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Background: The sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization.Methods and Findings: A total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26-22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21-2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03-0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed treatment and underwent lung resection surgery. These results still need further exploration and validation in larger and more diverse cohorts.Conclusions: Our results suggest that the ability to reach and maintain therapeutic concentrations is both lesion and drug specific, indicating that stratifying patients based on disease extent, lesion types, and individual drug-susceptibility profiles may eventually be useful for guiding the selection of patient-tailored drug regimens and may lead to improved TB treatment outcomes. We provide a web-based tool to further explore this model and results at http://saviclab.org/tb-lesion/. [ABSTRACT FROM AUTHOR]

Background: We have previously reported that TNF-α levels correlate to total mycobacterial burden in tuberculosis (TB) patients. Objective: To characterize the dynamics of cytokine responses in TB patients during chemotherapy to identify potential surrogate markers for effective treatment. Methods: Following induction by culture filtrate proteins in whole blood, production patterns of TNF-α, IL-10, IFN-γ and IL-12 were measured in 23 non-multidrug-resistant (MDR)-TB and 16 MDR-TB patients and in 31 healthy controls. Rates of mycobacterial clearance from the sputum were then measured and compared. Results: Prior to the initiation of chemotherapy, TNF-α and IL-10 levels were significantly higher in TB patients than in healthy controls while IFN-γ and IL-12 levels were similar. During chemotherapy, the levels of all 4 cytokines increased. We evaluated these responses separately in patients that did and did not clear their sputum culture at 2 and 6 months. At 2 months, decreases in both IFN-γ and IL-12 correlated strongly with a successful early response, while after 6 months of therapy, when half (7/14) of MDR-TB patients were still sputum culture positive, downregulation of TNF-α was uniquely correlated with sputum conversion between the groups. Conclusion: Our findings suggest the possibility that the regulation of TNF-α production in whole blood may be a more specific indicator of sputum conversion at 6 months than IFN-γ, IL-12 or IL-10 in MDR-TB patients. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. Extensively drug-resistant (XDR) tuberculosis (TB) is a major public health threat in South Korea. Methods. We analyzed baseline epidemiological data for 250 patients enrolled in an ongoing prospective observational study of TB at a large tertiary referral hospital in South Korea. Results. Twenty-six subjects with XDR TB were identified; all were patients who had previously received TB therapy. Cumulative previous treatment duration (range, 18-34 months; odds ratio [OR], 5.6; 95% confidence interval [CI], 1.0-59), number of previously received second-line anti-TB drugs (OR, 1.3; 95% CI, 1.1-1.5), and female sex (OR, 3.2; 95% CI, 1.1-8.3) were significantly associated with XDR TB in crude analyses. After controlling for other factors in a multivariable model, cumulative previous treatment duration remained significantly associated with XDR TB (OR, 5.8; 95% CI, 1.0-61). Subjects with XDR TB were more likely to produce culture-positive sputum at 6 months, compared with patients with non-multidrug resistant TB (risk ratio, 13; 95% CI, 5.1-53). Kanamycin resistance was found to be predictive of 6-month culture positivity after adjustment for ofloxacin and streptomycin resistance (risk ratio, 3.9; 95% CI, 1.9-11). Conclusions. XDR TB was found to be associated with the cumulative duration of previous treatment with second-line TB drugs among subjects in a tertiary care TB hospital. Patients with XDR TB were more likely to not respond to therapy, and successful conversion of sputum culture results to negative was correlated with initial susceptibility to both fluoroquinolones and kanamycin but not to streptomycin. [ABSTRACT FROM AUTHOR]