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A study of the intrapulmonary pharmacology and immunology of tuberculosis therapy

McCallum, Andrew (2018) A study of the intrapulmonary pharmacology and immunology of tuberculosis therapy, Thesis (Doctoral), Liverpool School of Tropical Medicine.

A McCallum - PhD Thesis (Final).pdf - Accepted Version

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Background: Shorter, more efficacious, treatments for pulmonary tuberculosis (TB) are required. Knowledge of the contributions of drug therapy and the immune system to TB cure will inform efforts to optimise treatment.
This study investigates whether antibiotic exposure at the site of infection determines the rate of bacterial clearance and clinical treatment response; and whether impaired alveolar macrophage function in HIV-infection limits the ability of the immune system to eradicate TB.
Methods: Malawian adults with microbiologically-confirmed pulmonary TB were recruited to a longitudinal cohort study. Participants received standard first-line therapy, and supplied serial sputum samples to assess TB bacillary elimination in the sputum. Two-month sputum culture status was recorded, and rates of failure or relapse to one-year post-treatment.
Plasma and intrapulmonary samples were collected at 8 and 16 weeks into treatment, and drug concentrations measured. Population PK modelling generated estimates of drug exposure in plasma, epithelial lining fluid (ELF), and alveolar cells.
Alveolar macrophage function was assessed using quantitative flow cytometry-based reporter bead assays, and ELF cytokine levels measured by ELISA.
Results: 157 participants were recruited. Despite weight-based dosing, peak plasma concentrations of first-line drugs were low relative to therapeutic drug monitoring targets. All 4 drugs achieved higher concentrations in ELF and alveolar cells, with isoniazid and pyrazinamide 20 and 50-fold higher in ELF than plasma respectively. Ethambutol concentrations were highest in alveolar cells.
Rifampicin and isoniazid AUC/Cmax in plasma and ELF were related to treatment response across several endpoints. Peak concentrations of both drugs in plasma were associated with a shorter time to sputum culture negativity, and more favourable final outcomes. AUC/Cmax in ELF were associated with more rapid bacillary elimination, shorter time to sputum culture negativity, and for rifampicin Cmax in plasma, more favourable late outcomes.
HIV infection modulated alveolar macrophage innate immune functions in pulmonary TB. Interferon-γ concentrations in ELF remained high out to 4-months of treatment in HIV-infected participants, with corresponding high superoxidative burst activity and blunted phagocytosis. Initiation of antiretroviral therapy in new HIV diagnoses, with a degree of immune reconstitution, may contribute to ongoing pulmonary inflammation in co-infected patients.
Conclusions: Higher plasma and ELF rifampicin and isoniazid drug concentrations in pulmonary TB are associated with improved treatment response. Combining agents with good intra- and extra-cellular drug penetration may be important when designing new regimens for TB.
TB/HIV co-infection is associated with alterations in the innate immune environment within the lungs that may reflect impaired control of TB infection. Ongoing efforts to expand test-and-treat and target hard to reach groups may reduce the number of late presenters with TB/HIV co-infection.

Item Type: Thesis (Doctoral)
Subjects: WF Respiratory System > Tuberculosis > WF 250 Immunological aspects
WF Respiratory System > Tuberculosis > WF 300 Pulmonary tuberculosis
WF Respiratory System > Tuberculosis > WF 310 Therapy
WF Respiratory System > Tuberculosis > WF 360 Drug therapy
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Depositing User: Lynn Roberts-Maloney
Date Deposited: 04 Jul 2019 08:59
Last Modified: 04 Oct 2019 01:02


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