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Delamanid Central Nervous System Pharmacokinetics in Tuberculous Meningitis in Rabbits and Humans.

ABSTRACT: Central nervous system tuberculosis (TB) is devastating and affects vulnerable populations. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculous meningitis (TBM) specifically are nearly uniformly fatal, with little information being available to guide the treatment of these patients. Delamanid (DLM), a nitro-dihydro-imidazooxazole, is a new, well-tolerated anti-TB drug with a low MIC (1 to 12?ng/ml) against Mycobacterium tuberculosis It is used for the treatment of pulmonary MDR-TB, but pharmacokinetic (PK) data for DLM in the central nervous system (CNS) of patients with TBM are not available. In the present study, we measured DLM concentrations in the brain and cerebrospinal fluid (CSF) of six rabbits with and without experimentally induced TBM receiving single-dose DLM. We report the steady-state CSF concentrations from three patients receiving DLM as part of multidrug treatment who underwent therapeutic drug monitoring. Drug was quantified using liquid chromatography-tandem mass spectrometry. In rabbits and humans, mean concentrations in CSF (in rabbits, 1.26?ng/ml at 9 h and 0.47?ng/ml at 24 h; in humans, 48?ng/ml at 4 h) were significantly lower than those in plasma (in rabbits, 124?ng/ml at 9 h and 14.5?ng/ml at 24 h; in humans, 726?ng/ml at 4 h), but the estimated free CSF/plasma ratios were generally >1. In rabbits, DLM concentrations in the brain were 5-fold higher than those in plasma (means, 518?ng/ml at 9 h and 74.0?ng/ml at 24 h). All patients with XDR-TBM receiving DLM experienced clinical improvement and survival. Collectively, these results suggest that DLM achieves adequate concentrations in brain tissue. Despite relatively low total CSF drug levels, free drug may be sufficient and DLM may have a role in treating TBM. More studies are needed to develop a fuller understanding of its distribution over time with treatment and clinical effectiveness.

SUBMITTER: Tucker EW

PROVIDER: S-EPMC6761520 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Delamanid Central Nervous System Pharmacokinetics in Tuberculous Meningitis in Rabbits and Humans.

Tucker Elizabeth W EW Pieterse Lisa L Zimmerman Matthew D MD Udwadia Zarir F ZF Peloquin Charles A CA Gler Maria Tarcela MT Ganatra Shashank S Tornheim Jeffrey A JA Chawla Prerna P Caoili Janice C JC Ritchie Brittaney B Jain Sanjay K SK Dartois Véronique V Dooley Kelly E KE

Antimicrobial agents and chemotherapy 20190923 10

Central nervous system tuberculosis (TB) is devastating and affects vulnerable populations. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculous meningitis (TBM) specifically are nearly uniformly fatal, with little information being available to guide the treatment of these patients. Delamanid (DLM), a nitro-dihydro-imidazooxazole, is a new, well-tolerated anti-TB drug with a low MIC (1 to 12 ng/ml) against <i>Mycobacterium tuberculosis</i> It is used for the treatment of p ...[more]

PMID: 31383662

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Project description:BackgroundThe immunopathogenesis of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) remains incompletely understood, and we know of only 1 disease site-specific study of the underlying immunology; we recently showed that Mycobacterium tuberculosis culture positivity and increased neutrophils in the cerebrospinal fluid (CSF) of patients with tuberculous meningitis (TBM) are associated with TBM-IRIS. In this study we investigated inflammatory mediators at the disease site in patients with TBM-IRIS.MethodsWe performed lumbar puncture at 3-5 time points in human immunodeficiency virus (HIV)-infected patients with TBM (n = 34), including at TBM diagnosis, at initiation of antiretroviral therapy (ART) (day 14), 14 days after ART initiation, at presentation of TBM-IRIS, and 14 days thereafter. We determined the concentrations of 40 mediators in CSF (33 paired with blood) with Luminex or enzyme-linked immunosorbent assays. Findings were compared between patients who developed TBM-IRIS (n = 16) and those who did not (TBM-non-IRIS; n = 18).ResultsAt TBM diagnosis and 2 weeks after ART initiation, TBM-IRIS was associated with severe, compartmentalized inflammation in the CSF, with elevated concentrations of cytokines, chemokines, neutrophil-associated mediators, and matrix metalloproteinases, compared with TBM-non-IRIS. Patients with TBM-non-IRIS whose CSF cultures were positive for M. tuberculosis at TBM diagnosis (n = 6) showed inflammatory responses similar to those seen in patients with TBM-IRIS at both time points. However, at 2 weeks after ART initiation, S100A8/A9 was significantly increased in patients with TBM-IRIS, compared with patients with TBM-non-IRIS whose cultures were positive at baseline.ConclusionsA high baseline M. tuberculosis antigen load drives an inflammatory response that manifests clinically as TBM-IRIS in most, but not all, patients with TBM. Neutrophils and their mediators, especially S100A8/A9, are closely associated with the central nervous system inflammation that characterizes TBM-IRIS.

Project description:The role of innate immunity in the pathogenesis of cryptococcal meningitis is unclear. We hypothesized that natural killer (NK) cell and monocyte responses show central nervous system (CNS) compartment-specific profiles, and are altered by antifungal therapy and combination antiretroviral therapy (cART) during cryptococcal meningitis/HIV coinfection.Substudy of a prospective cohort study of adults with cryptococcal meningitis/HIV coinfection in Durban, South Africa.We used multiparametric flow cytometry to study compartmentalization of subsets, CD69 (a marker of activation), CXCR3 and CX3CR1 expression, and cytokine secretion of NK cells and monocytes in freshly collected blood and cerebrospinal fluid (CSF) at diagnosis (n = 23), completion of antifungal therapy induction (n = 19), and after a further 4 weeks of cART (n = 9).Relative to blood, CSF was enriched with CD56(bright) (immunoregulatory) NK cells (P = 0.0004). At enrolment, CXCR3 expression was more frequent among blood CD56(bright) than either blood CD56(dim) (P < 0.0001) or CSF CD56(bright) (P = 0.0002) NK cells. Antifungal therapy diminished blood (P < 0.05), but not CSF CXCR3(pos) NK-cell proportions nor CX3CR1(pos) NK-cell proportions. CD56(bright) and CD56(dim) NK cells were more activated in CSF than blood (P < 0.0001). Antifungal therapy induction reduced CD56(dim) NK-cell activation in CSF (P = 0.02). Activation of blood CD56(bright) and CD56(dim) NK cells was diminished following cART commencement (P < 0.0001, P = 0.03). Immunoregulatory NK cells in CSF tended to secrete higher levels of CXCL10 (P = 0.06) and lower levels of tumor necrosis factor ? (P = 0.06) than blood immunoregulatory NK cells. CSF was enriched with nonclassical monocytes (P = 0.001), but antifungal therapy restored proportions of classical monocytes (P = 0.007).These results highlight CNS activation, trafficking, and function of NK cells and monocytes in cryptococcal meningitis/HIV and implicate immunoregulatory NK cells and proinflammatory monocytes as potential modulators of cryptococcal meningitis pathogenesis during HIV coinfection.

Dataset Information

Delamanid Central Nervous System Pharmacokinetics in Tuberculous Meningitis in Rabbits and Humans.

Publications

Delamanid Central Nervous System Pharmacokinetics in Tuberculous Meningitis in Rabbits and Humans.

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