-year intervals from 40 years to above 70 years. Ninety-five percent (95%) confidence intervals were used and the accepted level of error was 0.05. Results: There were 3836 cases of Pulmonary TB in Florida for the period of 2009-2014. The majority of cases (65%) were males and likely unemployed (59.1%). The prevalence of DM was 12 % but when adjusted for age the prevalence of DM was 3.9% amongst patients aged below 40 years and 16.7 % in patients aged above 40 years. An estimated 469 cases had TB/DM comorbidity (12.2%). The majority of TB/DM cases were above 40 years amongst the patients with DM, 44/469 (9.4%) had drug resistant TB and a majority were resistant to Rifampin. Population density did not influence the distribution of TB in this study. Conclusion: Diabetes Mellitus, Aging, and low immunity are linked with increased rates of progressing from latent TB infection to active disease. To achieve the goal of TB elimination it is important to fully understand and identify known TB comorbidities for proper diagnosis and early initiation to care. There is a positive correlation between high DM burden and increased TB prevalence. Therefore, it is recommended that prevention of DM, hyperglycemia and comprehensive management of DM be intensified to prevent TB, improve TB treatment outcomes and reduce the risk of drug resistant TB in Florida, USA.

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Pym, Alexander Stephen. "Understanding attenuation in drug-resistant and vaccine strains of the mycobacterium tuberculosis complex". Thesis, University of Liverpool, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425695.

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Mekler, Kathryn Ann. "Factors influencing the decentralisation of Multi-Drug Resistant Tuberculosis care: A management perspective". University of the Western Cape, 2018. http://hdl.handle.net/11394/6866.

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Master of Public Health - MPH
Decentralisation of multi-drug resistant tuberculosis (MDR-TB) services has resulted in improved access to care, with community-based treatment of MDR-TB shown to be more effective than centralised hospital-based care. Furthermore, increasing bed shortages resulted in the National Department of Health establishing MDR-TB policy guidelines in 2011. However, the extent to which this policy has been implemented by the decentralised MDR- TB sites and the factors influencing implementation of the policy from a management perspective were not well described. The aim of this study was therefore to explore and compare the actual and ascribed roles and responsibilities of key management-level role players at the decentralised MDR-TB sites, and to explore the factors influencing implementation of the MDR-TB decentralisation policy (2011).

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Johnson, Rabia. "Understanding the mechanisms of drug resistance in enhancing rapid molecular detection of drug resistance in Mycobacterium tuberculosis". Thesis, Link to the online version, 2007. http://hdl.handle.net/10019.1/1265.

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Adewumi, Olayinka Anthony. "Treatment outcomes in patients infected with multidrug resistant tuberculosis and in patients with multidrug resistant tuberculosis coinfected with human immunodeficiency virus at Brewelskloof Hospital". Thesis, University of the Western Cape, 2012. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_8245_1375971752.

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Many studies have reported low cure rates for multidrug-resistant tuberculosis (MDRTB) patients and MDR-TB patients co-infected with human immunodeficiency virus (HIV). However, little is
known about the effect of HIV infection and antiretroviral therapy on the treatment outcomes of MDR-TB in South Africa. Therefore, the objectives of the study are: to find out whether HIV infection
and interactions between ARVs and second line anti-TB drugs have an impact on the following MDR-TB treatment outcomes: cure rate and treatment failure at Brewelskloof Hospital. MDR-TB
patients were treated for 18-24 months. The study was designed as a case-control retrospective study comparing MDR-TB treatment outcomes between HIV positive (cases) and HIV negative
patients (controls). Patients were included in the study only if they complied with the following criteria: sensitivity to second line anti-TB drugs, MDR-TB infection, co-infection with HIV (for some
of them), male and female patients, completion of treatment between 1 January 2006 and 31 December 2008. Any patients that presented with extreme drug-resistant tuberculosis (XDR-TB)
were excluded from the study. Data were retrospectively collected from each patient&rsquo
s medical records. There were a total of 336 patients of which 242 (72%) were MDR-TB patients and 94
(27.9%) MDRTB co-infected with HIV patients. Out of the 242 MDR-TB patients, 167 (69.2%) were males and 75 (30.7%) were females. Of the 94 patients with MDR-TB co-infected with HIV, 51
(54.2%) males and 43 (45.7%) females. Patients with multidrug-resistant tuberculosis co-infected with HIV who qualify for antiretroviral therapy were treated with stavudine, lamivudine and
efavirenz while all MDR-TB patients were given kanamycin, ethionamide, ofloxacin, cycloserine and pyrazinamide. The cure rate of MDR-TB in HIV (+) patients and in HIV (-) patients is 34.5%
and 30 % respectively. There is no significant difference between both artes (pvalue = 0.80). The MDR-TB cure rate in HIV (+) patients taking antiretroviral drugs and in HIV (+) patients without
antiretroviral therapy is 35% and 33% respectively. The difference between both rates is not statistically significant. The study shows that 65 (28.0%) patients completed MDR-TB treatment but
could not be classified as cured or failure, 29 (12.5%) patients failed, 76 (32.7%) defaulted, 18 (7.7%) were transferred out and 44 (18.9%) died. As far as treatment completed and defaulted is concerned,
there is no significant statistical difference between HIV (+) and HIV (-) The number of patients who failed the MDR-TB treatment and who were transferred out is significantly higher in the HIV (-)
group than in the HIV (+) group. Finally the number of MDR-TB patients who died is significantly higher in the HIV (+) group). The median (range) duration of antiretroviral therapy before starting
anti-tuberculosis drugs is 10.5 (1-60) months. According to this study results, the MDR-TB treatment cure rate at Brewelkloof hospital is similar to the cure rate at the national level. The study also
hows that HIV infection and antiretroviral drugs do not influence any influence on MDR-TB treatment outcomes.

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Lobacheva, Tatiana. "Pulmonary tuberculosis in pre-trial detentions in St. Petersburg, Russia /". Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-638-7/.

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Law, Yuen Shan. "Comparing the cost-effectiveness of different standardized tuberculosis treatment regimens in settings with varying prevalence of drug-resistant tuberculosis". Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96907.

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Background: There is a growing need to identify appropriate standardized treatment strategies that will adequately treat drug-resistant TB (DR-TB) and prevent multidrug-resistant TB (MDR-TB). Methods: We built a Markov model comparing treatment-related morbidities, mortality and costs in Ecuador, Brazil and hypothetical settings with varying prevalence of DR-TB. We compared four treatment strategies: 1) standard WHO-recommended treatment strategy; 2) adding EMB throughout 6-month initial treatment; 3) strengthening WHO standard retreatment with 2nd-line drugs; and 4) treating failures from initial treatment with a standardized MDR regimen. We also compared four combinations of those strategies. Probabilities of tuberculosis outcomes were derived from published literature. Costs were collected using direct surveys.Results: Strengthening retreatment with second-line drugs was highly cost-effective in Ecuador and Brazil. Adding EMB throughout initial treatment prevented acquired drug resistance and TB deaths, but led to excess cases of blindness.Conclusion: There is growing evidence that the WHO standard retreatment regimen is inadequate and should be strengthened with second-line drugs.
Contexte: Des stratégies normalisées de traitement de la tuberculose résistante et de prévention de la tuberculose multi résistante doivent être identifiées.Méthodes: La morbidité, la mortalité et les coûts associés au traitement de la tuberculose en Equateur, au Brésil et dans des contextes hypothétiques ont été comparés dans un modèle de Markov. Quatre stratégies ont été évaluées: 1) le traitement normalisé recommandé par l'OMS, 2) l'ajout d'EMB au traitement initial, 3) le renforcement du retraitement avec des médicaments de 2e ligne, 4) l'utilisation d'un traitement normalisé pour la tuberculose multi résistante lors d'échec du traitement initial. Les probabilités ont été tirées de la littérature. Les coûts ont été recueillis par questionnaires.Résultat: Renforcer le retraitement a un rapport coût-efficacité élevé en Équateur et au Brésil. Ajouter l'EMB pendant le traitement initial prévient le développement de résistance et les décès, mais conduit à une augmentation des cas de cécité.Conclusion: La stratégie de retraitement normalisé de l'OMS devrait être renforcée avec des médicaments de deuxième ligne.

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Falmer, Alecia Angelique. "Molecular characterization of drug resistant Mycobacterium tuberculosis isolates from different regions in South Africa". Thesis, Stellenbosch : Stellenbosch University, 2012. http://hdl.handle.net/10019.1/21656.

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Thesis (MScMedSc)--Stellenbosch University, 2008.
ENGLISH ABSTRACT: Application of molecular fingerprinting highlights transmission as the driving force behind the drug resistant epidemic in South Africa. Different strains dominate within different geographical regions, which is a reflection of micro-epidemics of drug resistance in the different regions. Cluster analysis shows that strains within the same strain family are different. The Beijing drug resistant strain family is the most dominant strain family (31%) in the Western Cape and of particular concern is the highly transmissible Beijing cluster 220 strain in the Western Cape communities. This cluster is widespread in the region and was previously identified in a MDR outbreak in a high school in Cape Town. Results suggest that the spread of Beijing drug resistant cluster 220 in the community was due to a combination of acquisition of drug resistant markers and transmission. This study also indicate that atypical Beijing can acquire drug resistance and become fit amongst HIV infected individuals. This is contrary to believe that atypical Beijing strains are not frequently associated with drug resistance and are attenuated. This implies that HIV levels the playing field for all drug resistant strains. Mechanisms leading to the evolution of MDR-TB and XDR-TB in a mine setting with a wellfunctioning TB control program which exceeds the target for cure rates set by the WHO were investigated. Despite the excellent control program, an alarming increase in the number of drug resistant cases was observed in 2003 and subsequent years. Phylogenetic analysis shows sequential acquisition of resistance to first and second-line anti-TB drugs leading to the development of MDR and XDR-TB. Contact tracing indicate extensive transmission of drug resistant TB in the shafts, hospital and place of residence. This study shows that despite exceeding the WHO cure rate target, it was not possible to control the spread and amplification of drug resistance. In summary, as a top priority, future TB control plans need to address diagnostic delay more vigorously.
AFRIKAANSE OPSOMMING: Molukulêre tegnieke toon transmissie as die hoofrede vir die toename in die anti-tuberkulose middelweerstandigheid epidemie in Suid-Afrika. Die verskillende Mikobakterium tuberkulose rasse wat domineer in verskillende areas is ‘n refleksie van middelweerstandige mikro-epidemies in verskillende gebiede. Analise van identiese rasgroepe demonstreer dat ras families bestaan uit verskillende rasse. Die Beijing middelweerstandige rasfamilie is die mees dominante familie in die Wes-Kaap (31% van monsters van middelweerstandige families) en van spesifieke belang is die hoogs oordraagbare Beijing 220 groep. Hierdie groep is die mees wydverspreide groep in die studie area en was voorheen geïdentifiseer tydens ‘n meervoudige middelweerstandige uitbreking in ‘n hoërskool in Kaapstad. Die resultate dui aan dat die Beijing middelweerstandige groep 220 in die gemeenskap versprei as gevolg van ‘n kombinasie van middelweerstand verwerwing en transmissie. Hierdie studie dui verder aan dat die atipiese Beijing ook middelweerstandigheid kan verwerf en hoogs geskik is vir infeksie veral in MIV geïnfekteerde individue. Hierdie data is in teenstelling met die algemene denke dat atipiese Beijing nie gereeld geassosieer word met middelweerstandigheid nie en dat dit dikwels geattenueer is. Dit beteken dat MIV die hoof faktor is wat alle middelweerstandige rasse kans gee om te versprei. Hierdie studie het die meganisme wat lei tot die evolusie van middelweerstandigheid en “XDRTB” in die myne ondersoek. Die myn besit ‘n goeie funksioneerde tuberkulose kontrole program wat alreeds die Wêreld Gesondheids Organisasie se mikpunt vir tuberkulose genesing oortref. Ten spyte van ‘n uitstekende tuberkulose kontrole program, is daar ‘n bekommerenswaardige toename in die aantal middelweerstandige tuberkulose gevalle waargeneem in 2003 en in die daaropvolgende jare. Filogenetiese analise wys dat opeenvolgende verwerwing van middelweerstandigheid teen eerste en tweede vlak anti-tuberkulose middels gelei het tot die ontwikkeling van meervoudige middelweerstandigheid en “XDR-TB”. Die opsporing van kontakpersone om transmissie te bewys dui aan dat transmissie van middelweerstandige tuberkulose in die werk plek, hospitaal en woon plek plaasvind. Hierdie studie wys dat ongeag die feit dat die Wêreld Gesondheids Organisasie se genesings verwagtinge oortref is, dit steeds onmoontlik was om die verspreiding en amplifisering van middelweerstandigheid te beheer. ‘n Top prioriteit vir tuberkulose kontrole planne in die toekoms behoort die vertraging van diagnose sterk aan te spreek.

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Sagwa, Evans Luvaha. "Prevalence and risk factors of adverse events during treatment of drug resistant tuberculosis in a setting of high human immunodeficiency virus co-infection in Namibia : 2009-10". University of the Western Cape, 2012. http://hdl.handle.net/11394/4625.

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Magister Public Health - MPH
Namibia is currently coping with a dual burden of human immunodeficiency (HIV) and HIV-associated tuberculosis (TB). In 2010, HIV prevalence was 18.8%, the TB case notification rate was 634 per 100,000 population, while TB/HIV co-infection was 58% in 2009. There were 372 reported cases of drug-resistant TB (DR-TB) in 2009. This study assessed the prevalence, profile and outcome of adverse events (AEs) associated with the treatment of DR-TB, and risk factors for the adverse events. The researcher used a cross-sectional design. Data was collected from the treatment records of all patients treated for DR-TB (N = 59) at the study facility between January 2008 and February 2010. Descriptive statistics were used to describe the frequency of the adverse events and logistic regression to analyse the association between possible risk factors and (specific) adverse events, with stratification (sub-group analysis) and multivariate analysis to adjust for measured confounders. Results of logistic regression analysis are reported as odds ratio (OR), 95% confidence interval (CI) and p-value, where p<0.05 was considered to be statistically significant. A total of 141 adverse events were experienced by 90% (53/59) of patients in the sample. HIV-associated TB occurred in 31 (53%) of the sample. The prevalence of gastrointestinal tract (GIT) adverse events was 64%, tinnitus 45%, joint pain 28% and decreased hearing 25%. Abdominal pain, rash, nausea, decreased hearing and joint pain were found to be more common in people living with HIV than in HIV-negative patients. Moderate-to-severe adverse events were mostly experienced after four weeks of DR-TB treatment (OR 6.4; 95% CI 1.6 – 25.6, p= 0.01). Drug-resistant TB patients who were coinfected with HIV were more prone to experiencing three or more adverse events (OR 3.9; 95% CI 1.2 – 13.6, p= 0.03). Patients treated with zidovudine-based ART were at an increased risk of experiencing nausea (OR 7.5; 95% CI 1.1 -51.5, p=0.04). Females were associated with an increased risk of skin rash (OR 15.7; 95% CI 1.7 – 143.7, p=0.01). The use of cycloserine-based DR-TB regimens was associated with joint pain (OR 6.5; 95% CI 1.6 – 25.8, p=0.01), while the risk of ototoxicity was associated with the use of amikacin-containing regimens (OR 12.0; 95% CI 1.3 – 111.3, p=0.03). Adverse events were found to be more common among patients treated for DR-TB (90% prevalence), particularly during the intensive phase of TB therapy. Most of these adverse events were mild and tolerable. Some adverse events were more common among DR-TB patients who were co-infected with HIV than in HIV-negative patients. The characteristics and risk factors of the serious adverse events need further research. The use of cycloserine-based DR-TB regimens was associated with joint pain. Findings of the risk factor analysis are inconclusive because of the small sample size, which severely limited the power of the study. Clinicians should invest more time in the prevention and management of adverse events, and should pay greater attention to the needs of HIV co-infected DR-TB patients who are using second-line anti-TB medications, especially those who are concomitantly undergoing treatment using antiretroviral medicines.

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Mulubwa, Mwila. "Population pharmacokinetics of terizidone and cycloserine in patients with drugresistant tuberculosis". University of the Western Cape, 2019. http://hdl.handle.net/11394/7083.

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Doctor Pharmaceuticae - DPharm
Introduction: Drug-resistant tuberculosis remains a major world health problem and one of the leading cause of death worldwide. Despite adequate adherence to antituberculosis drugs by patients, the emergence of drug-resistance tuberculosis still occurs. This fact implies other factors leading to the emergence of resistant strains of Mycobacterium tuberculosis. A multidrug treatment regimen, which may consist of five to seven different drugs including terizidone, is used in the treatment of drugresistance tuberculosis. Terizidone is part of the multidrug regimen whose pharmacokinetics is scarce in literature and plasma concentration profile unknown. Two molecules of cycloserine joined by terephtalaldehyde moiety makes up a molecule of terizidone, which is thought to undergo complete metabolism into cycloserine in vivo. Additionally, the current literature report that terizidone and cycloserine can be used interchangeably as they are thought to be equivalent. The aim of this thesis was first to develop and validate bioanalytical methods for determination of terizidone and cycloserine in patients’ plasma samples. Secondly, to model population pharmacokinetics of terizidone and cycloserine. Thirdly, to determine the amount of cycloserine resulting from metabolism of terizidone.

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Winterton, Laura. "Conflicted cure: explorting concepts of default and adherence in drug resistant tuberculosis patients in Khayelitsha". Master's thesis, University of Cape Town, 2013. http://hdl.handle.net/11427/3614.

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Includes abstract.
Includes bibliographical references.
This dissertation examines default and adherence in drug-resistant tuberculosis (DR-TB) patients in Khayelitsha, Cape Town, South Africa. The ethnographic data is drawn from three and a half months of participant-observation, illness-narrative interviews, in-depth interviews, focus groups, support-group sessions and creative methodologies such as collage and emotional mapping. The various methods revealed some contradictory experiences with treatment and cure that some patients faced when undergoing treatment for DR-TB. Through an analytical framework of affect and emotions, this paper traces the complexities and disparate conceptions of default and adherence that circulate amongst patients. This paper argues that default and adherence do not operate in isolation but are part of dynamic entanglements of relationships and self-introspection that surface throughout the course of treatment for DR-TB.

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Kusimo, Oluremilekun Comfort. "Effect of Model of Care and Comorbidities on Multiple-Drug-Resistant Tuberculosis Treatment in Nigeria". ScholarWorks, 2019. https://scholarworks.waldenu.edu/dissertations/6596.

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Multidrug-resistant tuberculosis (MDR-TB) is a public health problem in several countries such as Angola, India, China, Kenya, and Nigeria. Due to the increasing high burden of MDR-TB, most of these countries do not have adequate capacities to manage MDR-TB patients effectively. This study investigated the effect of model of care; human immunodeficiency virus comorbidity; and demographic factors such as age, gender, and marital status on the treatment outcomes of MDR-TB patients in Nigeria. The study was based on the analysis of secondary data of 402 MDR-TB patients accessed from the data systems of the National Tuberculosis, Buruli Ulcer, and Leprosy Control Program. The theoretical framework for this study was the health belief model. The results of the study showed that treatment outcomes were similar for hospital and community-based models of care. Age was the only factor found to be significantly associated with treatment outcomes; age > than 40 years was a predictor of unsuccessful treatment outcomes among MDR-TB patients at a p-value of 0.026. In the multivariate logistics regression analysis, age and model of care were found to be significantly associated with treatment outcomes at p-values of 0.043 and 0.048, respectively. Marital status, gender, and HIV comorbidity were not significantly associated with treatment outcomes. Implications of the findings of this study for social change in a health care program include opportunities to help reduce the number of patients on waiting lists for MDR-TB treatment. These strategies may ultimately help to reduce the spread of MDR-TB infection as well as the mortality associated with late treatment.

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Hansen, Tarrant William. "Evaluation of molecular methods used for the rapid detection of multi-drug resistant Mycobacterium tuberculosis". Thesis, Queensland University of Technology, 2008. https://eprints.qut.edu.au/20723/1/Tarrant_Hansen_Thesis.pdf.

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Tuberculosis remains a major public health issue globally, with an estimated 9.2 million new cases in 2006. A new threat to TB control is the emergence of drug resistant strains. These strains are harder to cure as standard anti-tuberculosis first line treatments are ineffective. Multi Drug Resistant Tuberculosis (MDR-TB) is defined as Mycobacterium tuberculosis that has developed resistance to at least rifampicin and isoniazid, and these strains now account for greater than 5% of worldwide cases. Mutations within the Rifampicin Resistance Determining Region (RRDR) of the rpoB gene are present in greater than 95% of strains that show rifampicin resistance by conventional drug susceptibility testing. As rifampicin mono resistance is extremely rare, and rifampicin resistance is usually associated with isoniaizd resistance, the RRDR region of the rpoB gene is a very useful surrogate marker for MDR-TB. Many molecular assays have been attempted based on this theory and have had varied levels of success. The three methods evaluated in this study are DNA sequencing of the rpoB, katG and inhA genes, the Genotype MTBDRplus line probe assay (Hain Lifesciences) and a novel method incorporating Real-Time PCR with High Resolution Melt analysis targeted at the RRDR using the Rotorgene 6000 (Corbett Lifesciences). The sensitivity for the detection of rifampicin resistance was far better using DNA sequencing or the commercially available line probe assay than detection by the Real-Time PCR method developed in this study.

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Hansen, Tarrant William. "Evaluation of molecular methods used for the rapid detection of multi-drug resistant Mycobacterium tuberculosis". Queensland University of Technology, 2008. http://eprints.qut.edu.au/20723/.

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Tuberculosis remains a major public health issue globally, with an estimated 9.2 million new cases in 2006. A new threat to TB control is the emergence of drug resistant strains. These strains are harder to cure as standard anti-tuberculosis first line treatments are ineffective. Multi Drug Resistant Tuberculosis (MDR-TB) is defined as Mycobacterium tuberculosis that has developed resistance to at least rifampicin and isoniazid, and these strains now account for greater than 5% of worldwide cases. Mutations within the Rifampicin Resistance Determining Region (RRDR) of the rpoB gene are present in greater than 95% of strains that show rifampicin resistance by conventional drug susceptibility testing. As rifampicin mono resistance is extremely rare, and rifampicin resistance is usually associated with isoniaizd resistance, the RRDR region of the rpoB gene is a very useful surrogate marker for MDR-TB. Many molecular assays have been attempted based on this theory and have had varied levels of success. The three methods evaluated in this study are DNA sequencing of the rpoB, katG and inhA genes, the Genotype MTBDRplus line probe assay (Hain Lifesciences) and a novel method incorporating Real-Time PCR with High Resolution Melt analysis targeted at the RRDR using the Rotorgene 6000 (Corbett Lifesciences). The sensitivity for the detection of rifampicin resistance was far better using DNA sequencing or the commercially available line probe assay than detection by the Real-Time PCR method developed in this study.

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ESPOSITO, MARTA. "Fighting drug-resistant tuberculosis: CTP-synthetase and pantothenate kinase as new targets for multitargeting compounds". Doctoral thesis, Università degli studi di Pavia, 2016. http://hdl.handle.net/11571/1203305.

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Tuberculosis (TB), the infectious disease brought about by Mycobacterium tuberculosis, is afflicting human health worldwide. Epidemiological data indicate 3 billion people latently infected globally, and only in 2014, 1.5 million people died due to this infection. Moreover, TB plague does not show signs to stop, particularly in view of the spread of M. tuberculosis drug-resistant strains (MDR, XDR and TDR), together with patients co-infected with HIV. Thus, considering all these aspects, the research for new antitubercular drugs and the identification of novel targets that could allow the killing of the pathogen through more efficient tools, are surely indispensable. Recently, from the screening of the National Institute of Allergy and Infectious Diseases (NIAID) chemical library, two compounds distinguished themselves for their efficacious antitubercular activity. These molecules, the thiophene-carboxamide 7947882 and the carbamothioyl-propanamide 7904688, displayed activity against the pathogen in vitro, ex vivo, and against a latent model. Genetic and biochemical approaches demonstrated that 7947882 and 7904688 are prodrugs activated by the monooxygenase EthA, already known to be the activator of ethionamide. Moreover, from the sequencing analysis of 7947882 and 7904688 M. tuberculosis spontaneous resistant mutants, the CTP-synthetase PyrG and pantothenate kinase PanK emerged as the putative targets of these compounds. The present work led to the demonstration that PyrG and PanK are the cellular targets of these compounds. Moreover, in view of the importance of finding new drugs targeting more than one cellular function, PyrG and PanK were exploited to perform an in silico screening of the Collaborative Drug Discovery (CDD) compound database, and an in vitro screening of the GSK TB-set chemical library of compounds against the two enzymes. From these screenings, a number of compounds affecting both enzymes emerged, thus strengthening the usefulness of PyrG and PanK for new multitargeting drugs research. Finally, all M. tuberculosis PyrG inhibitors were tested against human CTP-synthetase-1, identifying one compound that inhibits almost exclusively the mycobacterial enzyme, and not the human one, paving the way for new M. tuberculosis PyrG selective inhibitors.

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Willemse, Danicke. "Regulation of efflux in rifampicin resistant mutants of Mycobacterium tuberculosis". Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/79820.

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Thesis (MScMedSc)--Stellenbosch University, 2013.
ENGLISH ABSTRACT: Multidrug resistant tuberculosis (MDR-TB), defined as having resistance to at least the first-line drugs, isoniazid and rifampicin (RIF), is a global health problem. Mutations in the rpoB gene, encoding the β-subunit of RNA polymerase, are implicated in RIF resistance - with the S531L and H526Y mutations occurring most frequently. The level of RIF resistance varies for strains with identical rpoB mutations, which suggests that other factors play a role in RIF resistance. Efflux has been implicated in determining the intrinsic level of RIF resistance. Increased expression of the multidrug efflux pump, Rv1258c, following RIF exposure was observed in some Mycobacterium tuberculosis MDR clinical isolates and H37Rv RIF mono-resistant mutants, but not others. The factors influencing the induction of Rv1258c are poorly understood. The aim of this study was to investigate the effects of rpoB mutations on expression of Rv1258c and whiB7, a transcriptional regulator of Rv1258c, in M. tuberculosis H37Rv in vitro generated RIF resistant mutants, in the absence and presence of RIF. The promoter region of M. tuberculosis H37Rv Rv1258c was cloned into a position upstream of a lacZ gene (encoding β-galactosidase) in multi-copy episomal and integrating vectors. Vector functioning and the effect of rpoB mutations on Rv1258c promoter activity were initially investigated in the non-pathogenic related species, Mycobacterium smegmatis mc2155 rpoB mutants and subsequently in M. tuberculosis by doing β-galactosidase assays. qRT-PCR was done to investigate the effects of rpoB mutations on native Rv1258c and whiB7 gene expression. Episomal and integrating vectors were functional and the integrating vector system was used for subsequent β-galactosidase assays in M. tuberculosis. Rv1258c promoter activity in the S531L mutant was approximately 1.5 times less and in the H526Y mutant 1.5 times higher than that of the wild-type in M. smegmatis. Similarly, Rv1258c promoter activity in the S531L mutant was approximately half and in the H526Y mutant approximately double that of the wild-type in M. tuberculosis. A similar trend in Rv1258c and whiB7 expression to those observed using β-galactosidase assays were observed when investigating the native Rv1258c and whiB7 gene transcript levels compared to the wild-type using qRT-PCR, although differences were not significant. Exposure of the M. smegmatis and M. tuberculosis rpoB mutants to sub-inhibitory levels of RIF did not affect Rv1258c promoter activity. Mutations in rpoB had a marginal effect on Rv1258c and whiB7 transcript levels, but showed the same trend as that seen for Rv1258c promoter activity. It remains to be determined whether these differences are biologically significant. When considering efflux pumps as new targets for treatment, possible differences in efflux pumps expression due to different rpoB mutations should be considered.
AFRIKAANSE OPSOMMING: Multi-middel weerstandige tuberkulose (MDR-TB) word gedefinieer as weerstandigheid tot ten minste rifampisien (RIF) en isoniasied, wat deel van die eerstelyn anti-tuberkulose behandeling vorm. Mutasies in die rpoB geen, wat die β-subeenheid van die RNA polimerase enkodeer, word geassosieer met RIF weerstandigheid. S531L en H526Y rpoB mutasies kom die algemeenste voor. RIF weerstandigheids vlakke verskil egter tussen isolate met identiese rpoB mutasies, wat impliseer dat ander faktore ook 'n rol in RIF weerstandigheid speel. 'n Toename in transkripsie van die Rv1258c geen, wat 'n multi-middel effluks pomp enkodeer, is waargeneem met blootstelling aan RIF, slegs in sommige M. tuberculosis H37Rv RIF mono-weerstandige mutante and MDR kliniese isolate, maar nie in ander nie. Die faktore wat die induksie van die Rv1258c effluks pomp beïnvloed is nie goed nagevors nie. Die studie ondersoek die effek van die rpoB mutasies op die uitdrukking van die Rv1258c en whiB7,'n transkripsionele regulator van Rv1258c, gene in M. tuberculosis H37Rv in vitro gegenereerde RIF weerstandige mutante, in die teenwoordigheid en afwesigheid van RIF. Die promotor area van die M. tuberculosis H37Rv Rv1258c geen is in 'n posisie stroomop van 'n lacZ geen, wat vir β-galaktosidase enkodeer, in multi-kopie episomale en integreerende vektors ingekloneer. Die funksionaliteit van die vektor en effek van rpoB mutasies op Rv1258c promotor aktiwiteit is ondersoek in die naverwante nie-patogeniese spesies, M. smegmatis en daarna in M. tuberculosis deur β-galaktosidase essais te doen. qRT-PCR is gedoen om die effek van rpoB mutasies op die vlak van transkripsie van die natuurlike Rv1258c geen en die whiB7 geen te bestudeer. Beide die episomale en integreerende vektors was funksioneel en daar is besluit om die integreerende vektor vir daaropeenvolgende β-galaktosidase essais in M. tuberculosis te gebruik. Rv1258c promotor aktiwiteit van die S531L mutant was ongeveer 1.5 keer minder as en die van die H526Y mutant 1.5 keer hoër as die van die ongemuteerde bakterië in M. smegmatis. Soortgelyk was die Rv1258c promoter aktiwiteit van die S531L mutant ongeveer die helfde van en die van H526Y mutant ongeveer dubbel die van die ongemuteerde bakterië in M. tuberculosis 'n Soortgelyke neiging in die vlakke van Rv1258c en whiB7 transkripte van die natuurlike geen is gedurende qRT-PCR waargeneem alhoewel die verskille nie beduidend was nie. Blootstelling aan sub-inhibitoriese konsentrasies van RIF het geen effek op Rv1258c uitdrukking in die M. smegmatis of M. tuberculosis rpoB mutante gehad nie. Die rpoB mutasies het net 'n effense effek op Rv1258c en whiB7 transkrip vlakke in M. tuberculosis rpoB mutante, maar transkrip vlakke het 'n soortgelyke neiging as die Rv1258c promoter aktiwiteit getoon. Of die waargenome verskille biologies betekenisvol is, moet nog bepaal word. Indien effluks pompe as teikens vir bahandeling gebruik sou word, moet in ag geneem word dat effluks pompe moontlik verskillend uitgedruk word in verskillende rpoB mutante.
The DST/NRF Centre of Excellence in Biomedical Tuberculosis Research, Stellenbosch University
DAAD-NRF in Country Scholarship and Ernst and Ethel Eriksen Trust
Harry Crossley Foundation

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Diogo, Gil Reynolds. "Characterization of IL-4Δ2 and assessment of its potential in immunotherapy for multi-drug resistant tuberculosis". Thesis, St George's, University of London, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.706520.

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Despite the availability of the Bacillus Calmette-Guerin (BCG) vaccine and current drug regimens, tuberculosis (TB) remains an ever growing global health burden, even more so with the emergence of new drug resistant strains. Therefore it is necessary to improve treatment regimens. Disproportionately high levels of the major Th2 cytokine, IL-4, have been linked to poor TB prognosis. However, T-lymphocytes also produce an alternative IL-4 variant (IL-4Δ2) which can antagonise its activity, and it is the ratio of IL-4 and its antagonist that has been associated with clinical status of Mycobacterium tuberculosis (MTB) infected individuals. This study aims to generate and characterise the mouse version of the IL-4Δ2 molecule and test its potential in vivo to modulate the Thl/Th2 immune response balance and inhibit MTB infection. The aim is to test the therapeutic potential of IL-4Δ2 in the context of the previously established ‘Combined Immunotherapy’ (CIT) utilising the human IgA antibody IgA2E9 and IFN-y. This treatment was shown previously to be protective against drug susceptible TB when administered intranasally to MTB-infected CD89-transgenic mice expressing human IgA receptor. However, the application of CIT would be more realistic in multi-drug resistant TB (MDR-TB) to increase treatment options, and therefore, one of the aims of this study is to test whether addition of IL-4Δ2 to CIT could be effective against MDR-TB. Murine IL-4Δ2 was able to inhibit IL-4 mediated cellular processes in macrophages, B, and T cells. IL-4Δ2 reversed IL-4 mediated inhibition of IFN-y induced nitric oxide release, and furthermore, it inhibited IL-4 mediated T cell proliferation and IgE synthesis by IL-4 treated B cells. In the present study IL-4Δ2 did not competitively bind to the IL-4Ra and did not interfere with the downstream STAT6 phosphorylation. Further studies are required to elucidate the antagonistic mechanism of this molecule. The combination immunotherapy significantly reduced the burden of infection in MDR-TB challenged CD89 positive transgenic mice, but IL-4Δ2 did not appear to enhance this effect.

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Vallie, Razia. "Assessing and comparing the effectiveness of treatment for multidrug resistant tuberculosis between specialized TB hospital in-patient and general outpatient clinic settings within the Western Cape Province, South Africa". University of the Western Cape, 2016. http://hdl.handle.net/11394/5600.

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Magister Public Health - MPH
Background: Multidrug resistant tuberculosis (MDR TB) is a growing threat globally. The large increase in the incidence and prevalence of MDR TB in South Africa in recent years has impacted on the way in which MDR TB is managed within the health services. It became logistically difficult to manage MDR TB by treating all patients as in-patients in a specialized tuberculosis (TB) hospital. The clinics, which are run by nurses and/or general medical officers, are then required to manage this more complex form of TB, with limited resources, less experience and assumingly with less MDR TB knowledge. Of particular concern is that shifting of the patient management from specialized TB hospitals to Primary Health Care clinics which might worsen the already poor MDR TB treatment outcomes. There has been minimal assessment of the management of MDR TB at clinic level and hence the comparison of treatment outcomes for those patients initiated on treatment in clinics compared to in-patients in specialized TB hospitals is urgently needed. Aim: To compare the treatment outcomes and the effectiveness of medication regimens provided to MDR TB patients initiated on treatment in specialized TB hospitals as inpatients, to that of MDR TB patients initiated on treatment as outpatients at community clinics within the Western Cape Province, South Africa. Methodology Study Design: A retrospective cohort study was undertaken, as the length of treatment for a MDR TB patient can be for 24 months or longer and this study was based on treatment outcome data. Study Population and sample: The study population was uncomplicated MDR TB patients initiated on treatment in hospitals and clinics from January 2010 to December 2012. The sample comprised of 568 participants that were laboratory confirmed to have MDR TB and had the outcomes of their treatment recorded in an electronic database or a paper register. Data Collection: The researcher collected MDR TB information from standardized MDR TB registers as well as an electronic MDR TB database. Analysis: Data was analyzed comparing the exposed (clinic initiated) and unexposed (hospital initiated) cohorts incidence of 4 key treatment outcomes, namely: successfully treated, failed treatment, died and defaulted treatment. Bivariate analysis (relative and absolute) was done to determine the cumulative incidence ratio and cumulative incidence difference and multivariate logistic regression analysis for the adjusted odds ratio to control for confounders and effect modifiers. Ethics: Permission to conduct this research was obtained from the relevant authorities. The confidentiality of the participants as per the Department of Health policy and in adherence to general ethical guidelines was strictly maintained. The study proposal received ethical clearance and approval from the University of the Western Cape Research Committee. Results: All participants within this study received the appropriate treatment as per the MDR TB guidelines. The incidence rate for the main outcomes of this study indicated that successfully treated for the clinic initiated participants was 41% and 31% for the hospital initiated participants. ‘Defaulted’ treatment was 39% and 41%, ‘failed’ treatment 7% and 13% and ‘died’ was 14% and 16%, respectively. The clinic initiated participants appeared to have better treatment outcomes on bivariate analysis, however on multivariate analysis, there was no difference in the treatment outcomes of the clinic initiated participants compared to the hospital initiated participants, and therefore the clinic initiated treatment is seen as effective. The time to treatment initiation for clinic and hospital initiated participants is excessively long for both cohorts, with a median of 29 days, and 37 days respectively. The key findings of note in the multivariate analysis is that the Human Immunodeficiency Virus positive (HIV+) participants provided with antiretrovirals therapy (ART) were, based on adjusted cumulative incidence ratios, 6.6 times more likely to have a successfully treated outcome (95% CI 1.48-29.84), and were 0.2 times less likely to die (95% CI 0.08-0.53). Having a previous cured history of TB and no previous history of TB were 2.9 times more likely to have a successfully treated outcome (95% CI 1.48-5.56) and were 0.1 times (0.04-0.38) less likely to fail treatment. An interesting finding was that participants living in the rural districts were 2.6 times more likely to die. Conclusion: Clinic initiated treatment for uncomplicated MDR TB is as effective as hospital initiated treatment. Also, those provided with ART and those without previous TB or who had a previous bout of TB cured, had better outcomes. Main Recommendations: The Western Cape health department should continue with the decentralization of MDR TB services to the clinics and could safely consider expanding the decentralization to include uncomplicated Preextensively drug-resistant TB and Extensively drug-resistant TB patients. Offering ART to HIV+ patients should be mandatory. The delays in the time to treatment initiation of MDR TB need to be further investigated.

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Tinzi, Siphokuhle. "Exploration of experiences of patients with the adverse-drug effects of multidrug-resistant tuberculosis treatment in a primary health care facility in the Western Cape". University of the Western Cape, 2017. http://hdl.handle.net/11394/5660.

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Magister Curationis - MCur
Multidrug resistant TB (MDR-TB) is a form of TB caused by bacteria (germs) that are resistant to the usual drugs that are used to treat "normal" TB. The duration of treatment for MDR-TB is a maximum of 22 months. People with MDR-TB are treated in specialized tertiary hospitals and in out-patient clinics in the PHC facilities. The treatment includes a six months injectable phase with a wide range of TB drugs. The adverse effects of MDR-TB drugs are among the worst side effects ever reported by patients. The aim of the current study was to explore the experiences of adverse effects of MDR-TB treatment amongst patients in a primary health care facility in the Western Cape. An explorative qualitative study design was used to explore the experiences of patient with the adverse effects of MDR-TB treatment in a primary health care facility in the Western Cape. In depth interviews were conducted with 12 MDR-TB patients. Data analysis was done by using the Tesch's method of content analysis. The study revealed that participating MDR-TB patients experienced various emotional, financial, physical and social challenges. Participants explained that the experience of being on MDR-TB treatment is emotionally draining; the pain and discomfort of the adverse effect of treatment makes a person to feel anxious and depressed. Financially they depended on social grants because they had to stop working after starting treatment. They could not function well physically because of the toxic nature of the adverse effects of treatment; which resulted in fatigue, dizziness and burning sensation on the feet and hands. They were faced with a lot of stigma from the community and even family members because of their illness. The study also revealed that in spite of the challenges and obstacles the participants were all motivated to complete their treatment and get cured. It is recommended that more support structures be made available for patients who are being treated for MDRT-TB such as; psychotherapy, social support and counselling on health education. Provision needs to be made for patients who are receiving daily injection; for it to be given in their homes. Health care providers treating MDR-TB patients need to do home visits together with MDR-TB adherence counsellors, to monitor the physical wellbeing of patients at home. This will also provide patients with the platform to discuss their health concerns in a more accommodative and relaxed environment. New drug regimen with fewer tablets and less treatment duration is needed for MDR-TB.

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Nhokwara, Primrose Tinashe. "Factors that influence the utilisation of ototoxicity monitoring services for patients on treatment for drug-resistant tuberculosis". Master's thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/15683.

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Multi-drug resistance is increasingly becoming a challenge to tuberculosis control programmes globally. Treatment of multi-drug resistance tuberculosis (MDR-TB) includes aminoglycoside antibiotics which are known to cause hearing loss. Ototoxicity monitoring services are often provided to patients undergoing treatment for MDR-TB for early detection of ototoxic hearing loss to facilitate alerting the patients and relevant medical staff about the presence and progression of any hearing loss. Previously, models of managing patients with MDR-TB required mandatory hospitalization for at least 6 months. This made it relatively easy to monitor the hearing status of patients during their stay in the hospital. However, with recent introduction of policy guidelines that support management of patients with MDR-TB on an outpatients basis, ototoxicity monitoring for these patients will need to be reorganized to align with the new policy guidelines. The extent of the uptake of these services when patients are accessing them as outpatients is however, unknown. This study therefore aimed to describe the patterns of utilisation and explore the barriers and factors that facilitate the use of ototoxicity monitoring services when provided on an outpatient basis in the Cape Town Metropolitan area, Western Cape, South Africa.

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El, Achkar Salam. "Prevalence of drug-resistant tuberculosis assessed by next-generation sequencing : an 18-month nationwide study in Lebanon". Thesis, Lille 2, 2019. http://www.theses.fr/2019LIL2S045.

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La tuberculose (TB) est la première maladie infectieuse mortelle, avec 10 millions de nouveaux cas estimés dans le monde en 2017. La résistance aux médicaments antituberculeux ainsi que le diagnostic de cette résistance sont particulièrement problématiques. Seulement 25% des 450 000 cas de tuberculose multi-résistante estimés au cours de la même année ont été diagnostiqués et traités comme tels.Bien que le Liban ait un faible taux de tuberculose, le contrôle de la maladie pose d’importants problèmes. Le Liban est le pays au monde accueillant la plus grande population de réfugiés par rapport à sa population nationale. Suite à la guerre en Syrie, le pays compte 1,5 million de réfugiés syriens, ainsi qu’un nombre important de réfugiés palestiniens et de travailleurs migrants. Ces populations sont particulièrement vulnérables face aux risques de tuberculose et à l’émergence de résistance aux antituberculeux. La dernière enquête nationale de prévalence de résistance aux antitberculeux avait été réalisée il y a 15 ans, bien avant le début de la crise syrienne en 2011. Même les taux les plus récents de tuberculose multi-résistante signalés reposaient en grande partie sur des estimations. Les tests de sensibilité aux antibiotiques (DST) de seconde intention et les traitements individualisés de tuberculose ultra-résistante (XDR) n'étaient jusqu’alors pas disponibles dans le pays.Afin d'obtenir une vue globale et actualisée de la situation de la tuberculose dans le pays, nous avons mis en place la première étude nationale combinant des tests phénotypiques et moléculaires avancés pour déterminer la prévalence et l'étendue de la résistance aux antituberculeux. Au total, 417 patients ont été inclus dans l’étude. Ils correspondent aux cas de tuberculose confirmés et signalés au programme national de lutte contre la tuberculose entre juin 2016 et novembre 2017. Des cultures en milieu Lowenstein-Jensen et/ou MGIT ainsi que des tests moléculaires GeneXpert MTB/RIF et/ou Anyplex MTB/NTM Real-Time ont été effectués au Liban pour confirmer le diagnostic et tester la sensibilité aux antituberculeux. À Lille, nous avons évalué, pour la première fois sur un échantillon national représentatif, un nouveau test de détection de résistances aux antibiotiques, Deeplex-MycTB. Ce test, basé sur le séquençage de nouvelle génération (NGS) et en profondeur de l’ADN, permet une prédiction étendue des résistances aux antituberculeux ainsi qu’un génotypage des isolats de patients. Le typage MIRU-VNTR standardisé a été utilisé en combinaison pour définir les clusters moléculaires potentiellement évocateurs de souches de mycobactéries à circulation endémique ou à transmission épidémique.Pour la première fois dans le pays, sur les 354 cas de tuberculose à culture positive avec DST disponible, 3 cas de XDR, résistants au moins à la rifampicine (RIF), à l'isoniazide (INH), à la kanamycine (KAN)/amikacine (AMI) et à la lévofloxacine (LFX) ont été détectés, en plus de 5 cas multi-résistants (résistant au moins à RIF, INH) et un cas mono-résistant à la RIF. Parmi les cas restants, 3,4% (12/354) présentaient une résistance à l'INH et à la streptomycine (SM), 3,4% (12/354) une mono-résistance à l'INH, 0,3% (1/354) une mono-résistance à l'éthambutol (EMB), 8,5% (30/354) une mono-résistance à la SM, tandis que 81,9% (290/354) étaient sensibles aux 4 médicaments de première intention testés. Bien qu'aucun cas de tuberculose multi- ou ultra-résistante n'ait été trouvé dans des clusters moléculaires, un cluster important comprenant 36 autres patients a été identifié, suggérant une souche non résistante hautement endémique ou transmise activement.Deeplex-MycTB a prédit un total de 4184 sur les 4407 (94,9%) phénotypes possibles pour 339/348 (97,4%) échantillons analysables, dont 1282/1380 (92,9%) correspondaient aux résultats phénotypiques disponibles [...]
Tuberculosis (TB) is the first killer infectious disease, with 10 million new cases estimated worldwide in 2017. TB drug resistance and its diagnosis are particularly problematic. Only 25% of the 450,000 incident multidrug resistant (MDR) TB patients estimated over the same year were diagnosed and treated as such.Although Lebanon is a low-TB burden country, significant challenges exist in terms of disease control. Lebanon is the country hosting the largest refugee population proportionally to its national population worldwide, with 1.5 million Syrian refugees as a consequence of the war in Syria, in addition to large populations of Palestinian refugees and migrant workers. Such populations are particularly vulnerable to risks of TB and emergence of drug resistance. The last national survey on the prevalence of drug resistant TB was done 15 years ago, well before the start of the Syrian crisis in 2011. Even most recent reported rates of MDR TB largely relied on estimates. Second-line drug susceptibility testing (DST) and individualized extensively drug-resistant (XDR) TB treatments were not available in the country.In order to gain a more comprehensive view of the TB situation, we set up the first nationwide study combining phenotypic and extensive molecular testing to determine the prevalence and extent of TB drug resistance in the country. A total of 417 patients were included, corresponding to all confirmed TB cases reported to the national tuberculosis program between June, 2016 and November, 2017. Lowenstein-Jensen and/or MGIT culturing, and molecular testing using GeneXpert MTB/RIF and/or Anyplex MTB/NTM Real-time were used in Lebanon for diagnostic confirmation and DST. In Lille, we evaluated, for the first time on a nationally representative sample, a new deep sequencing assay called Deeplex-MycTB, for extensive drug resistance prediction and genotyping of patient isolates. MIRU-VNTR typing was used in combination for defining molecular clusters, potentially suggestive of endemically circulating or epidemically transmitted TB strains.For the first time in the country, out of the 354 culture positive TB cases with available DST, 3 XDR cases, resistant to at least rifampicin (RIF), isoniazid (INH), kanamycin (KAN)/amikacin (AMI) and levofloxacin (LFX) were detected, in addition to 5 MDR (resistant to at least RIF, INH) cases and one RIF mono-resistant case. Among the remaining cases, 3.4% (12/354) had resistance to INH and streptomycin (SM), 3.4% (12/354) mono-resistance to INH, 0.3% (1/354) mono-resistance to ethambutol (EMB), 8.5% (30/354) mono-resistance to streptomycin (SM), while 81.9% (290/354) were susceptible to all 4 first line drugs. While none of MDR and XDR TB cases were found in molecular clusters, a large cluster comprising 36 other patients was identified, suggestive of a highly endemic or actively transmitted drug susceptible strain.A total of 4184 out of 4407 (94.9%) possible phenotypes could be predicted by Deeplex-MycTB for 339/348 (97.4%) analyzable samples, of which 1282/1380 (92.9%) matched the available phenotypic results. Based on detectable resistance determinants, INH, RIF, EMB and SM resistance was concordantly predicted with 90.3%, 100%, 100%, 52.8% sensitivity, respectively, and susceptibility with 99.6%, 100%, 99.4%, 99.6% specificity, respectively. While predicted first and second-line drug resistance matched almost completely the available phenotypic profiles of the 8 MDR and XDR cases, mutations were additionally detected in all of these 8 cases in targets predicting supplementary pyrazinamide and/or ethionamide resistance, not phenotypically tested. Moreover, resistance to fluoroquinolones was also predicted in 34/339 (10%) non-MDR cases, not subjected to LFX DST. Finally, the use of advanced molecular testing allowed us to identify the first 12 (3.4%) zoonotic TB cases identified in the country [...]

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Firfirey, Nousheena. "Occupational adaptation : the experiences of adult patients with MDR- TB who undergo long- term hospitalisation". University of the Western Cape, 2011. http://hdl.handle.net/11394/5300.

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Magister Scientiae (Occupational Therapy) - MSc(OT)
TB is a multi- faceted public health problem spurred on by the biological progression of the disease as well as the social issues associated with it. The treatment of TB is however primarily driven by the medical model where the focus is on the disease and not on a holistic view of the patient. Occupational therapy is a profession concerned with the use of occupation in the promotion of health and well being through the facilitation of the process of occupational adaptation. There is however a paucity of literature pertaining to the role that occupational therapy could play within the TB context. The aim of this study was to explore how adults with MDR- TB who undergo long-term hospitalisation at a hospital in the Western Cape experience occupational adaptation. The objectives of the study were to explore how the participants perceive their occupational identity, to explore the meaning and purpose the participants assign to their occupational engagement and to explore the how the participants perceive their occupational competence. The interpretive research paradigm employing a phenomenological qualitative research approach was utilized in this study. Purposive sampling was used to select four participants based on specific selection criteria. The data gathering methods utilized included diaries, semistructured interviews, participant observation and a focus group. Photographs taken by the researcher for the purpose of participant observation were used to elicit a rich, in depth response from the participants during the focus group discussion. All data was analysed through thematic content analysis. The study findings highlighted that the participants viewed themselves as occupational beings and that they valued the role that occupational engagement played in facilitating their occupational competence and ultimately their ability to adapt to long- term hospitalisation. The environmental demands and constraints that they experienced however infringed their engagement in meaningful occupation and hampered their ability to achieve occupational competence. It was recommended that the hospital adopt an integrative intervention approach to the management of MDR- TB patients that include principles of psychosocial rehabilitation and occupational enrichment to address occupational risk factors and institutionalisation.

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Harris, Michelle J. "Characterization of Drug Resistance in Mycobacterium Tuberculosis via Saturating Mutagenesis of Drug Targets: A Master’s Thesis". eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/605.

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Mycobacterium tuberculosis isolates from multiple drug resistant or extensively drug resistant patients show a particular set of mutations in drug targets conferring resistance. However, the selection of drug-resistant strains in vitro yields an alternative set of mutations, thought to result from the cost-benefit associated with drug resistance. Mutations allowing for survival under antibiotic may not be beneficial when presented with the host environment or with a drug-free environment. These fitness effects drive the natural evolution of this bacterium. Using recombineering a large cohort of mutations was generated within two drug targets, inhA and gyrA, to study in vitro the variability of mutations allowable under either isoniazid or ofloxacin, respectively. As a proof of concept this process was carried out in Mycobacterium smegmatis. Analysis of survivors allowed for identification of novel mutations and substitutions, as well as showing mutations previously found only in clinical isolates can be present in laboratory isolates.

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Kuzeljevic, Brigitta. "The Potentials and Difficulties of Two New Drugs, TMC 207 and PA-824, against Drug-Susceptible and Drug-Resistant Strains of Mycobacterium tuberculosis". Thesis, Linnéuniversitetet, Institutionen för kemi och biomedicin (KOB), 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-25284.

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Tuberculosis has for decades been the leading cause of death, worldwide, originating from merely one infectious matter i.e. the bacilli Mycobacterium tuberculosis (MTB). It is killing approximately 1.5 million people every year. The World Health Organization (WHO) estimates that 2 billion people might be infected by this specific bacterium, and that there emerges about 9 million new, active cases of TB each year. The aim with this thesis is to elucidate the possibilities and the difficulties with two new drugs against susceptible and resistant, latent and replicating strains of M. tuberculosis. A search for relevant articles on Pub Med, through the university library, was undertaken and approximately 35 articles were found. These articles were read; facts were sorted out and used for this paper. Figures were found through Creative Commons. The two new drugs discussed in this paper are TMC 207 and PA-824. They have two different mechanisms of action, and additionally and most importantly, that differ from the drugs used as first-line and second-line options. TMC 207 targets the mycobacterial ATP synthase. PA-824, a pro-drug, targets the cell wall synthesis and in addition causes respiratory poisoning, through the release of nitric oxide. The different mechanisms are vital in order to combat emerging resistance, due to various missense mutations in specific genes in the bacilli. The bactericidal activity of the drugs against mycobacteria is high, promising a successful cure for MDR (multi drug resistant)/XDR (extensively drug resistant) patients. The median survival is 4.1 years for MDR patients and 2.9 years for XDR patients, with currently available treatments. This is noticeably worse than some cancer prognoses. Perhaps with these drugs there is even a possibility of shortening the treatment time. The adverse events are mild to moderate, for both drugs. This is another additive advantage, since the toxicity of the drugs will be minimal and hopefully tolerable, and most importantly will bring about treatment commitment and the sought elimination of the disease. However, as with all new drugs the outcomes are still to be proven in real settings, the complex fields (in low- and middle income countries, with difficult TB cases), and with complicated cases (e.g. HIV co-morbidity) during a longer period of time. Reporting and evaluating the outcomes is crucial, since whatever is displayed from the drug consumption and the effects of it can lead to alterations in regimens, doses and treatment commitment.

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Xie, Yan. "A PhenoTarget Approach for Identifying Bioactive Compounds that Interact with TB Proteins". Thesis, Griffith University, 2021. http://hdl.handle.net/10072/407560.

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Tuberculosis (TB) is the number one cause of human death from infectious disease in the world. Current treatments are challenged by the high levels of drug-resistant Mtb infection, which including rifampicin-resistant TB (RR-TB), multidrug-resistant TB (MDR-TB), and extensively drug resistant TB (XDR-TB). New drugs with mechanism of action (MOA) are required for more effective treatments. The literature review covered TB disease, the discovery of current treatments and clinic candidates, natural products in TB drugs, two drug discovery strategies phenotypic based drug discovery (PDD) and target based drug discovery (TDD), and a platform to directly observe protein-ligand complexes. A combination of phenotypic screening with NMR fingerprints led to the isolation kokusaginine (2.1) from Flindersia maculosa Lindl. , a mixture of flindersiamine (2.2) and maculine (2.3) from Flindersia maculosa Lindl., fascaplysin (2.4) from Fascaplysinopsis sp., and agelasine D (2.5) from Agelas axifera. Fascaplysin (2.4) and agelasine D (2.5) showed strong inhibitory activities against M. smegmatis. Data analysis of phenotypic screening and molecular target screening prioritised four PFs fractions for identification of the active constituents. Polycarpine (4.1) from the marine organism, Polycarpa aurata, formed a covalent bond with Rv1466. Polycarpine (4.1) had a pseudo-KD as 5.3 ± 0.4 μM with Rv1466. Rv1466 (5IRD) has a single cysteine that is exposed on the surface of the protein Polycarpaurine C (4.2) was also identified as a covalent ligand bound to Rv1466. Isogoyazensolide (5.1) and goyazensolide (5.3), and one new compound (5.2) were isolated from Centratherum sp.. Both isogoyazensolide (5.1) and goyazensolide (5.3) formed protein-ligand complexes with Rv1466 but the binding affinities were weak. Given the reported anti-TB activity of isogoyazensolide (5.1) and goyazensolide (5.3) against Mtb H37Ra, Rv1466 is likely NOT the target. Five compounds, dibromophakellin (6.1), (10Z)-debromohymenialdisine (6.2), aldisin (6.3), 2-bromoaldisin (6.4), and stylisine A (6.5) were isolated from Stylissa flabellate Dibromophakellin (6.1) interacted with Rv3606c while the other four compounds did not. The similar binding affinities of dibromophakellin (6.1) with Rv3606c from M. fortuitum and M. abscessus. indicated that Rv3606c as a drug target in M. fortuitum and M. abscessus. Analysis of the chemical constituents and biological activities of an ethnic medicine, Ardisia japonica, used to treat TB in China gave a PhenoTarget correlation map of isolated compounds, the traditional application, cell-based phenotypes and molecular targets. The advantages and disadvantages of the novel PhenoTarget approach are discussed relative to the overall aim to combine PDD and TDD to identify the compounds with anti-TB activities.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
Science, Environment, Engineering and Technology
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