Academic literature on the topic 'Multiple drug resistant tb'

South Africa has one of the world’s highest burdens of TB, HIV/TB co-infection, and drug-resistant TB. Second-line TB treatment is less effective, more expensive, and more toxic than treatment for drug-sensitive TB. Nearly 1 in every 5 persons who starts treatment for drug-resistant TB in South Africa will die; 1 in every 3 persons who survives treatments experiences permanent, profound hearing loss. For decades there was little progress in TB research, however, and so treatment with old regimens continued despite safety concerns. In 2012 the US and European regulatory authorities approved a new drug, bedaquiline, but only for treatment in cases with no other options. In 2015, the South African Medicines Control Council approved bedaquiline for drug-resistant TB, but only a limited number of doses were approved in the 2016/2017 annual budget and the focus, again, was only for the patients who had no other options. In order to inform policy makers in planning and budgeting for drug-resistant TB treatment, the aim of this thesis was to determine whether the simple calculation that bedaquiline was too expensive relative to standard regimens using kanamycin was too simple. Particularly, given the high burden of adverse drug reactions (ADR) associated with kanamycin, would the inclusion of the cost and burden of ADR affect the incremental cost effectiveness ratio of a new treatment regimen where bedaquiline replaces kanamycin? Analysis of the national drug-resistant TB case register showed that mortality during second-line treatment was early, primarily in the first 6 months of treatment, even when patients do not have extensive drug resistance. HIV-positive patients not on anti-retroviral therapy (ART) at initiation of drug-resistant TB treatment have the highest risk of mortality. The high early mortality is a real risk that clinicians have to balance when deciding to initiate ART and effective second-line TB treatment both as quickly as possible. Daily injections coupled with taking more than 10 pills each day are a heavy burden for patient compliance, but also pose concerns in terms of overlapping and compounding toxicities; this burden was confirmed through a meta-analysis of the pooled frequency of adverse events among cohorts with at least 25% of the patients HIV-positive. A competing risk analysis of a cohort of drug-resistant TB patients from Johannesburg – addressing the reality that patients may not have experienced an ADR because they died rather than because they were at lower risk – indicated that HIV-infected patients who are not yet stable on ART and second-line TB treatment are at the highest risk of ADR. A Markov model built and parameterized using the data from the South African national TB programme indicates that bedaquiline for all drug-resistant TB led to a small gain in effectiveness at a cost that was under the costs of the drug itself, due to savings from daily injection visits. While cost-effective, it was not clear that South African policy makers needed to move beyond the offer of bedaquiline for patients with extensive drug resistance. However, the calculation, and the decision point, were different once the costs and disability associated with ADRs was included in the analysis. Bedaquiline-based regimens offer a cost-saving and more effective alternative to an injection-based regimen for drug-resistant TB patients treated in the public sector in South Africa.

Background: Even with newer and repurposed anti-TB drugs almost a third of patients with XDR-TB have unfavourable outcomes. In patients with localised disease and adequate pulmonary reserve, surgery is an important adjunctive treatment. However, there are no outcome data from TB endemic countries, and the prognostic significance of pre-operative PET-CT findings remains unknown. Objectives: To report outcomes for resectional surgery in our setting, and to study whether PET activity outside of the resection influences treatment outcomes. Methods: A retrospective study of all XDR-TB patients undergoing surgery at Groote Schuur Hospital (GSH) between July 2010 and December 2016 was performed. PET-CT was performed in a subgroup. Patients were followed up to determine treatment outcomes at 24-months post- surgery. Treatment success and failure, including all-cause mortality, was determined. Results: In total, 35 patients underwent surgery. The mean age was 36, 49% were male and 26% were HIV-infected. Pneumonectomy was the most common procedure (57%). Three patients (9%) were lost to follow up by 24 months. Total all-cause mortality was 34%. Treatment success was achieved in 15/35 (43%). In patients who underwent pre-operative PET-CT, there were no overall radiological features or PET parameters that were found to be prognostic for treatment failure. Conclusion: Resectional surgery for DR-TB in combination with chemotherapy resulted in cure in less than half of patients. Our data do not support the use of PET-CT to preselect patients or prognosticate about their outcome. These data inform clinical practice and underscore the need to support antibiotic stewardship strategies in TB-endemic settings.

Magister Public Health - MPH<br>Ototoxic induced hearing loss is a common adverse event related to aminoglycosides used in Multi Drug Resistant -Tuberculosis treatment. Exposure to ototoxic drugs damages the structures of the inner ear. Symptomatic hearing loss presents as tinnitus, decreased hearing, a blocked sensation, difficulty understanding speech, and perception of fluctuating hearing, dizziness and hyperacusis/recruitment. The World Health Organization (1995) indicated that most cases of ototoxic hearing loss globally could be attributed to treatment with aminoglycosides. The aim of the study was to determine the proportion of DR-TB patients initiated on treatment at three decentralized sites during a defined period (1st October to 31st December 2015) who developed ototoxic induced hearing loss and the corresponding risk factors, whilst receiving audiological monitoring with an extended high frequency audiometer (KUDUwave). A retrospective cross-sectional study was conducted. Cumulatively across the three decentralized sites, 69 patient records were reviewed that met the inclusion criteria of the study. The mean age of the patients was 36.1, with a standard deviation (SD) of 10.7 years; more than half (37) were female. Ototoxicity , a threshold shift, placing patients at risk of developing a hearing loss was detected in 56.5% (n=39)of patients and not detected in 30.4%(n=21).The remaining 13,1% (n=9)is missing data. As a result, the regimen was adjusted in 36.2% of patients. . From the 53 patients who were tested for hearing loss post completion of the injectable phase of treatment, 22.6% (n=12) had normal hearing, 17.0 % (n=9) had unilateral hearing loss, and 60.4% (n=32) had bilateral hearing loss. Therefore, a total of 41 patients had a degree of hearing loss: over 30% (n=22)had mild to moderate hearing loss, and only about 15% (n=11)had severe to profound hearing loss. Analysis of risk factors showed that having ototoxicity detected and not adjusting regimen significantly increases the risk of patients developing a hearing loss. The key findings of the study have shown that a significant proportion of DR-TB patients receiving an aminoglycoside based regimen are at risk of developing ototoxic induced hearing loss, despite receiving audiological monitoring with an extended high frequency audiometer that allows for early detection of ototoxicity (threshold shift).

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.

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.

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. <p><p>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.<p>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.<p><p>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.<p><p>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.<p><p>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.<p><br>Doctorat en Sciences biomédicales et pharmaceutiques<br>info:eu-repo/semantics/nonPublished

The emergence of drug-resistance of tumor cells is a major complication for succesful chemotherapy. In this study, the molecular mechanisms of resistance to prednisone, vincristine and melphalan in multiple myeloma cell lines, RPMI-8226 and U-266 were investigated. Drug resistance was induced by application of the drugs by stepwise dose increments and confirmed by XTT cytotoxicity assay. Gene expression analysis demostrated that MDR1 gene is one of the most important factor causing the multidrug resistance phenotype in prednisone, vincristine and melphalan resistant multiple myeloma cell lines. According to microarray analysis alterations in laminin, integrin and collagen genes were detected. Additionally, upregulation of some oncogenes and growth factors (Rho family of GTPases, YES1, ACT2, TGFBR, EPS15, PDGF) was shown to have a role in MDR in multiple myeloma. Significant downregulation of suppressors of cytokine signalling gene expressions and upregulation of different types of interleukine and interferon gene expressions (IL3 and interferon-gamma receptor) which are related to JAK-STAT signalling pathay was shown. Alterations in expression levels of genes related to ceramide metabolism were shown especially for melphalan resistance in multiple myeloma. The data from vincristine/prednisone and vincristine/melphalan drug combination studies were shown that the usage of vincristine on prednisone and melphalan resistant multiple myeloma cell lines increase the efficacy of the chemotherapy. On the other hand the cross-resistance development of prednisone and melphalan resistant sublines to irradiation was detected. These results may help to understand the molecular mechanisms of prednisone, vincristine and melphalan resistance in multiple myeloma model cell lines RPMI-8226 and U-266.

In spite of recent therapeutic advances, multiple myeloma (MM) remains a malignancy with very low curability. This has been partly attributed to the existence of a drug-resistant subpopulation known as cancer stem cells (CSCs). MM-CSCs are equipped with the necessary tools that render them highly resistant to virtually all conventional therapies. In this study, the growth inhibitory effects of withanolide D (WND), a steroidal lactone isolated from Withania somnifera, on drug-sensitive tumoral plasma cells and drug-resistant MM cells have been investigated. In MTT/XTT assays, WND exhibited similar cytostatic effects between drug-resistant and drug-sensitive cell lines in the nM range. WND also induced cell death and apoptosis in MM-CSCs and RPMI 8226 cells, as examined by the calcein/ethidium homodimer and annexin V/propidium iodide stainings, respectively. To determine whether P-glycoprotein (P-gp) efflux affected the cytostatic activity of WND, P-gp was inhibited with verapamil and results indicated that the WND cytostatic effect in MM-CSCs was independent of P-gp efflux. Furthermore, WND did not increase the accumulation of the fluorescent P-gp substrate rhodamine 123 in MM-CSCs, suggesting that WND may not inhibit P-gp at the tested relevant doses. Therefore, the WND-induced cytostatic effect may be independent of P-gp efflux. These findings warrant further investigation of WND in MM-CSC animal models.

Doctor Educationis<br>Ototoxic induced hearing loss is a common adverse event related to aminoglycosides used in Multi Drug Resistant -Tuberculosis treatment. Exposure to ototoxic drugs damages the structures of the inner ear. Symptomatic hearing loss presents as tinnitus, decreased hearing, a blocked sensation, difficulty understanding speech, and perception of fluctuating hearing, dizziness and hyperacusis/recruitment. The World Health Organization (1995) indicated that most cases of ototoxic hearing loss globally could be attributed to treatment with aminoglycosides. The aim of the study was to determine the proportion of DR-TB patients initiated on treatment at three decentralized sites during a defined period (1st October to 31st December 2015) who developed ototoxic induced hearing loss and the corresponding risk factors, whilst receiving audiological monitoring with an extended high frequency audiometer (KUDUwave). A retrospective cross-sectional study was conducted. Cumulatively across the three decentralized sites, 69 patient records were reviewed that met the inclusion criteria of the study. The mean age of the patients was 36.1, with a standard deviation (SD) of 10.7 years; more than half (37) were female. Ototoxicity , a threshold shift, placing patients at risk of developing a hearing loss was detected in 56.5% (n=39)of patients and not detected in 30.4%(n=21).The remaining 13,1% (n=9)is missing data. As a result, the regimen was adjusted in 36.2% of patients. . From the 53 patients who were tested for hearing loss post completion of the injectable phase of treatment, 22.6% (n=12) had normal hearing, 17.0 % (n=9) had unilateral hearing loss, and 60.4% (n=32) had bilateral hearing loss. Therefore, a total of 41 patients had a degree of hearing loss: over 30% (n=22)had mild to moderate hearing loss, and only about 15% (n=11)had severe to profound hearing loss. Analysis of risk factors showed that having ototoxicity detected and not adjusting regimen significantly increases the risk of patients developing a hearing loss. The key findings of the study have shown that a significant proportion of DR-TB patients receiving an aminoglycoside based regimen are at risk of developing ototoxic induced hearing loss, despite receiving audiological monitoring with an extended high frequency audiometer that allows for early detection of ototoxicity (threshold shift).