Objective The consistent emerging of multidrug-resistant tuberculosis (MDR-TB) cases are increasingly becoming a major threat and challenge in global TB control, especially in some resource-limited settings like India, China, South Africa. Currently there is no widely acknowledged treatment strategy for MDR-TB. Effectiveness and of current DOTS-Plus strategy is remaining controversial. This systematic review aims to investigate treatment outcomes for MDR-TB under DOTS-Plus and potential factors associated with poor outcome (death, default and failure). Methodology The literatures were searched in Pubmed, Medline, the Cochrane library, Essential Evidence Plus, EMBASE and CNKI. Some manual search articles were also added and 164 literatures in total were founded related to treatment outcomes for multidrug resistant patients under DOTS-Plus. After basically screening and carefully full-text reading, nine studies meeting the inclusion criteria were included. A total of 3358 participants from 8 high MDR-TB countries were investigated. Result Baseline characters were varied across these nine studies, including HIV prevalence (0-1.6%), MDR-TB prevalence (0-4.7%), previous treatment history (without TB treatment, with TB treatment but not under directly observed therapy, short courses (DOTS) and with TB treatment under DOTS), and male/female ratio (54%-86.5%). All studies reported a successful outcome rate (cure and complete) higher than 60 percent, and three of the studies reported higher than 70 percent, which are comparatively high in MDR-TB treatment. Factors associated with poor outcomes that reported by these studies were including alcohol use/ abuse, homelessness, unemployment, imprisonment, BMI, cavitary and bilateral disease, missing doses, and resistant to some second-line drugs. Conclusion In sum, the overall treatment outcomes from these nine studies under DOTS-Plus were acceptable, and most of them were satisfactory. Nevertheless, in consideration of potential bias arising from these cohort analyses, conclusions should be drawn carefully. Several major challenges restrict low- and middle- income countries from implementing DOTS-Plus, which put high command on TB infrastructure, policy commitment, human resources and financial support. Further effort could be put on systematical review and meta-analysis on cost-effectiveness of DOTS-Plus programs. In China, policy makers should pay attention to arrive at national and provincial guidelines of MDR-TB treatment under DOTS-Plus. / published_or_final_version / Public Health / Master / Master of Public Health

Until the recent introduction of short course regimens, treatment regimens for multidrug resistant TB (MDR-TB) were long and toxic. Consequently, only approximately half of MDRTB patients completed their treatment. TB dosing guidelines have historically been unrefined with little consideration for pharmacokinetic/pharmacodynamic relationships. Large knowledge gaps therefore exist in the understanding of pharmacokinetic/pharmacodynamic relationships for both efficacy and toxicity in MDR-TB. My PhD used clinical pharmacology approaches to improve the understanding of drug exposures, toxicity, and exposure-toxicity relationships during the first 12 weeks of MDR-TB therapy. Aims and methods 1. Using non-compartmental analyses, describe the pharmacokinetics of cycloserine and, using regression modelling, explore the association of covariates with cycloserine exposure. 2. Using validated screening tools, describe the incidence of neuropsychiatric toxicity in MDR-TB patients, and explore associations with cycloserine pharmacokinetics. 3. Using a validated pain-rating scale in a crossover study design, investigate whether the addition of a local anaesthetic reduces kanamycin-related injection pain, and explore effects on kanamycin pharmacokinetics. 4. Using geometric mean ratios, compare the exposures of crushed versus whole formulations of pyrazinamide, moxifloxacin, ethionamide, ethambutol, cycloserine, and isoniazid. Results and conclusions We found no measurable terizidone in plasma supporting the hypothesis that terizidone is hydrolysed pre-systemically to cycloserine. The cycloserine time-concentration profile supports once daily dosing of terizidone. We describe a high incidence of peripheral neuropathy in MDR-TB patients with both cycloserine clearance and high-dose pyridoxine significantly associated with neuropathy on multivariate analysis. The addition of a local anaesthetic reduced the pain experienced by MDR-TB patients in the first 15 minutes post intramuscular administration of kanamycin, which could improve adherence to MDR-TB treatment. We also found the bioavailability of crushed isoniazid to be approximately 42% less than the whole tablet formulation, and therefore recommend that the crushing of isoniazid be avoided. Although some recent treatment advances have improved MDR-TB outcomes, enhancing the understanding of drugs used to treat MDR-TB, which continues to have an unacceptably high mortality and treatment-related morbidity, is a public health priority. This thesis comprises four peer-reviewed publications, all of which made a pragmatic contribution to the fight against MDR-TB.

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

Dissertation ( PhD)--University of Stellenbsoch, 2007. / Bibliography. Also available via the Internet.

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.

Objectives: We aimed to assess the variation in patient body weight over time according to the treatment outcome among multidrug-resistant tuberculosis (MDR-TB) cases. Methods: This was a retrospective cohort study. The data of patients commencing MDR-TB therapy were analyzed. Data were collected from different public TB treatment facilities located in peri-urban areas to the south of Lima, Peru. The outcome was patient body weight (kilograms) from treatment commencement, measured monthly. A random effects model was fitted using robust standard errors to calculate 95% confidence intervals. Results: Of a total of 1242 TB cases, 243 (19.6%) were MDR-TB. Only 201 cases were included in the analysis; 127 (63.2%) were males and the mean patient age was 33.6 (standard deviation 16.2) years. Weight changes over time among the patients who were cured differed from changes in those who died during therapy (p < 0.001). Weight curve divergence was important at the end of the third, fourth, and fifth treatment months: on average, the weight difference was 2.18 kg (p < 0.001), 3.27 kg (p = 0.007), and 3.58 kg (p = 0.03), respectively, when cured patients were compared to those who died. Conclusions: Our results show that weight variation during treatment can be a useful surrogate for the treatment outcome, specifically death during therapy. MDR-TB patients with weight loss should be followed more closely, as they are at greater risk of death. / Revisión por pares

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.

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