84 research outputs found

    Antimicrobial Resistance in Mycobacterium tuberculosis: The Odd One Out

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    Antimicrobial resistance (AMR) threats are typically represented by bacteria capable of extensive horizontal gene transfer (HGT). One clear exception is Mycobacterium tuberculosis (Mtb). It is an obligate human pathogen with limited genetic diversity and a low mutation rate which lacks any evidence for HGT. Such features should, in principle, reduce its ability to rapidly evolve AMR. We identify key features in its biology and epidemiology that allow it to overcome its low adaptive potential. We focus in particular on its innate resistance to drugs, its unusual life cycle, including an often extensive latent phase, and its ability to shelter from exposure to antimicrobial drugs within cavities it induces in the lungs

    Intervensi pada Pasien Tuberkulosis untuk Meningkatkan Kepatuhan dan Manajemen Diri

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    This study aims to design and analyze interventions that can be used in tuberculosis patients to improve adherence and self-management in preventing multi-drug-resistant tuberculosis (MDR-TB) events. The research method is a literature review conducted to analyze the concept of intervention in tuberculosis patients. A comprehensive literature search was carried out through an electronic database of CINAHL and PUBMED from publications from early 2020 to December 30, 2022. The results showed that interventions that could be carried out were increasing knowledge, increasing the role of medical staff in motivating and observing both through messages, text, or telephone, improving education through health promotion so that TB patients can comply with treatment, and improving self-management. Other interventions that can improve adherence to TB treatment are psychological counseling, individual education, digital-based medication monitoring (DOTS) WOT, telephone-based pill refill reminders, and medication monitoring), and peer support. In conclusion, good self-management behavior is proven to reduce the progression of diseases, including tuberculosis. Age, attitude, marital status, and home conditions influence self-management. While the knowledge factor indirectly affects self-management through mentality. Thus, knowledge and attitudes require the intervention of other parties who can mediate. This is to avoid the occurrence of Multidrug-Resistant Tuberculosis (MDR-TB).   Keywords: Intervention, Compliance, Self Management, Tuberculosi

    Epidemiologic impact of treatment interventions for tuberculosis control

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    Background Once thought to be on its way to elimination, tuberculosis (TB) has resurged in recent decades and is now the leading cause of death among infectious diseases globally. Effective TB control will require optimal implementation of treatment interventions in order to maximize the potential benefits not only for individual patients but also at the population level. Methods We conducted three studies using dynamic compartmental models of TB transmission to project the potential impact of shortened duration of first-line TB therapy on TB incidence and mortality (Chapter II), the effect of re-using pyrazinamide in both first- and second-line treatment on the emergence of extensive drug resistance (Chapter III), and the value of treatment scale-up and programmatic improvements in the control of multidrug-resistant (MDR) TB (Chapter IV). Results Contrary to previous studies, we find that shortening the duration of first-line TB therapy is unlikely to yield major reductions in incidence over a time span of 15 years (projected reduction 1.9% with 4-month vs. 6-month treatment). We then demonstrate how the routine use of pyrazinamide in both first- and second-line TB treatment may promote the emergence of extensively drug-resistant TB. In the last study, we find that although scaling up treatment of MDR TB may substantially reduce future prevalence (median reduction in MDR TB prevalence 28.1% over 20 years), combining scale-up with programmatic interventions that improve linkage to care and treatment completion maximizes impact (median reduction 74.5%). Conclusions This work provides valuable guidance in optimizing treatment interventions to achieve population-level impact in global TB control

    Undetected isoniazid mono resistance in rural Eastern Cape Province - A risk for the emergence of multidrug-resistant TB

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    Thesis (MSc)--Stellenbosch University, 2021.ENGLISH ABSTRACT: The emergence of drug-resistant tuberculosis (TB) remains a major challenge in South Africa, particularly the Eastern Cape, being one of the most severely affected provinces in the country. Due to resource limitations, many isoniazid (INH) mono-resistant TB cases remain undiagnosed, as TB control programmes generally focus on rifampicin-resistant strains. Rifampicin resistance, which is a marker of multidrug-resistant (MDR) TB, is more difficult to treat than INH mono-resistant (IMR) TB, often resulting in high morbidity and mortality. The effectiveness of INH, an important first-line anti-TB drug, has been compromised by resistance, which arises through spontaneous mutations in the genome of Mycobacterium tuberculosis (M. tuberculosis). Occurrence of these mutations is often missed by the current diagnostic algorithm, which fails to detect IMR-TB cases at diagnosis, hence threatening the efficacy of TB treatment. Consequently, these patients are likely to be treated with a weakened regimen, which may increase the risk of treatment failure or relapse. Previous studies have reported IMR as the source for the emergence of MDR-TB. This study aimed to provide the first in-depth analysis of the molecular epidemiology of IMR-TB in the Eastern Cape. Clinical isolates from patients with rifampicin-susceptible TB were obtained via the National Health Laboratory Services (NHLS) in Port Elizabeth and analysed by using a series of microbiological and molecular techniques. These tests were done to identify IMR-TB cases, describe the molecular mechanisms of INH resistance, identify cases of acquisition of IMR and MDR, as well as to describe risk factors associated with IMR at diagnosis (baseline). We also used spoligotyping to classify isolates into their respective lineages and strain families. Phenotypic INH drug susceptibility testing on solid media identified 107 (13.9%) cases of IMR among the cohort of 993 TB cases enrolled, which was nearly double the estimated national average. No association between patient demographic or clinical parameters was identified. This may be due to the inaccuracies of the electronic TB database. Genetic drug susceptibility testing only identified causal mutations in 25 baseline isolates, while 4 baseline isolates showed evidence of heteroresistance, possibly masking the detection of underlying INH-resistant populations. This was confirmed in a small sub-analysis using a highly sensitive targeted deep sequencing approach. Subsequent analysis of serial isolates showed acquisition of IMR in 9 cases, as well as loss of IMR in 12 cases. Repeat analysis identified heteroresistance as the possible cause of the observed flip flopping of the IMR phenotype. Spoligotyping failed to identify reinfection as a major mechanism causing the flip flopping IMR phenotype. IMR was associated with the Atypical Beijing genotype (p < 0.0001). This study highlights the need to change TB policy through: (1) understanding the local epidemiology of IMR to identify potential risk factors for targeted interventions and to strengthen current first-line regimens for the continuation phase of TB treatment, (2) improving surveillance studies in neglected rural areas by monitoring IMR to inform policy, (3) developing new rapid molecular technologies to ensure early identification of IMR-TB cases and close monitoring of patients following appropriate treatment and care. These strategies will be essential to contain the spread of IMR-TB, improve outcomes and prevent progression of disease to more severe forms of drug resistance often culminating in death.AFRIKAANSE OPSOMMING: Die opkoms van middelweerstandige tuberkulose (TB) bly 'n groot uitdaging in Suid-Afrika, veral die Oos-Kaap, as een van die provinsies in die land wat die ergste geraak word. As gevolg van hulpbronbeperkte kapasiteit, bly baie isoniasid (INH) mono-weerstandige TB gevalle nie gediagnoseer nie, aangesien TB-beheerprogramme oor die algemeen fokus op rifampisin-weerstandige stamme. Rifampisin weerstand is 'n merker van multimiddel weerstandige (MDR) TB, wat moeiliker is om te behandel as INH mono-weerstandige (IMR) TB, wat dikwels lei tot hoë morbiditeit en mortaliteit. Die effektiwiteit van INH, 'n belangrike eersterangse middel teen TB, word verminder deur weerstand wat ontstaan deur spontane mutasies in die genoom Mycobacterium tuberculosis (M. tuberculosis). Die voorkoms van hierdie mutasies word dikwels gemis deur die huidige diagnostiese algoritme, wat nie IMR-TB-gevalle kan opspoor tydens diagnose nie. Gevolglik word die doeltreffendheid van TB-behandeling bedreig, aangesien hierdie pasiënte meer geneig is om met 'n verswakte behandeling behandel te word, wat die risiko van versuim of terugval kan verhoog. Vorige studies het IMR as die bron vir die opkoms van MDR-TB gerapporteer. Hierdie studie het ten doel gehad om die eerste diepgaande analise van die molekulêre epidemiologie van IMR-TB in die Oos-Kaap te bied. Kliniese isolate van pasiënte met rifampisin-vatbare TB is verkry deur die National Health Laboratory Services (NHLS) in Port Elizabeth en geanaliseer deur gebruik te maak van 'n reeks mikrobiologiese en molekulêre tegnieke. Hierdie toetse is gedoen om IMR-TB-gevalle te identifiseer, die molekulêre meganismes van INH-weerstand te beskryf, gevalle van verkryging van IMR en MDR te identifiseer, asook om risikofaktore wat verband hou met IMR tydens diagnose (basislyn) te beskryf. Ons het ook spoligotipering gebruik om isolate in hul onderskeie geslagte en stamfamilies te klassifiseer. Fenotipiese toetsing vir vatbaarheid vir INH-geneesmiddels op vaste media het 107 (13,9%) gevalle van IMR geïdentifiseer onder die groep 993 TB-gevalle wat ingeskryf is, wat byna dubbel die geskatte nasionale gemiddelde was. Geen verband tussen pasiënte se demografiese of kliniese parameters is geïdentifiseer nie. Dit kan te wyte wees aan die onakkuraathede van die elektroniese databasis. Die toetsing van vatbaarheid vir genetiese geneesmiddels het slegs oorsaaklike mutasies in 25 basislyn-isolate geïdentifiseer, terwyl vier basislyn-isolate bewyse van heteroresistensie getoon het, wat moontlik die opsporing van onderliggende INH weerstandige populasies kon wegsteek. Dit is bevestig in 'n klein sub-analise deur gebruik te maak van 'n baie sensitiewe, gerigte diepvolgorde-benadering. Daaropvolgende ontleding van reeksisolate het die verkryging van IMR in 9 gevalle getoon, asook verlies aan IMR in 12 gevalle. Heranalise het heteroresistensie geïdentifiseer as die moontlike oorsaak van die waargenome “flip-flopping” van die IMR-fenotipe. Spoligotipering kon nie herinfeksie identifiseer as 'n belangrike meganisme wat die IMR-fenotipe omkeer. IMR word geassosieer met die Atipiese Beijing-genotipe (p <0.0001). Hierdie studie beklemtoon die behoefte om TB-beleid te verander deur: (1) die plaaslike epidemiologie van IMR te verstaan om potensiële risikofaktore vir geteikende intervensies te identifiseer en die huidige eerste-lyn-regimes vir die voortsettingsfase van TB-behandeling te versterk, (2) verbetering van toesigstudies by verwaarloosde landelike gebiede deur IMR te monitor om beleid in te lig, (3) die ontwikkeling van nuwe vinnige molekulêre tegnologieë om vroeë identifikasie van IMR-TB-gevalle te verseker en noukeurige monitering van pasiënte na toepaslike behandeling en sorg. Hierdie strategieë is noodsaaklik om die verspreiding van IMR te beperk, die uitkomste te verbeter en die progressie van siektes na meer ernstige vorme van middelweerstandigheid te voorkom, wat dikwels op die dood uitloop.Master

    Temporal Factors and Missed Doses of Tuberculosis Treatment: A Causal Associations Approach to Analyses of Digital Adherence Data

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    Rationale: Tuberculosis treatment lasts for 6 months or more. Treatment adherence is critical; regimen length, among other factors, makes this challenging. Globally, analyses mapping common types of nonadherence are lacking. For example, is there a greater challenge resulting from early treatment cessation (discontinuation) or intermittent missed doses (suboptimal dosing implementation)? This is essential knowledge for the development of effective interventions and more "forgiving" regimens, as well as to direct national tuberculosis programs.Objectives: To granularly describe how patients take their tuberculosis medication and the temporal factors associated with missed doses.Methods: The present study included patients with pulmonary tuberculosis enrolled in the control arm of a pragmatic, cluster-randomized trial in China of electronic reminders to improve treatment adherence. Treatment was the standard 6-month course (180 d), dosed every other day (90 doses). Medication monitor boxes recorded adherence (box opening) without prompting reminders. Patterns of adherence were visualized and described. Mixed-effects logistic regression models examined the temporal factors associated with per-dose suboptimal dosing implementation, adjusting for clustering within a participant. Cox regression models were used to examine the association between early suboptimal dosing implementation and permanent discontinuation.Results: Across 780 patients, 16,794 (23.9%) of 70,200 doses were missed, 9,487 of which were from suboptimal dosing implementation (56.5%). By 60 days, 5.1% of participants had discontinued, and 14.4% had discontinued by 120 days. Most participants (95.9%) missed at least one dose. The majority of gaps were of a single dose (71.4%), although 22.6% of participants had at least one gap of 2 weeks or more. In adjusted models, the initiation-continuation phase transition (odds ratio, 3.07 [95% confidence interval, 2.68-3.51]) and national holidays (1.52 [1.39-1.65]) were associated with increased odds of suboptimal dosing implementation. Early-stage suboptimal dosing implementation was associated with increased discontinuation rates.Conclusions: Digital tools provide an unprecedented step change in describing and addressing nonadherence. In our setting, nonadherence was common; patients displayed a complex range of patterns. Dividing nonadherence into suboptimal dosing implementation and discontinuation, we found that both increased over time. Discontinuation was associated with early suboptimal dosing implementation. These apparent causal associations between temporal factors and nonadherence present opportunities for targeted interventions.Clinical trial registered with the ISRCTN Registry (ISRCTN46846388)

    The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis.

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    Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues

    IMPACT study on intervening with a manualised package to achieve treatment adherence in people with tuberculosis: protocol paper for a mixed-methods study, including a pilot randomised controlled trial

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    Kielmann, Karina - ORCID 0000-0001-5519-1658 https://orcid.org/0000-0001-5519-1658Introduction Compared with the rest of the UK and Western Europe, England has high rates of the infectious disease tuberculosis (TB). TB is curable, although treatment is for at least 6 months and longer when disease is drug resistant. If patients miss too many doses (non-adherence), they may transmit infection for longer and the infecting bacteria may develop resistance to the standard drugs used for treatment. Non-adherence may therefore risk both their health and that of others. Within England, certain population groups are thought to be at higher risk of non-adherence, but the factors contributing to this have been insufficiently determined, as have the best interventions to promote adherence. The objective of this study was to develop a manualised package of interventions for use as part of routine care within National Health Services to address the social and cultural factors that lead to poor adherence to treatment for TB disease.Methods and analysis This study uses a mixed-methods approach, with six study components. These are (1) scoping reviews of the literature; (2) qualitative research with patients, carers and healthcare professionals; (3) development of the intervention; (4) a pilot randomised controlled trial of the manualised intervention; (5) a process evaluation to examine clinical utility; and (6) a cost analysis.Ethics and dissemination This study received ethics approval on 24 December 2018 from Camberwell St. Giles Ethics Committee, UK (REC reference 18/LO/1818). Findings will be published and disseminated through peer-reviewed publications and conference presentations, published in an end of study report to our funder (the National Institute for Health Research, UK) and presented to key stakeholders.Trial registration number ISRCTN95243114Secondary identifying numbers University College London/University College London Hospitals Joint Research Office 17/0726. National Institute for Health Research, UK 16/88/06.https://doi.org/10.1136/bmjopen-2019-032760http://bmjopen.bmj.com/cgi/content/full/bmjopen-2019-0327609pubpub1

    Predictors of recurrent TB in sputum smear and culture positive adults: a prospective cohort study

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    Objective: To explore simple inexpensive non-culture based predictors of recurrent pulmonary tuberculosis (PTB). Setting and study population: HIV-infected and uninfected adults with the first episode of smear positive, culture-confirmed pulmonary tuberculosis in a high tuberculosis burden country.Design: A nested prospective cohort study of participants with pulmonary tuberculosis (PTB) presenting to a hospital out-patient clinic.Results: A total of 630 TB culture confirmed participants were followed up for eighteen months of which 57 (9%) developed recurrent recurrent TB. On univariate analysis,4.7% low grade(1+) pre-treatment sputum smear participants developed recurrent tuberculosis Vs 8.8% with high grade(3+) smears (OR=0.31,95%CI: 0.10-0.93, p=0.037).On multivariate analysis:participants with extensive fibro-cavitation had a high risk of recurrent TB Vs minimal end of treatment fibro-cavitation (18%Vs12%,OR=2.3,95%CI:1.09-4.68, p=0.03).Weight gain with HIV infection was assosciated with a high risk of recurrentTB Vs weight gain with no HIV infection(18%Vs 6%,OR=6.8,95%CI:165-27.83,p=0.008) where as weight gain with a low pre-treatment high bacillary burden was assosciated with a low risk of recurrent TB Vs weight gain with a high pre-treatmentbacillary burden(6.5%Vs7.9%,OR=0.2,95%CI:0.05-0.79,p=0.02).Conclusion: Extensive end of treatment pulmonary fibro-cavitation, high pre-treatment bacillary burden with no weight gain and HIV infection could be reliable predictors of recurrent tuberculosis.Keywords: Grade, fibrosis, cavities, weight

    Forgiveness Is the Attribute of the Strong:Nonadherence and Regimen-Shortening in Drug-Sensitive TB

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    RATIONALE: 'Forgiveness' charts the ability of a drug or regimen to withstand non-adherence without negative clinical consequences. OBJECTIVES: We aimed to determine the influence of regimen length, regimen drugs and dosing, and when during treatment non-adherence occurs on the forgiveness of anti-tuberculosis regimens. METHODS: Using data from three randomised controlled trials comparing experimental four-month regimens for drug-sensitive tuberculosis with the standard six-month regimen, we used generalised linear models to examine how the risk of a negative composite outcome changed as dose-taking decreased. The percentage of doses taken and absolute number of doses missed were calculated, during the intensive and continuation phases of treatment, and overall. A mediation analysis was undertaken to determine how much of the association between intensive phase dose-taking and the negative composite outcome was mediated through continuation phase dose-taking. MEASUREMENTS AND MAIN RESULTS: Forgiveness of the four-month and six-month regimens did not differ for any treatment period. Importantly, four-month regimens were no less forgiving of small numbers of absolute missed doses than the six-month regimen (e.g. for 3-7 missed doses versus no missed doses (baseline), six-month regimen adjusted risk ratio 1.65 (95% confidence interval 0.80-3.41) and four-month regimens 1.80 (1.33-2.45)). No four-month regimen was conclusively more forgiving than another. We found evidence of mediation by continuation phase dose-taking on the intensive phase dose-taking and negative composite outcome relationship. CONCLUSIONS: With the current appetite for, and progress towards, shorter drug-sensitive tuberculosis regimens worldwide, we offer reassurance that shorter regimens are not necessarily less forgiving of non-adherence. Given the importance of continuation phase adherence, patient support during this period should not be neglected

    A study to determine the palliative care needs of patients with drug resistant tuberculosis in the Southern sub-district of Cape Town

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    Introduction: The Palliative Care needs of patients with Drug-Resistant Tuberculosis (DR-TB) are under-researched, yet pertinent in the management and control of DR-TB. Most literature reviewed focused on treatment schedules, outcomes, transmission, drug adherence, drug side effects and further drug-resistance. Aim: The aim was to determine the palliative care needs of patients infected with DR-TB living in the Southern sub-district of Cape Town. The Objectives The objectives were to determine the quality of life and symptom burden of DR-TB patients and to assess for correlation between these variables and palliative care needs. Methodology: In this cross-sectional study, twenty-eight participants were posed a culturally sensitive questionnaire designed by the researcher, that comprised: demographic questions, Likert-type questions for the African Palliative Care Association – Palliative Outcome Score (APCA-POS) tool, Eastern Co-operative Oncology Group (ECOG) score, a symptom checklist and open patient dignity questions. Quantitative and qualitative data of the respondents’ quality of life, functional status and burden of symptoms in the preceding week were ascertained. Pre-determined numerical scores in the Likert-type questions were deemed indicative of palliative care need. Results: Quantitative and qualitative analysis of the data showed that each participant had a palliative care need: be it either (or a combination of) unmet clinical, psychological, social and/or spiritual needs - despite being at differing stages of the DR-TB disease trajectory. These needs required contextualizing within the respondents’ communities where socio-economic issues were prevalent. Predominant physical complaints were tiredness (79%), joint pain (64%), confusion (61%) and shortness of breath (51%). Respondents’ also experienced a loss of autonomy, poor self-value and financial insecurity. Fifty percent of patients interviewed required urgent further management and referral to the local clinic. Conclusion: Despite the small cohort of patients and possible recruitment bias, this research concurred that a palliative care approach be adopted from the point of DR-TB diagnosis and throughout the treatment period – regardless of treatment outcome; and that DR-TB patients had significant unmet palliative care needs that affected their quality of life, functional status and dignity, regardless of whether pain was present
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