Center for Tuberculosis Research

Tygerberg, South Africa

Center for Tuberculosis Research

Tygerberg, South Africa
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Lilienkampf A.,University of Illinois at Chicago | Lilienkampf A.,University of Edinburgh | Pieroni M.,University of Illinois at Chicago | Pieroni M.,University of Parma | And 3 more authors.
Current Topics in Medicinal Chemistry | Year: 2012

New antituberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis (Mtb) strains and to shorten the long treatment regimen. A series of isoxazole-based compounds, bearing a carboxy moiety at the C3 position, are highly potent and versatile anti-TB agents. Several members of this compound class exhibit submicromolar in vitro activity against replicating Mtb (R-TB) and thus comparable activity to the current first-line anti-TB drugs. Remarkably, certain compounds also show low micromolar activity in a model for nonreplicating Mtb (NRP-TB) phenotype, which is considered a key to shortening the current long treatment protocol. The series shows excellent selectivity towards Mtb and, in general, shows no cytotoxicity on Vero cells (IC 50's > 128 μM). Selected compounds retain their activity against isoniazid (INH), rifampin (RMP), and streptomycin (SM) resistant Mtb strains. The foregoing facts make derivatives of 3-isoxazolecarboxylic acid esters a promising anti-TB chemotype, and as such present attractive lead compounds for TB drug development. © 2012 Bentham Science Publishers.

Lamichhane G.,Center for Tuberculosis Research | Shah M.,Center for Tuberculosis Research
International Journal of Tuberculosis and Lung Disease | Year: 2016

Carbapenems, a more recent β-lactam class, represent a unique anti-tuberculosis option, as emerging evidence demonstrates that they target the Mycobacterium tuberculosis cell wall and β-lactamase. This provides a potentially new agent against M. tuberculosis, in particular for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), where options are limited. In this review, we examine the current evidence on the activity of carbapenems against M. tuberculosis. The predominance of work is in vitro, and suggests that carbapenems kill M. tuberculosis at least in the active phase, with possible greater potency with the addition of a β-lactamase inhibitor. The few in vivo and clinical studies suggest that there are benefits and that they are generally tolerated, although the variability in duration, dosing, and background regimen and lack of pharmacokinetic analyses limit interpretation of efficacy. We outline further areas of research to better understand the role of carbapenems to add a needed new agent to the treatment of MDR- and XDRTB. © 2016 The Union.

Diacon A.H.,Center for Tuberculosis Research | Diacon A.H.,Stellenbosch University | Dawson R.,University of Cape Town | Von Groote-Bidlingmaier F.,Task Applied Science | And 11 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2015

Rationale: New regimens to shorten tuberculosis treatment and manage patientswith drug-resistant tuberculosiswho are infectedwith HIV are urgently needed. Experimental and clinical evidence suggests that the new drugs bedaquiline (B) and pretomanid (Pa), combined with an existing drug, pyrazinamide (Z), and a repurposed drug, clofazimine (C), may assist treatment shortening of drug-susceptible and drug-resistant tuberculosis. Objectives: To evaluate the 14-day bactericidal activity of C and Z in monotherapy and in combinations with Pa and B. Methods: Groups of 15 treatment-naive, sputum smear-positive patients with pulmonary tuberculosis were randomized to receive combinations of B with Z-C, Pa-Z, Pa-Z-C, and Pa-C, orCor Z alone, or standard combination treatment for 14 days. The primary endpoint was the mean daily fall in log10 Mycobacterium tuberculosis CFU per milliliter sputum estimated by joint nonlinear mixed-effects Bayesian regression modeling. Measurements and Main Results: Estimated activities were 0.167 (95% confidence interval [CI], 0.075-0.257) for B-Pa-Z, 0.151 (95% CI, 0.071-0.232) for standard treatment, 0.124 (95% CI, 0.035-0.214) for B-Z-C, 0.115 (95% CI, 0.039-0.189) for B-Pa-Z-C, and 0.076 (95% CI, 0.005-0.145) for B-Pa-C. Z alone had modest activity (0.036; 95% CI, -0.026 to 0.099). C had no activity alone (-0.017; 95% CI, -0.085 to 0.053) or in combinations. Treatments were well tolerated and safe. Conclusions: B-Pa-Z, including two novel agents without resistance in prevalent M. tuberculosis strains, is a potential new tuberculosis treatment regimen. C had no measurable activity in the first 14 days of treatment. Copyright © 2015 by the American Thoracic Society.

Hiruy H.,Center for Tuberculosis Research | Rogers Z.,Kwazulu Natal Research Institute for TB and HIV | Adamson J.,Kwazulu Natal Research Institute for TB and HIV | Ngotho L.,Kwazulu Natal Research Institute for TB and HIV | And 5 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2014

Objectives: There is a paucity of evidence regarding the optimal dosing of anti-TB drugs in children. The aim of this study was to identify the pharmacokinetic parameters of first-line anti-TB drugs and the concentrations achieved after implementation of the 2010 WHO-recommended paediatric dosages. Methods: We conducted a prospective, observational pharmacokinetic study in children 10 years old or younger whowere on isoniazid, rifampicin, pyrazinamide and ethambutol therapy in Durban, KwaZulu-Natal, South Africa. Blood was collected at six timepoints over a 24 h period, chosen using optimal sampling theory. The drug concentrations were simultaneously modelled to identify the compartmental pharmacokinetics of each drug in each child, using the ADAPT program. Results: The best six sampling timepoints in children were identified as 0 (pre-dose) and 0.42, 1.76, 3.37, 10.31 and 24 h post-dose. Thirty-one children were recruited and blood was drawn at these timepoints. Rifampicin, ethambutol and pyrazinamide were best described using a one-compartment model, while isoniazid was best described with a two-compartment model. Only 2/31 (6%), 20/31 (65%), 17/31 (55%) and 2/13 (15%) of children attained the WHO 2 h target therapeutic concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol, respectively. Moreover, only 24/31 (77%), 6/31 (19%) and 8/31 (26%) achieved the AUCs associated with an optimal clinical response to rifampicin, pyrazinamide and isoniazid, respectively. No single risk factorwas significantly associated with below-normal drug levels. Conclusions: The drug concentrations of all first-line anti-TB drugs were markedly below the target therapeutic concentrations in most South African children who received the revised WHO-recommended paediatric weightbased dosages. © The Author 2014.

Farley J.E.,Johns Hopkins University | Waldman S.,Eli Lilly and Company | Cassell G.H.,Eli Lilly and Company | Chaisson R.E.,Center for Tuberculosis Research | And 3 more authors.
PLoS ONE | Year: 2011

Background: Multidrug-resistant tuberculosis (MDR-TB) is a major clinical challenge, particularly in patients with human immunodeficiency virus (HIV) co-infection. MDR-TB treatment is increasingly available, but outcomes have not been well characterized. South Africa has provided MDR-TB treatment for a decade, and we evaluated outcomes by HIV status for patients enrolled between 2000 and 2004 prior to anti-retroviral access. Methods: We assessed treatment outcomes in a prospective cohort of patients with MDR-TB from eight provincial programs providing second line drugs. World Health Organization definitions were used. Results were stratified by HIV status. Results: Seven hundred fifty seven patients with known HIV status were included in the final analysis, and HIV infection was documented in 287 (38%). Overall, 348 patients (46.0%) were successfully treated, 74 (9.8%) failed therapy, 177 (23.4%) died and 158 (20.9%) defaulted. Patients with HIV were slightly younger and less likely to be male compared to HIV negative patients. Patients with HIV were less likely to have a successful treatment outcome (40.0 vs. 49.6; P<0.05) and more likely to die (35.2 vs. 16.2; P<0.0001). In a competing risk survival analysis, patients with HIV had a higher hazard of death (HR: 2.33, P<0.0001). Low baseline weight (less than 45 kg and less than 60 kg) was also associated with a higher hazard of death (HR: 2.52, P<0.0001; and HR: 1.50, P<0.0001, respectively, compared to weight greater than 60 kg). Weight less than 45 kg had higher risk of failure (HR: 3.58, P<0.01). Any change in treatment regimen was associated with a higher hazard of default (HR: 2.86; 95% CI 1.55-5.29, P<0.001) and a lower hazard of death (HR: 0.63, P<0.05). Conclusions: In this MDR-TB treatment program patients with HIV infection and low weight had higher hazards of death. Overall treatment outcomes were poor. Efforts to improve treatment for MDR-TB are urgently needed. © 2011 Farley et al.

Background: Current approaches are unlikely to achieve the aggressive global tuberculosis (TB) control targets set for 2035 and beyond. Active case finding (ACF) may be an important tool for augmenting existing strategies, but the cost-effectiveness of ACF remains uncertain. Program evaluators can often measure the cost of ACF per TB case detected, but how this accessible measure translates into traditional metrics of cost-effectiveness, such as the cost per disability-adjusted life year (DALY), remains unclear. Methods: We constructed dynamic models of TB in India, China, and South Africa to explore the medium-term impact and cost-effectiveness of generic ACF activities, conceptualized separately as discrete (2-year) campaigns and as continuous activities integrated into ongoing TB control programs. Our primary outcome was the cost per DALY, measured in relationship to the cost per TB case actively detected and started on treatment. Results: Discrete campaigns costing up to $1,200 (95% uncertainty range [UR] 850-2,043) per case actively detected and started on treatment in India, $3,800 (95% UR 2,706-6,392) in China, and $9,400 (95% UR 6,957-13,221) in South Africa were all highly cost-effective (cost per DALY averted less than per capita gross domestic product). Prolonged integration was even more effective and cost-effective. Short-term assessments of ACF dramatically underestimated potential longer term gains; for example, an assessment of an ACF program at 2 years might find a non-significant 11% reduction in prevalence, but a 10-year evaluation of that same intervention would show a 33% reduction. Conclusions: ACF can be a powerful and highly cost-effective tool in the fight against TB. Given that short-term assessments may dramatically underestimate medium-term effectiveness, current willingness to pay may be too low. ACF should receive strong consideration as a basic tool for TB control in most high-burden settings, even when it may cost over $1,000 to detect and initiate treatment for each extra case of active TB.

Guerra R.L.,Federal University of Rio de Janeiro | Dorman S.E.,Center for Tuberculosis Research | Luiz R.R.,Hospital Universitario Clementino Fraga Filho | Conde M.B.,Federal University of Rio de Janeiro
International Journal of Tuberculosis and Lung Disease | Year: 2013

SETTING: Primary health care unit in Rio de Janeiro City, Brazil. OBJECTIVE: To estimate and compare the cost-effectiveness of strategies used for passive case finding of pulmonary tuberculosis (PTB) cases using tests available at the primary care level. DESIGN: Data on PTB suspects were reviewed, and a decision model was developed using sputum smear microscopy and chest radiography (CXR) according to three different strategies for PTB detection. A cost-effectiveness analysis was performed to estimate the cost per correct PTB diagnosis. Mycobacterial culture was used to calculate the effectiveness of the strategies. Unit costs of health resource utilisation were obtained from the payer's perspective (the Brazilian Public Health System). RESULTS: For the evaluation of 254 PTB suspects, the total costs of strategies ranged from US$5369 to US$5944; the probability of a correct PTB diagnosis ranged from 0.66 to 0.86; the number of visits required to complete the diagnostic process ranged from two to three, and cost per PTB case identified ranged from US$47.93 to US$53.07. The cost-effectiveness of the three strategies studied varied between US$56.69 and US$72.55 per correct PTB case detected. CONCLUSION: A strategy in which sputum smears and CXR were requested for all PTB suspects at the initial evaluation was cost-effective, had a high probability of correct PTB diagnosis and could be accomplished in two visits. © 2013 The Union.

Gupta S.,Center for Tuberculosis Research | Gupta S.,Howard Hughes Medical Institute | Cohen K.A.,Brigham and Women's Hospital | Cohen K.A.,KwaZulu Natal Research Institute for Tuberculosis and HIV | And 7 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

Drug efflux is an important resistance mechanism in Mycobacterium tuberculosis. We found that verapamil, an efflux inhibitor, profoundly decreases the MIC of bedaquiline and clofazimine to M. tuberculosis by 8- to 16-fold. This exquisite susceptibility was noted among drug-susceptible and drug-resistant clinical isolates. Thus, efflux inhibition is an important sensitizer of bedaquiline and clofazimine, and efflux may emerge as a resistance mechanism to these drugs. © 2014, American Society for Microbiology. All Rights Reserved.

Chopra S.,SRI International | Matsuyama K.,SRI International | Tran T.,SRI International | Malerich J.P.,SRI International | And 9 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2012

Objectives: New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance to existing agents and shorten the duration of therapy. Targeting DNA gyrase is a clinically validated therapeutic approach using fluoroquinolone antibiotics to target the gyrase subunit A (GyrA) of the heterotetramer. Increasing resistance to fluoroquinolones has driven interest in targeting the gyrase subunit B (GyrB), which has not been targeted for TB. The biological activities of two potent small-molecule inhibitors of GyrB have been characterized to validate its targeting as a therapeutic strategy for treating TB. Materials and methods: Novobiocin and aminobenzimidazole 1 (AB-1) were tested for their activity against Mycobacterium tuberculosis (Mtb) H37Rv and other mycobacteria. AB-1 and novobiocin were also evaluated for their interaction with rifampicin and isoniazid as well as their potential for cytotoxicity. Finally, AB-1 was tested for in vivo efficacy in a murine model of TB. Results: Novobiocin and AB-1 have both been shown to be active against Mtb with MIC values of 4 and 1 mg/L, respectively. Only AB-1 exhibited time-dependent bactericidal activity against drug-susceptible and drug-resistant mycobacteria, including a fluoroquinolone-resistant strain. AB-1 had potent activity in the low oxygen recovery assay model for non-replicating persistent Mtb. Additionally, AB-1 has no interaction with isoniazid and rifampicin, and has no cross-resistance with fluoroquinolones. In a murine model of TB, AB-1 significantly reduced lung cfu counts in a dose-dependent manner. Conclusions: Aminobenzimidazole inhibitors of GyrB exhibit many of the characteristics required for their consideration as a potential front-line antimycobacterial therapeutic. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Pieroni M.,University of Illinois at Chicago | Tipparaju S.K.,University of Illinois at Chicago | Lun S.,Center for Tuberculosis Research | Song Y.,University of Illinois at Chicago | And 3 more authors.
ChemMedChem | Year: 2011

The struggle against tuberculosis (TB) is still far from over. TB, caused by Mycobacterium tuberculosis, is one of the deadliest infections worldwide. Co-infection with human immunodeficiency virus (HIV) and the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains have further increased the burden for this disease. Herein, we report the discovery of 2-(4-chlorobenzyl)-3-methyl-1-oxo-1H,5H-pyrido[1,2-a]benzimidazole-4-carbonitrile as an effective antitubercular agent and the structural modifications of this molecule that have led to analogues with improved potency and lower toxicity. A number of these derivatives were also active at sub-micromolar concentrations against resistant TB strains and devoid of apparent toxicity to Vero cells, thereby underscoring their value as novel scaffolds for the development of new anti-TB drugs. Waging war on TB: Using high-throughput screening, we have identified a pyrido[1,2-a]benzimidazole as a potent antitubercular agents. Chemical modifications to the hit compound led to an analogue (3h) with improved potency and reduced toxicity. Of considerable interest was the finding that 3h maintained activity against two extensively drug-resistant strains and one multidrug-resistant strain of tuberculosis (TB). These compounds represent promising leads in the quest for improved anti-TB drugs. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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