The tuberculosis epidemic is escalating in South Africa as well as globally. This escalation is exacerbated by the increasing prevalence of multidrug-resistant tuberculosis (MDRTB), which is defined by the World Health Organisation (WHO) as resistance of Mycobacteria to at least isoniazid and rifampicin. Multi-drug resistant tuberculosis is estimated to occur in 1-2% of newly diagnosed tuberculosis (TB) patients and in 4-8% of previously treated patients. MDRTB is both difficult and expensive to treat, costing up to 126 times that of drug-sensitive TB. Resource constrained countries such as South Africa often lack both the money and the infrastructure to treat this disease. The aim of this project was to determine whether the performance of a systematic review with subsequent economic modelling could influence the decision making process for policy makers. Data was gathered and an economic evaluation of MDRTB treatment was performed from the perspective of the South African Department of Health. Three treatment alternatives were identified: a protocol regimen of second line anti-tuberculosis agents, as recommended in the South African guidelines for MDRTB, an appropriate regimen designed for each patient according to the results of culture and drug susceptibility tests, and non-drug management. A decision-analysis model using DATA 3.0 by Treeage® was developed to estimate the costs of each alternative. Outcomes were measured in terms of cost alone as well as the ‘number of cases cured’ and the number of ‘years of life saved’ for patients dying, being cured or failing treatment. Drug, hospital and laboratory costs incurred using each alternative were included in the analysis. A sensitivity analysis was performed on all variables in order to identify threshold values that would change the outcome of the evaluation. Results of the decision analysis indicate that the individualised regimen was both the cheaper and more cost-effective regimen of the two active treatment options, and was estimated to cost R50 661 per case cured and R2 070 per year of life saved. The protocol regimen was estimated to cost R73 609 per case cured and R2 741 per year of life saved. The outcome of the decision analysis was sensitive to changes in some of the variables used to model the disease, particularly the daily cost of drugs, the length of time spent in hospital and the length of treatment received by those patients dying or failing treatment. This modelling exercise highlighted significant deficiencies in the quality of evidence on MDRTB management available to policy makers. Pragmatic choices based on operational and other logistic concerns may need to be reviewed when further information becomes available. A case can be made for the establishment of a national database of costing and efficacy information to guide future policy revisions of the South African MDRTB treatment programme, which is resource intensive and of only moderate efficacy. However, due to the widely disparate range of studies on which this evaluation was based, the outcome of the study may not be credible. In this case, the use of a systematic review with subsequent economic modelling could not validly influence policy-makers to change the decision that they made on the basis of drug availability.

MexCD-OprJ is an RND-type multidrug efflux pump present in P. aeruginosa and is capable of exporting, and as such providing resistance to, several clinically important antimicrobials including fluoroquinolones, cephems, macrolides, and several biocides including chlorhexidine (CHX). Expression of mexCD-oprJ is negatively regulated by NfxB, a LacI-type repressor. The promoter region of mexCD-oprJ was identified and included two inverted repeat operator sites, B1 and B2, both of which are required in order for NfxB to bind, thereby repressing mexCD-oprJ. NfxB oligomerizes into a tetramer in solution and likely functions as a dimer of NfxB homodimers. In addition to being derepressed by loss of NfxB, MexCD-OprJ is inducible by a variety of non-antibiotic membrane-damaging agents (MDAs) such as CHX. A homologue of NfxB, PA4596, was found to be induced in response to CHX-promoted envelope stress in an AlgU-dependent manner and is directly repressed by NfxB. Loss of PA4596 resulted in increased resistance to the biocide CHX, shown to be a result of increased CHX-dependent expression of mexCD-oprJ. Susceptibility to CHX was restored upon expression of PA4596 from the plasmid pAK1900 as was decreased expression of mexCD-oprJ in the presence of CHX, indicating that PA4596 contributes to mexCD-oprJ repression in the presence of CHX. PA4596 was found to form oligomers in solution, likely dimers and tetramers. In the absence of NfxB, PA4596 is unable to contribute to repression of mexCD-oprJ. However, NfxB and PA4596 interact and together form a repressor capable of regulating mexCD-oprJ expression. Screening of transposon mutants for increased resistance to erythromycin potentially indicative of increased mexCD-oprJ expression lead to the identification of several novel genes including PA0479, cupA3, faoA, PA3259, mucD, and clpA whose loss generated a multidrug resistance profile consistent with increased production of MexCD-OprJ. However, further studies are required to determine how each of these genes may be affecting expression of mexCD-oprJ. / Thesis (Ph.D, Microbiology & Immunology) -- Queen's University, 2013-06-12 12:07:28.67

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

No description available.

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.

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 107-111). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph. D.)--Massachusetts Institute of Technology and Woods Hole Oceanographic Institution, 2000. / "February, 2001." "Funding was provided by National Institute of Health grant ES-07381 and a Rinehart Coastal Research Center grant." Includes bibliographical references (p. 174-177).

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