Sorafenib-Induced Tuberculosis Reactivation

Teo, Min Yuen; O’Connor, Terence M.; O’Reilly, Seamus; Power, Derek G.

doi:10.1159/000341829

Cited by 7 publications

(4 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The issues surrounding the concurrent optimizations of Mtb kinase inhibition and antitubercular whole-cell efficacy are known [44] and certainly are magnified given the concern over mammalian cell cytotoxicity. Additionally, studies demonstrating the antagonistic effects of human kinase inhibitors on TB infection through, for example, reactivation must be noted [45], [46]. The largest selectivity indices in our study were 6 for XL880 and 3 for NVP-TAE684 and AP24534.…”

Section: Discussionmentioning

confidence: 61%

Enhancing Hit Identification in Mycobacterium tuberculosis Drug Discovery Using Validated Dual-Event Bayesian Models

et al. 2013

View full text Add to dashboard Cite

High-throughput screening (HTS) in whole cells is widely pursued to find compounds active against Mycobacterium tuberculosis (Mtb) for further development towards new tuberculosis (TB) drugs. Hit rates from these screens, usually conducted at 10 to 25 µM concentrations, typically range from less than 1% to the low single digits. New approaches to increase the efficiency of hit identification are urgently needed to learn from past screening data. The pharmaceutical industry has for many years taken advantage of computational approaches to optimize compound libraries for in vitro testing, a practice not fully embraced by academic laboratories in the search for new TB drugs. Adapting these proven approaches, we have recently built and validated Bayesian machine learning models for predicting compounds with activity against Mtb based on publicly available large-scale HTS data from the Tuberculosis Antimicrobial Acquisition Coordinating Facility. We now demonstrate the largest prospective validation to date in which we computationally screened 82,403 molecules with these Bayesian models, assayed a total of 550 molecules in vitro, and identified 124 actives against Mtb. Individual hit rates for the different datasets varied from 15–28%. We have identified several FDA approved and late stage clinical candidate kinase inhibitors with activity against Mtb which may represent starting points for further optimization. The computational models developed herein and the commercially available molecules derived from them are now available to any group pursuing Mtb drug discovery.

show abstract

Section: Discussionmentioning

confidence: 61%

Enhancing Hit Identification in Mycobacterium tuberculosis Drug Discovery Using Validated Dual-Event Bayesian Models

et al. 2013

View full text Add to dashboard Cite

show abstract

“… 117 , 118 , 119 The use of sorafenib has been associated with reactivation of latent tuberculosis. 120 With the expanding list of targeted therapies becoming available in the market and being used in endemic regions of T. marneffei , it would be important for clinicians to maintain a high index of suspicion and possibly perform serial serological surveillance for T. marneffei infection in patients who have received these agents to avoid a delay in diagnosis and treatment. 121 …”

Section: Specific Characteristics Of Non-aids Conditions Associated Wmentioning

confidence: 99%

Talaromyces (Penicillium) marneffeiinfection in non-HIV-infected patients

Chan

Lau

Yuen

et al. 2016

Emerging Microbes & Infections

207

247

View full text Add to dashboard Cite

Talaromyces (Penicillium) marneffei is an important pathogenic thermally dimorphic fungus causing systemic mycosis in Southeast Asia. The clinical significance of T. marneffei became evident when the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome epidemic arrived in Southeast Asia in 1988. Subsequently, a decline in the incidence of T. marneffei infection among HIV-infected patients was seen in regions with access to highly active antiretroviral therapy and other control measures for HIV. Since the 1990s, an increasing number of T. marneffei infections have been reported among non-HIV-infected patients with impaired cell-mediated immunity. Their comorbidities included primary adult-onset immunodeficiency due to anti-interferon-gamma autoantibodies and secondary immunosuppressive conditions including other autoimmune diseases, solid organ and hematopoietic stem cell transplantations, T-lymphocyte-depleting immunsuppressive drugs and novel anti-cancer targeted therapies such as anti-CD20 monoclonal antibodies and kinase inhibitors. Moreover, improved immunological diagnostics identified more primary immunodeficiency syndromes associated with T. marneffei infection in children. The higher case-fatality rate of T. marneffei infection in non-HIV-infected than HIV-infected patients might be related to delayed diagnosis due to the lack of clinical suspicion. Correction of the underlying immune defects and early use of antifungals are important treatment strategies. Clinicians should be familiar with the changing epidemiology and clinical management of T. marneffei infection among non-HIV-infected patients.

show abstract

“…Similarly, patients with impaired JAK-STAT signaling, but not those with diabetes mellitus or splenectomy (case-patient 3), are predisposed to T. marneffei infection ( 6 ). Sorafenib is a multikinase inhibitor with various immunomodulatory effects, including impaired T-cell response and proliferation and reduced IFN-γ production ( 18 ). These immune defects have been associated with reactivation of latent tuberculosis and might also predispose patients to opportunistic infections caused by intracellular organisms such as T. marneffei ( 18 ).…”

Section: Discussionmentioning

confidence: 99%