[Show abstract][Hide abstract] ABSTRACT: The treatment of tuberculosis is based on combinations of drugs that directly target Mycobacterium tuberculosis. A new global initiative is now focusing on a complementary approach of developing adjunct host-directed therapies.
[Show abstract][Hide abstract] ABSTRACT: New regimens capable of shortening tuberculosis treatment without increasing the risk of recurrence are urgently needed. A 2013 meta-regression analysis, using data from trials published from 1973 to 1997 involving 7793 patients, identified 2-month sputum culture status and treatment duration as independent predictors of recurrence. The resulting model predicted that if a new 4-month regimen reduced the proportion of patients positive at month 2 to 1%, it would reduce to 10% the risk of a relapse rate >10% in a trial with 680 subjects per arm. The 1% target was far lower than anticipated.
Data from the 8 arms of 3 recent unsuccessful phase 3 treatment-shortening trials of fluoroquinolone-substituted regimens (REMox, OFLOTUB, and RIFAQUIN) were used to assess and refine the accuracy of the 2013 meta-regression model. The updated model was then tested using data from a treatment shortening trial reported in 2009 by Johnson et al.
The proportions of patients with recurrence as predicted by the 2013 model were highly correlated with observed proportions as reported in the literature (R2 = 0.86). Using the previously proposed threshold of 10% recurrences as the maximum likely considered acceptable by tuberculosis control programs, the original model correctly identified all 4 six-month regimens as satisfactory, and 3 of 4 four-month regimens as unsatisfactory (sensitivity = 100%, specificity = 75%, PPV = 80%, and NPV = 100%). A revision of the regression model based on the full dataset of 66 regimens and 11181 patients resulted in only minimal changes to its predictions. A test of the revised model using data from the treatment shortening trial of Johnson et al found the reported relapse rates in both arms to be consistent with predictions.
Meta-regression modeling of recurrence based on month 2 culture status and regimen duration can inform the design of future phase 3 tuberculosis clinical trials.
PLoS ONE 04/2015; 10(4):e0125403. DOI:10.1371/journal.pone.0125403 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Improved treatments are needed for nearly all forms of Mycobacterium tuberculosis infection. Adjunctive host-directed therapies have the potential to shorten tuberculosis treatment duration, prevent resistance and reduce lung injury by promoting autophagy, antimicrobial peptide production and other macrophage effector mechanisms, as well as by modifying specific mechanisms that cause lung inflammation and matrix destruction. The range of candidates is broad, including several agents approved for other clinical indications that are ready for evaluation in Phase II clinical trials. The promise of new and existing host-directed therapies that could accelerate response and improve tuberculosis treatment outcomes is discussed in this Opinion article.
[Show abstract][Hide abstract] ABSTRACT: Sutezolid (PNU-100480) is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. Like linezolid, it is unaffected by mutations conferring resistance to standard TB drugs. This study of sutezolid is its first in tuberculosis patients.
Sputum smear positive tuberculosis patients were randomly assigned to sutezolid 600 mg BID (N = 25) or 1200 mg QD (N = 25), or standard 4-drug therapy (N = 9) for the first 14 days of treatment. Effects on mycobacterial burden in sputum (early bactericidal activity or EBA) were monitored as colony counts on agar and time to positivity in automated liquid culture. Bactericidal activity was also measured in ex vivo whole blood cultures (whole blood bactericidal activity or WBA) inoculated with M. tuberculosis H37Rv.
All patients completed assigned treatments and began subsequent standard TB treatment according to protocol. The 90% confidence intervals (CI) for bactericidal activity in sputum over the 14 day interval excluded zero for all treatments and both monitoring methods, as did those for cumulative WBA. There were no treatment-related serious adverse events, premature discontinuations, or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. Seven sutezolid-treated patients (14%) had transient, asymptomatic ALT elevations to 173±34 U/L on day 14 that subsequently normalized promptly; none met Hy's criteria for serious liver injury.
The mycobactericidal activity of sutezolid 600 mg BID or 1200 mg QD was readily detected in sputum and blood. Both schedules were generally safe and well tolerated. Further studies of sutezolid in tuberculosis treatment are warranted.
PLoS ONE 04/2014; 9(4):e94462. DOI:10.1371/journal.pone.0094462 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tuberculosis (TB) is an airborne infectious disease that kills almost 2 million individuals every year. Multidrug-resistant (MDR) TB is caused by strains of Mycobacterium tuberculosis (M. tb) resistant to isoniazid and rifampin, the backbone of first-line antitubercular treatment. MDR-TB affects an estimated 500,000 new patients annually. Genetic analysis of drug-resistant MDR-TB showed that airborne transmission of undetected and untreated strains played a major role in disease outbreaks. The need for new TB vaccines and faster diagnostics, as well as the development of new drugs, has recently been highlighted. The major problem in terms of current TB research and clinical demands is the increasing number of cases of extensively drug-resistant and ‘treatment-refractory’ TB. An emerging scenario of adjunct host-directed therapies is intended to target pulmonary TB where inflammatory processes can be deleterious and lead to immune exhaustion. ‘Target-organ saving’ strategies may be warranted to prevent damage to infected tissues and achieve focused, clinically relevant and long-lasting anti-M. tb-directed cellular immune responses. Candidates for such interventions may be biological agents or already approved drugs that can be ‘re-purposed’ to interfere with biologically relevant cellular checkpoints. Here we review current concepts of inflammation in TB disease and discuss candidate pathways for host-directed therapies in order to achieve better clinical outcomes.This article is protected by copyright. All rights reserved.
Journal of Internal Medicine 04/2014; 277(4). DOI:10.1111/joim.12256 · 6.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:Sutezolid (PNU-100480 or U-480) is an oxazolidinone antimicrobial being developed for treatment of tuberculosis. An active sulfoxide metabolite (PNU-101603 or U-603), which reaches concentrations in plasma several times those of the parent, has been reported to drive killing of extracellular M. tuberculosis by sutezolid in hollow fiber culture. However, the relative contributions of parent and metabolite against intracellular M. tuberculosis in vivo are not fully understood.Methods:The relationships between plasma concentrations of U-480 and U-603 and intracellular whole blood bactericidal activity (WBA) in ex vivo cultures were examined using a direct competitive population PK-PD 4 parameter sigmoid model. The dataset included 690 PK and 345 WBA determinations from 50 tuberculosis patients enrolled in a phase 2 sutezolid trial. The model parameters were solved iteratively.Results:The median U-603/U-480 concentration ratio was 7.1 (range, 1 to 28). The apparent U-603 IC50 for intracellular M. tuberculosis was 17-fold greater than U-480 (90% CI, 9.9 to 53). Model parameters were used to simulate in vivo activity after oral dosing with sutezolid 600 mg BID and 1200 mg QD. Divided dosing resulted a greater cumulative activity (-.269 log10 per day, 90% CI: -.237 to -.293) compared to single daily dosing (-.186, 90% CI: -.160 to -.208). U-480 accounted for 84% and 78% of activity for BID and QD dosing, respectively, despite the higher concentrations of U-603.Conclusions:Killing of intracellular M. tuberculosis by orally administered sutezolid is mainly due to activity of the parent compound. Taken together with other studies in the hollow fiber model, these findings suggest sutezolid and its metabolite act on different mycobacterial subpopulations.
[Show abstract][Hide abstract] ABSTRACT: There is increasing interest in the potential role of adjunctive anti-inflammatory therapy to accelerate tuberculosis (TB) treatment. Sputum culture conversion is an important biomarker predictor of durable TB cure.
This study used meta-regression analysis to examine the relationship between corticosteroid dose and sputum culture conversion, using published data from controlled clinical trials including 1806 corticosteroid-treated TB patients.
Linear models with 2 or 3 variables, including corticosteroid dose and the proportion of culture positive control subjects, predicted therapeutic benefit of corticosteroids at 1 and 2 months. The 3-variable model predicted that 134 mg of prednisolone per day, given together with standard 4-drug TB chemotherapy, would reduce the proportion of positive culture at 2 months from 15% to 2%. The estimate accounts for a 50% reduction in steroid exposure due to rifampin. A proportion of 2% of subjects with positive cultures at 2 months has been proposed as a target for new 4-month TB regimens.
These positive findings must be tempered by recognition that the metabolic and cardiovascular risks of corticosteroids administered at this dose for this duration are unlikely to be acceptable when examined from a patient-level benefit-risk perspective. In future research studies to shorten TB treatment, biologic anti-inflammatory therapies with similar therapeutic effects but superior safety profiles should be considered.
[Show abstract][Hide abstract] ABSTRACT: Despite the widespread use of the BCG vaccine there are more than 9 million new cases of tuberculosis (TB) every year and there is an urgent need for better TB vaccines. TB vaccine candidates are selected for evaluation based in part on the detection of an antigen-specific IFN-γ response. The measurement of mycobacterial growth in blood specimens obtained from subjects immunized with investigational TB vaccines may be a better in vitro correlate of in vivo vaccine efficacy. We performed a clinical study with 30 UK adults who were followed for 6 months to evaluate the ability of both a whole blood and a novel PBMC based mycobacterial growth inhibition assay to measure a response to primary vaccination and revaccination with BCG. Using cryopreserved PBMC we observed a significant improvement in mycobacterial growth inhibition following primary vaccination, but no improvement in growth inhibition following revaccination with BCG (p<0.05). Mycobacterial growth inhibition following primary BCG vaccination was not correlated with PPD antigen specific IFN- γ ELISPOT responses. We demonstrate that a mycobacterial growth inhibition assay can detect improved capacity to control growth following primary immunization but not revaccination with BCG. This is the first study to demonstrate that an in vitro growth inhibition assay can identify a difference in a vaccine response comparing both primary and secondary BCG vaccination, suggesting that in vitro growth inhibition assays may serve as better surrogates of clinical efficacy than those assays currently used for the assessment of candidate TB vaccines.
[Show abstract][Hide abstract] ABSTRACT: New drugs and regimens with the potential to transform tuberculosis treatment are presently in early stage clinical trials.
The goal of the present study was to infer the required duration of these treatments.
A meta-regression model was developed to predict relapse risk using treatment duration and month 2 sputum culture positive rate as predictors, based on published historical data from 24 studies describing 58 regimens in 7793 patients. Regimens in which rifampin was administered for the first 2 months but not subsequently were excluded. The model treated study as a random effect.
The model predicted that new regimens of 4 or 5 months duration with rates of culture positivity after 2 months of 1% or 3%, would yield relapse rates of 4.0% or 4.1%, respectively. In both cases, the upper limit of the 2-sided 80% prediction interval for relapse for a hypothetical trial with 680 subjects per arm was <10%. Analysis using this model of published month 2 data for moxifloxacin-containing regimens indicated they would result in relapse rates similar to standard therapy only if administered for ≥5 months.
This model is proposed to inform the required duration of treatment of new TB regimens, potentially hastening their accelerated approval by several years.
PLoS ONE 08/2013; 8(8):e71116. DOI:10.1371/journal.pone.0071116 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Biomarkers are indispensable to the development of new tuberculosis therapeutics and vaccines. The most robust biomarkers measure factors that are essential to the underlying pathological process of the disease being treated, and thus can capture the full effects of many types of interventions on clinical outcomes in multiple prospective, randomised clinical trials. Many Mycobacterium tuberculosis and human biomarkers have been studied over the past decade. Present research focuses on three areas: biomarkers predicting treatment efficacy and cure of active tuberculosis, the reactivation of latent tuberculosis infection, and the induction of protective immune responses by vaccination. Many older, non-specific markers of inflammation, when considered in isolation, do not have sufficient predictive values for clinical use in tuberculosis. Although no new accurate, tuberculosis-specific biomarkers have yet been discovered, substantial progress has been made in some areas. However, the qualification of biomarkers as a surrogate for a clinical endpoint in tuberculosis is very challenging, and, for biomarkers that are non-culture-based, impossible to pursue without the availability of well characterised biobanks containing biospecimens from patients who have had adequate follow-up to establish long-term treatment outcome. We review progress in tuberculosis biomarker development and efforts being made to harness resources to meet future challenges.
[Show abstract][Hide abstract] ABSTRACT: In this manuscript we apply stochastic modeling to investigate the risk of reactivation of latent mycobacterial infections in patients undergoing treatment with tumor necrosis factor inhibitors. First, we review the perspective proposed by one of the authors in a previous work and which consists in predicting the occurrence of reactivation of latent tuberculosis infection or newly acquired tuberculosis during treatment; this is based on variational procedures on a simple set of parameters (e.g. rate of reactivation of a latent infection). Then, we develop a full analytical study of this approach through a Markov chain analysis and we find an exact solution for the temporal evolution of the number of cases of tuberculosis infection (re)activation. The analytical solution is compared with Monte Carlo simulations and with experimental data, showing overall excellent agreement. The generality of this theoretical framework allows to investigate also the case of non-tuberculous mycobacteria infections; in particular, we show that reactivation in that context plays a minor role. This may suggest that, while the screening for tuberculous is necessary prior to initiating biologics, when considering non-tuberculous mycobacteria only a watchful monitoring during the treatment is recommended. The framework outlined in this paper is quite general and could be extremely promising in further researches on drug-related adverse events.
PLoS ONE 01/2013; 8(1):e55017. DOI:10.1371/journal.pone.0055017 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Six new antituberculosis compounds in 4 classes are presently in clinical trials. Although these show substantial promise for drug-resistant (DR) tuberculosis, the presently planned studies of these compounds will not inform their optimal use, as each will be tested singly vs placebo with existing drugs, rather than in new regimens. Each successive regulatory approval will increase the size, cost, and complexity of trials for those that follow, causing delays during which suboptimal use will occur and resistance will emerge. This paper proposes the development of a novel regimen with the potential for use in both drug-sensitive (DS) and DR tuberculosis. Adaptive licensing for DR tuberculosis based on 2-month sputum culture would shorten time to initial approval by several years. A global outcomes registry would confirm safety and effectiveness in both DS and DR tuberculosis, making possible the second transformation of tuberculosis treatment. We should do our utmost to see it succeed.
[Show abstract][Hide abstract] ABSTRACT: Novel oral regimens composed of new drugs with potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ≥ clofazimine ≥ rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further.
[Show abstract][Hide abstract] ABSTRACT: There presently is no rapid method to assess the bactericidal activity of new regimens for tuberculosis. This study examined PNU-100480, TMC207, PA-824, SQ109, and pyrazinamide, singly and in various combinations, against intracellular M. tuberculosis, using whole blood culture (WBA). The addition of 1,25-dihydroxy vitamin D facilitated detection of the activity of TMC207 in the 3-day cultures. Pyrazinamide failed to show significant activity against a PZA-resistant strain (M. bovis BCG), and was not further considered. Low, mid, and high therapeutic concentrations of each remaining drug were tested individually and in a paired checkerboard fashion. Observed bactericidal activity was compared to that predicted by the sum of the effects of individual drugs. Combinations of PNU-100480, TMC207, and SQ109 were fully additive, whereas those including PA-824 were less than additive or antagonistic. The cumulative activities of 2, 3, and 4 drug combinations were predicted based on the observed concentration-activity relationship, published pharmacokinetic data, and, for PNU-100480, published WBA data after oral dosing. The most active regimens, including PNU-100480, TMC207, and SQ109, were predicted to have cumulative activity comparable to standard TB therapy. Further testing of regimens including these compounds is warranted. Measurement of whole blood bactericidal activity can accelerate the development of novel TB regimens.
PLoS ONE 01/2012; 7(1):e30479. DOI:10.1371/journal.pone.0030479 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate in vitro interaction between two compounds, SQ109 and PNU-100480, currently in development for the treatment of Mycobacterium tuberculosis (MTB).
The two-drug interactions between SQ109 and PNU-100480 and its major metabolite PNU-101603 were assessed by chequerboard titration, and the rate of killing and intracellular activity were determined in both J774A.1 mouse macrophages and whole blood culture.
In chequerboard titration, interactions between SQ109 and either oxazolidinone were additive. In time-kill studies, SQ109 killed MTB faster than PNU compounds, and its rate of killing was further enhanced by both oxazolidinones. The order of efficacy of single compounds against intracellular MTB was SQ109 > PNU-100480 > PNU-101603. At sub-MIC, combinations of SQ109 + PNU compounds showed improved intracellular activity over individual drugs; at ≥MIC, the order of efficacy was SQ109 > SQ109 + PNU-100480 > SQ109 + PNU-101603. In whole blood culture, the combined bactericidal activities of SQ109 and PNU-100480 and its major metabolite against intracellular M. tuberculosis did not differ significantly from the sum of the compounds tested individually.
SQ109 and PNU combinations were additive and improved the rate of MTB killing over individual drugs. These data suggest that the drugs may work together cooperatively to eliminate MTB in vivo.
[Show abstract][Hide abstract] ABSTRACT: In the decade since tumor necrosis factor α (TNF-α) antagonists were first approved for clinical use, they have proven invaluable for the treatment of specific types of chronic inflammation. Currently licensed TNF blockers fall into two classes, monoclonal antibody (or antibody fragments) and soluble receptor. Although they are equally effective in rheumatoid arthritis and psoriasis, important differences have emerged with regard to efficacy in granulomatous inflammation and risks of granulomatous infections, particularly tuberculosis. This article focuses on recent studies that inform prevention and management of infections in this susceptible patient population.
Infectious disease clinics of North America 12/2011; 25(4):895-910. DOI:10.1016/j.idc.2011.08.002 · 2.73 Impact Factor