Bedaquiline is a medication recently approved by the FDA for the treatment of multidrug resistant tuberculosis. Due to its recent nature, there exists little information on the efficacy and safety of the drug. A systematic review and meta-analysis was performed to collect what data exist on bedaquiline and assess its efficacy and safety relative to currently recommended regimens, and some specific medications used in those regimens for treating both multidrug resistant and extensively drug-resistant tuberculosis. Nine studies were collected from databases and direct journal searches and pooled to make a sample size of 950 patients receiving a treatment regimen containing bedaquiline. Of these 950 patients on bedaquiline-containing regimens, a high percentage had culture conversion at six months (84.13%, 95% CI = 72.53% - 92.98%), treatment cure (71.86%, 95% CI = 60.94% - 81.60%), and treatment success (70.80%, 95% CI = 61.57% - 79.24%), and a low percentage discontinued bedaquiline (3.65%, 95% CI = 1.98% - 5.81%), or died (6.56%, 95% CI = 4.15% - 9.45%), despite a high number of XDR-TB and HIV co-infected patients. Adverse events due to bedaquiline (21.39%, 95% CI = 11.66% - 33.11%), total severe adverse events (26.50%, 95% CI = 6.98% - 52.86%), hepatotoxicity (14.37%, 95% CI = 2.56 – 33.47%), and QT prolongation percentages (10.37%, 95% CI = 3.19% - 21.01%) were high, but did not lead to bedaquiline discontinuation or death. The efficacy and relative safety of bedaquiline make it a viable option versus current alternative medications and, as part of a regimen, it is far more successful at treating multidrug-, and extensively drug-, resistant tuberculosis than conventional regimens. New treatment regimens only just being put into use, however, such as the Bangladesh regimen, still seem to be superior. More research, including randomized controlled trials, is required to identify how bedaquiline should be incorporated into making multidrug resistant tuberculosis treatment more effective and safe. / 2020-02-20T00:00:00Z

ABSTRACT INTRODUCTION: Multi-drug resistant tuberculosis (MDR-TB) poses a great threat to the eradication of TB. In the US, MDR-TB is faced with inadequate diagnostic tools and long and expensive treatment regimens. Therefore, preventing the disease is the key to saving lives and resources. Social and behavioral variables play a big part in this prevention. It is important to determine the social factors that may lead to MDR-TB in order to set up prevention programs and more efficient treatment regimens. AIM: This study was conducted to ascertain the social determinants of MDR-TB in the US between the years of 2005 and 2009 to better equip public health officials to deal with this growing threat. METHODS: This study used the Centers for Disease Control and Prevention (CDC) Online Tuberculosis Information System (OTIS) database to find associations between certain social variables and MDR-TB. The variables that were tested were whether or not the individual had lived in a correctional facility for the past year; HIV status; homelessness; whether or not the individual had an occupation; and whether the individual was foreign-born or US-born. An unadjusted odds ratio (OR) was calculated to find this association. The variables were then stratified with age; sex; race; age and race; age and sex; and age, sex, and race to see whether or not the strata were confounders. RESULTS: The variables of having lived in a correctional facility and homelessness were found to be associated with MDR-TB. However, all of the strata were found to be confounders for this relationship. Having HIV and being US-born were not found to be associated with MDR-TB. All of the strata for HIV were found to be confounders. But for place of birth, stratifying by age, sex, and both age and sex were not confounders. The rest of the strata were. The OR for occupation versus MDR-TB was almost at 1, meaning that those with a job and those without a job had almost equal odds of having MDR-TB. Effect modification was present for the strata in all variables, meaning that the risk of having MDR-TB varied with each different age, sex, and racial group. DISCUSSION: Results from this study showed which variables were more likely to be associated with MDR-TB in the US between the years of 2005 and 2009. However, when compared to the literature that exists, the results showed that more research needs to be done to properly ascertain this relationship. Using this study, public health officials can identify which populations to focus prevention efforts on.

Over the last few years the World Health Organization (WHO) has endorsed several tests for the rapid detection of multidrug-resistant tuberculosis (MDR-TB) in resource-poor settings. The objective of this study was to compare the cost-effectiveness of a line probe assay test (less than one week for results) to conventional (bacterial culture) drug susceptibility testing (one month for results) for the detection of MDR-TB in an HIV-positive South African population by estimating the incremental cost-effectiveness ratio (ICER) per disability-adjusted life-year (DALY) averted. Costs of testing, drug treatment, hospitalization, as well as estimates for mortality, treatment success, and failure rates were obtained from literature sources, the South African Department of Health, the WHO, the Foundation of Innovative Diagnostics (FIND), and expert opinion. The willingness-to-pay threshold for a DALY averted was pre-set at 3 times the 2009 GDP per capita (about $17,400) for South Africa. In the base-case scenario for a prevalence of 30% of MDR-TB among HIV-positive patients, the average cost per person for the line probe assay testing strategy was $3,539/0.458 DALY averted and the conventional testing approach was $3,011/0.430 DALY averted. The base-line ICER was about $18,800 per DALY averted – about $1,400 above the pre-set threshold. In sensitivity analyses, the model was robust to changes in prevalence (+ 50%); costs (+ 10%), and probabilities of death, success and failure (+ 20%). However, when the treatment success rate for the line probe assay test was increased to 60% (one of the targets set by WHO in TB treatment) the ICER was below the willingness-to-pay level (i.e., cost-effective). The probabilistic sensitivity analysis showed there is a 70% chance that the additional cost of the line probe assay, compared with conventional testing, was less than $30,000 per DALY averted. However, the model may have underestimated the benefits of the line probe assay because it did not account for a decrease in the transmission of the disease due to earlier treatment nor did it measure any benefits more than a year after testing. / text

published_or_final_version / Microbiology / Master / Master of Medical Sciences

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

The study aimed to explore and describe the experiences of people treated for multidrug resistant tuberculosis (MDR-TB) in Omaheke region, Namibia in order to make relevant recommendations regarding their management. A descriptive qualitative design approach was used. Data was collected using in-depth individual interviews with six participants. The interview transcripts were analysed using thematic content analysis. Three themes emerged namely (1) Stressors related to MDR-TB diagnosis and treatment which involved nature of disease and compulsory hospitalisation (2) Impact of being treated for MDR-TB which related to emotional , social , spiritual and financial impact (3) Support structures for people treated for MDR-TB which included family members, health care professionals and friends. Systemic practical patient-centred, staff-centred and community-centred recommendations are suggested as well as recommendations for future research and an appraisal of the limitations of this study. / Health Studies / M.A. (Public Health)

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.

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.

Background: Multidrug-resistant tuberculosis (MDR-TB) patients receive aminoglycosides as part of their treatment. These drugs are ototoxic, and can cause permanent damage to the cochlea, resulting in a debilitating hearing loss, which has a negative impact on an individual's quality of life. Early detection and management of an ototoxic hearing loss can minimise the impact of the hearing loss on the person's social, emotional, and vocational wellbeing. While patients with MDR-TB are often very ill, it might be ideal to use an objective test that does not require active participation from the patient. In this way, the reliability and validity of the test will not be affected by the patient's state. Distortion product otoacoustic emissions (DPOAEs) at 2f1-f2 are a viable option, as it evaluates cochlear function, specifically the outer hair cells, which are affected first by ototoxic medication. Method: This thesis used a sequential study design aimed to determine the DPOAE stimulus parameters that yield (a) the highest level and the most reliable, sensitive and specific DPOAEs reported in the literature, (b) the highest level and the most reliable DPOAEs in healthy, normally hearing adults, and (c) the most sensitive and specific DPOAEs in participants with MDR-TB patients receiving ototoxic medication. High frequency pure tone audiometry (defined in this thesis as frequencies > 8 kHz) was used as the gold standard. Descriptive statistics, the intraclass correlation coefficient, Pearson's correlation coefficient and mixed model analyses were used to analyse the data. Results: Systematic review: The results of the systematic review indicated an L1/L2 setting of 75/75 dB SPL and f2/f1 value from 1.20 to 1.22 yielded the highest level DPOAEs. The systematic review results for stimulus parameters that yielded the highest test-retest reliability, sensitivity and specificity were inconclusive. Preliminary study with healthy normal hearing participants: The results of the preliminary study in healthy, normal-hearing participants indicated that the highest levels of DPOAEs were elicited with L1/L2 intensity levels of 65/65 and 65/55 dB SPL, and f2/f1 ratios of 1.18, 1.20 and 1.22, as determined by mixed model analyses (p < 0.05). These same stimulus parameters yielded the most reliable DPOAEs in both ears, as determined by intraclass correlation coefficient analysis. Main study with healthy, normal-hearing participants: Descriptive statistics and mixed model analysis showed stimulus intensity levels L1/L2 of 65/55 dB SPL, and f2/f1 ratios of 1.18 and 1.20, elicited the largest DPOAEs. The ratio of 1.20 yielded the largest DPOAEs < 5000 Hz and f2/f1 ratio of 1.18 the largest DPOAEs ≥ 5000 Hz. The second highest DPOAE levels were elicit by L1/L2 = 65/65 dB SPL and f2/f1 = 1.18. The test-retest reliability in this sample was not influenced by changing the stimulus parameters, and DPOAEs were only unreliable at an f2 frequency of 8 000 Hz. Study in participants with MDR-TB: Results in participants with MDR-TB receiving ototoxic medication indicated that the highest levels of DPOAEs were elicited with L1/L2 = 65/55 and an f2/f1 ratio of 1.18 at f2 ≥ 5000 Hz, followed by 65/65 and 1.18. For f2 < 5000 Hz, stimulus intensities of L1/L2 = 65/55 and an f2/f1 ratio of 1.20 yielded the largest DPOAE levels. Relating to sensitivity and specificity, the stimulus parameter combination of 65/55 dB and 1.18 detected the highest number of ears with outer hair cell damage in participants with MDR-TB receiving ototoxic medication. Conclusion: It should be considered to use an f2/f1 ratio of 1.18 for f2 ≥ 5000 Hz and 1.20 for f2 < 5000 Hz when monitoring for ototoxicity, to assist with early identification of outer hair cell damage, in conjunction with high frequency pure tone audiometry. This finding needs to be confirmed in a larger sample of participants with MDR-TB receiving ototoxic medication.

Thesis (M.Cur) --University of Limpopo, 2011 / The aim of this study was to determine the factors that contribute to the increase in the number of tuberculosis (TB) patients in Mpumalanga Province, and to develop guidelines and recommendations to address the challenges of this health issue. The design of the study was qualitative phenomenological. The population consisted of all TB patients who were receiving treatment either at the intensive or the continuation phase. The sampling method was purposive and the sample size comprised 20 participants, of whom 10 were drawn from Shatale clinic at Bushbuckridge, and 10 from Mashishing clinic at Thabachweu municipalities in the Ehlanzeni district of Mpumalanga Province. The data was gathered by means of semi-structured interviews. Data analysis was performed, from which themes and categories were derived. This study revealed several factors that contributed to the increase in the number of TB patients at the study sites. The factors considered most important in this study were the general lack of knowledge of TB among participants, despite their various levels of education, poverty, overcrowding, poor ventilation in the shacks and Reconstruction and Development Program (RDP) houses, unemployment, lack of support while taking treatment, religious and ritual beliefs, and the influence of traditional healers who dispense herbal medicines with the dictum that participants have been possessed by evil spirits and witches. The majority of patients developed TB as a secondary opportunistic infection because of their HIV-positive status, and lack of capacity to practice personal hygiene and proper infection control. Guidelines, strategies and recommendations were formulated to address these public health challenges in the context nursing education, research, administration and practice