New and Repurposed Drugs for the Treatment of Active Tuberculosis: An Update for Clinicians

Díaz, Jéssica; Abulfathi, Ahmed A.; Brake, L.H. te; Ingen, Jakko van; Kuipers, Saskia; Magis-Escurra, Cécile; Raaijmakers, Jelmer; Svensson, Elin M; Boeree, Martin J.

doi:10.1159/000528274

Cited by 16 publications

(4 citation statements)

References 172 publications

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“…Multidrug-resistant tuberculosis (MDR-TB), defined as tuberculosis (TB) resistant to rifampicin and isoniazid, is still a threat to the worldwide control of TB [ 1 ]. In the past few decades, significant progress has been made, such as more effective treatment regimens including new and repurposed anti-TB drugs [ 2 ]. In 2016, the WHO recommended an 18–24-month all-oral regimen including bedaquiline (BDQ), linezolid (LZD), and moxifloxacin (MFX) as Group A drugs, in which pyrazinamide was classified as a Group C agent [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Drug Exposure and Susceptibility of Pyrazinamide Correlate with Treatment Response in Pyrazinamide-Susceptible Patients with Multidrug-Resistant Tuberculosis

Dong,

Shao,

Davies Forsman

et al. 2024

Pharmaceutics

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Exploring the influence of pyrazinamide exposure and susceptibility on treatment response is crucial for optimizing the management of multidrug-resistant tuberculosis (MDR-TB). This study aimed to investigate the association between pyrazinamide exposure, susceptibility, and response to MDR-TB treatment, as well as find clinical thresholds for pyrazinamide. A prospective multi-center cohort study of participants with MDR-TB using pyrazinamide was conducted in three TB-designated hospitals in China. Univariate and multivariate analyses were applied to investigate the associations. Classification and Regression Tree (CART) analysis was used to identify clinical thresholds, which were further evaluated by multivariate analysis and receiver operating characteristic (ROC) curves. The study included 143 patients with MDR-TB. The exposure/susceptibility ratio of pyrazinamide was associated with two-month culture conversion (adjusted risk ratio (aRR), 1.1; 95% confidence interval (CI), 1.07–1.20), six-month culture conversion (aRR, 1.1; 95% CI, 1.06–1.16), treatment success (aRR, 1.07; 95% CI, 1.03–1.10), as well as culture conversion time (adjusted hazard ratio (aHR) 1.18; 95% CI,1.14–1.23). The threshold for optimal improvement in sputum culture results at the sixth month of treatment was determined to be a pyrazinamide AUC0–24h/MIC ratio of 7.8. In conclusion, the exposure/susceptibility ratio of pyrazinamide is associated with the treatment response of MDR-TB, which may change in different Group A drug-based regimens.

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Section: Introductionmentioning

confidence: 99%

Drug Exposure and Susceptibility of Pyrazinamide Correlate with Treatment Response in Pyrazinamide-Susceptible Patients with Multidrug-Resistant Tuberculosis

Dong,

Shao,

Davies Forsman

et al. 2024

Pharmaceutics

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“…Notable instances include the repurposing of ketoconazole, an antifungal, for Cushing's syndrome, and investigations into the use of levofloxacin and tetracyclines for Alzheimer's disease [3]. Conversely, repurposing antimicrobials for different infectious diseases than their initial targets have proven beneficial, as seen with tetracycline for malaria [3] and linezolid for tuberculosis [4].…”

Section: Introductionmentioning

confidence: 99%

Repurposing of anti-malarial drugs for the treatment of tuberculosis: realistic strategy or fanciful dead end?

Hanscheid,

del Portal Luyten,

Hermans

et al. 2024

Malar J

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Background Drug repurposing offers a strategic alternative to the development of novel compounds, leveraging the known safety and pharmacokinetic profiles of medications, such as linezolid and levofloxacin for tuberculosis (TB). Anti-malarial drugs, including quinolones and artemisinins, are already applied to other diseases and infections and could be promising for TB treatment. Methods This review included studies on the activity of anti-malarial drugs, specifically quinolones and artemisinins, against Mycobacterium tuberculosis complex (MTC), summarizing results from in vitro, in vivo (animal models) studies, and clinical trials. Studies on drugs not primarily developed for TB (doxycycline, sulfonamides) and any novel developed compounds were excluded. Analysis focused on in vitro activity (minimal inhibitory concentrations), synergistic effects, pre-clinical activity, and clinical trials. Results Nineteen studies, including one ongoing Phase 1 clinical trial, were analysed: primarily investigating quinolones like mefloquine and chloroquine, and, to a lesser extent, artemisinins. In vitro findings revealed high MIC values for anti-malarials versus standard TB drugs, suggesting a limited activity. Synergistic effects with anti-TB drugs were modest, with some synergy observed in combinations with isoniazid or pyrazinamide. In vivo animal studies showed limited activity of anti-malarials against MTC, except for one study of the combination of chloroquine with isoniazid. Conclusions The repurposing of anti-malarials for TB treatment is limited by high MIC values, poor synergy, and minimal in vivo effects. Concerns about potential toxicity at effective dosages and the risk of antimicrobial resistance, especially where TB and malaria overlap, further question their repurposing. These findings suggest that focusing on novel compounds might be both more beneficial and rewarding.

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“…Active TB is curable with chemotherapy, but despite drug treatment, patients may not develop sterilizing immunity (2)(3)(4). Moreover, the BCG vaccine can prevent disseminated forms of TB in children but fails to protect adults from pulmonary TB (5).…”

Section: Introductionmentioning

confidence: 99%

Delivery of Mycobacterium tuberculosis epitopes by Bordetella pertussis adenylate cyclase toxoid expands HLA-E-restricted cytotoxic CD8+ T cells

Badami,

La Manna,

Di Carlo

et al. 2023

Front. Immunol.

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IntroductionTuberculosis (TB) remains the first cause of death from infection caused by a bacterial pathogen. Chemotherapy does not eradicate Mycobacterium tuberculosis (Mtb) from human lungs, and the pathogen causes a latent tuberculosis infection that cannot be prevented by the currently available Bacille Calmette Guerin (BCG) vaccine, which is ineffective in the prevention of pulmonary TB in adults. HLA-E-restricted CD8+ T lymphocytes are essential players in protective immune responses against Mtb. Hence, expanding this population in vivo or ex vivo may be crucial for vaccination or immunotherapy against TB.MethodsThe enzymatically inactive Bordetella pertussis adenylate cyclase (CyaA) toxoid is an effective tool for delivering peptide epitopes into the cytosol of antigen-presenting cells (APC) for presentation and stimulation of specific CD8+ T-cell responses. In this study, we have investigated the capacity of the CyaA toxoid to deliver Mtb epitopes known to bind HLA-E for the expansion of human CD8+ T cells in vitro.ResultsOur results show that the CyaA-toxoid containing five HLA-E-restricted Mtb epitopes causes significant expansion of HLA-E-restricted antigen-specific CD8+ T cells, which produce IFN-γ and exert significant cytotoxic activity towards peptide-pulsed macrophages.DiscussionHLA-E represents a promising platform for the development of new vaccines; our study indicates that the CyaA construct represents a suitable delivery system of the HLA-E-binding Mtb epitopes for ex vivo and in vitro expansion of HLA-E-restricted CD8+ T cells inducing a predominant Tc1 cytokine profile with a significant increase of IFN-γ production, for prophylactic and immunotherapeutic applications against Mtb.

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New and Repurposed Drugs for the Treatment of Active Tuberculosis: An Update for Clinicians

Cited by 16 publications

References 172 publications

Drug Exposure and Susceptibility of Pyrazinamide Correlate with Treatment Response in Pyrazinamide-Susceptible Patients with Multidrug-Resistant Tuberculosis

Drug Exposure and Susceptibility of Pyrazinamide Correlate with Treatment Response in Pyrazinamide-Susceptible Patients with Multidrug-Resistant Tuberculosis

Repurposing of anti-malarial drugs for the treatment of tuberculosis: realistic strategy or fanciful dead end?

Delivery of Mycobacterium tuberculosis epitopes by Bordetella pertussis adenylate cyclase toxoid expands HLA-E-restricted cytotoxic CD8+ T cells

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