The importance of clinical pharmacokinetic–pharmacodynamic studies in unraveling the determinants of early and late tuberculosis outcomes

Tuberculosis remains a major infectious cause of morbidity and mortality worldwide. Current antibiotic regimens, constructed prior to the development of modern pharmacokinetic-pharmacodynamic (PK–PD) tools, are based on incomplete understanding of exposure–response relationships in drug susceptible and multidrug resistant tuberculosis. Preclinical and population PK data suggest that clinical PK–PD studies may enable therapeutic drug monitoring for some agents and revised dosingf or others. Future clinical PK–PD challenges include: incorporation of PK methods to assay free concentrations for all active metabolites; selection of appropriate early outcome measures which reflect therapeutic response; elucidation of genetic contributors to interindividual PK variability; conduct of targeted studies on special populations (including children); and measurement of PK–PD parameters at the site of disease.Publisher PDFPeer reviewe

Rational Design of Superhydrophilic/Superoleophobic Surfaces for Oil-Water Separation via Thiol-Acrylate Photopolymerization

We report a simple, rapid, and scalable strategy to fabricate surfaces exhibiting in-air superoleophobic/superhydrophilic wetting via sequential spray deposition and photopolymerization of nanoparticle-laden thiol–acrylate resins comprising both hydrophilic and oleophobic chemical constituents. The combination of spray deposition with nanoparticles provides hierarchical surface morphologies with both micro- and nanoscale roughness. Mapping the wetting behavior as a function of resin composition using high- and low-surface-tension liquid probes enabled facile identification of coatings that exhibit a range of wetting behavior, including superhydrophilic/superoleophilic, superhydrophobic/superoleophobic, and in-air superhydrophilic/superoleophobic wetting. In-air superhydrophilic/superoleophobic wetting was realized by a dynamic rearrangement of the interface to expose a greater fraction of hydrophilic moieties in response to contact with water. We show that these in-air superoleophobic/superhydrophilic coatings deposited onto porous supports enable separation of model oil–water emulsions with separation efficiencies up to 99.9% with 699 L·m–2 h–1 permeate flux when the superhydrophilic/superoleophobic coatings are paired with 0.45 μm nylon membrane supports

Apoptosis and antigen receptor function in T and B cells following exposure to herpes simplex virus

AbstractT cells are an essential component of the immune response against herpes simplex virus (HSV) infection. We previously reported that incubation of T cells with HSV-infected fibroblasts inhibits subsequent T cell antigen receptor signal transduction. In the current study, we found that incubation of T cells with HSV-infected fibroblasts also leads to apoptosis in exposed T cells. Apoptosis was observed in Jurkat cells, a T cell leukemia line, and also in CD4+ cells isolated from human peripheral blood mononuclear cells. Direct infection of these cells with HSV also resulted in apoptosis. Clinical isolates of both HSV type 1 and 2 induced apoptosis in infected T cells at comparable levels to cells infected with laboratory strains of HSV, suggesting an immune evasion mechanism that may be clinically relevant. Further understanding of these viral immune evasion mechanisms could be exploited for better management of HSV infection

Perceptions of Research Bronchoscopy in Malawian Adults with Pulmonary Tuberculosis: A Cross-Sectional Study

Bronchoscopy is an established research tool in Malawi, enabling collection of pulmonary samples for immunological, pharmacological, and microbiological studies. It is, however, an invasive clinical procedure that offers no direct benefit to volunteering participants when used in a research capacity alone, and thus informed consent is essential. This study aimed to explore TB patients’ understanding of research bronchoscopy, what would motivate them to participate in research bronchoscopy, and their concerns, in order to inform consenting processes for future clinical studies. We used a qualitative research design. Two focus group discussions were conducted with community members and TB patients to understand their perceptions of bronchoscopy. Transcripts were coded by multiple co-authors and thematic content analysis was used to analyse main findings. We found that Malawian patients with pulmonary TB were willing to participate in a study using research bronchoscopy for health assessment and access to improved healthcare. We identified information of value to potential participants when consenting to that may lessen some of the anxieties expressed by participants. Patient and public involvement is essential to improve informed consent and institutional trust

Vitamin D deficiency in Malawian adults with pulmonary tuberculosis : risk factors and treatment outcomes

The study was supported by a Wellcome Trust (London, UK) Clinical PhD Fellowship awarded to DS (086757/Z/08/A) and the Malawi Liverpool Wellcome Trust (MLW) Core grant from the Wellcome Trust.SETTING: Vitamin D deficiency is common in African adults with tuberculosis (TB), and may be exacerbated by the metabolic effects of anti-tuberculosis drugs and antiretroviral therapy (ART). It is unclear whether vitamin D deficiency influences response to antituberculosis treatment. OBJECTIVES : To describe risk factors for baseline vitamin D deficiency in Malawian adults with pulmonary TB, assess the relationship between serum 25-hydroxy vitamin D (25[OH]D) concentration and treatment response, and evaluate whether the administration of anti-tuberculosis drugs and ART is deleterious to vitamin D status during treatment. DESIGN: A prospective longitudinal cohort study. RESULTS : The median baseline 25(OH)D concentration of the 169 patients (58% human immunodeficiency virus [HIV] infected) recruited was 57 nmol/l; 47 (28%) had vitamin D deficiency (<50 nmol/l). Baseline 25(OH)D concentrations were lower during the cold season (P < 0.001), with food insecurity (P = 0.034) or in patients who consumed alcohol (P = 0.019). No relationship between vitamin D status and anti-tuberculosis treatment response was found. 25(OH)D concentrations increased during anti-tuberculosis treatment, irrespective of HIV status or use of ART. CONCLUSIONS : Vitamin D deficiency is common among TB patients in Malawi, but this does not influence treatment response. Adverse metabolic effects of drug treatment may be compensated by the positive impact of clinical recovery preventing exacerbation of vitamin D deficiency during anti-tuberculosis treatment.Publisher PDFPeer reviewe

Genetic determinants of the pharmacokinetic variability of rifampin in Malawian adults with pulmonary tuberculosis

D.J.S. was supported by a Wellcome Trust Clinical PhD Fellowship (086757/Z/08/A to D.J.S.). A.D.M. was supported by a National Institute for Health Research Integrated Clinical Academic Training Fellowship and a Wellcome Trust Clinical PhD Fellowship (105/392/B/14/Z). The Malawi Liverpool Wellcome Trust Clinical Research Programme is supported by a strategic award from the Wellcome Trust.Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC and CES-1) to interindividual pharmacokinetic variability in Malawi. A total of 174 adults with pulmonary TB underwent sampling of plasma rifampin concentrations at 2 and 6 h postdose. Data from a prior cohort of 47 intensively sampled, similar patients from the same setting were available to support population pharmacokinetic model development in NONMEM v7.2, using a two-stage strategy to improve information during the absorption phase. In contrast to recent studies in South Africa and Uganda, SNPs in SLCO1B1 did not explain variability in AUC0-∞ of rifampin. No pharmacokinetic associations were identified with AADAC or CES-1 SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampin exposure may vary between African populations. SLCO1B1 and other novel candidate genes, as well as nongenetic sources of interindividual variability, should be further explored in geographically diverse, adequately powered cohorts.Publisher PDFPeer reviewe

Perceptions of research bronchoscopy in Malawian adults with pulmonary tuberculosis : a cross-sectional study

Funding: Liverpool Integrated Clinical Academic Training Programme, experience at another institution (ADM); Wellcome Trust Clinical PhD Fellowship 105392/B/14/Z.Bronchoscopy is an established research tool in Malawi, enabling collection of pulmonary samples for immunological, pharmacological, and microbiological studies. It is, however, an invasive clinical procedure that offers no direct benefit to volunteering participants when used in a research capacity alone, and thus informed consent is essential. This study aimed to explore TB patients' understanding of research bronchoscopy, what would motivate them to participate in research bronchoscopy, and their concerns, in order to inform consenting processes for future clinical studies. We used a qualitative research design. Two focus group discussions were conducted with community members and TB patients to understand their perceptions of bronchoscopy. Transcripts were coded by multiple coauthors and thematic content analysis was used to analyse main findings. We found that Malawian patients with pulmonary TB were willing to participate in a study using research bronchoscopy for health assessment and access to improved healthcare. We identified information of value to potential participants when consenting to that may lessen some of the anxieties expressed by participants. Patient and public involvement is essential to improve informed consent and institutional trust.Publisher PDFPeer reviewe

Intrapulmonary Pharmacokinetics of First-line Anti-tuberculosis Drugs in Malawian Patients With Tuberculosis

BACKGROUND: Further work is required to understand the intrapulmonary pharmacokinetics of first-line anti-tuberculosis drugs. This study aimed to describe the plasma and intrapulmonary pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol, and explore relationships with clinical treatment outcomes in patients with pulmonary tuberculosis. METHODS: Malawian adults with a first presentation of microbiologically-confirmed pulmonary tuberculosis received standard 6-month first-line therapy. Plasma and intrapulmonary samples were collected 8 and 16 weeks into treatment and drug concentrations measured in plasma, lung/airway epithelial lining fluid, and alveolar cells. Population pharmacokinetic modelling generated estimates of drug exposure (Cmax and AUC) from individual-level post-hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics. RESULTS: One-hundred-and-fifty-seven patients (58% HIV co-infected) participated. Despite standard weight-based dosing, peak plasma concentrations of first-line drugs were below therapeutic drug monitoring targets. Rifampicin concentrations were low in all three compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in epithelial lining fluid and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6 (95% CI: 11.2-18.0) and 49.8-fold (95% CI: 34.2-65.3) higher in lining fluid than plasma respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cells:plasma ratio 15.0, 95% CI 11.4-18.6). Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response. CONCLUSIONS: We report differential drug concentrations between plasma and the lung. While plasma concentrations were below therapeutic monitoring targets, accumulation of drugs at the site of disease may explain the success of the first-line regimen. The low rifampicin concentrations observed in all compartments lend strong support for ongoing clinical trials of high-dose rifampicin regimens

Mycobacterium tuberculosis transmission from patients with drug-resistant compared to drug-susceptible TB: a systematic review and meta-analysis.

The extent to which drug-resistant (DR) Mycobacterium tuberculosis strains cause infection and progression to tuberculosis (TB) disease in comparison to drug-susceptible (DS) strains is unknown. Studies in guinea pigs and in vitro experiments have suggested a reduced fitness of organisms that harbour mutations that confer drug resistance [1, 2]; it was therefore believed that transmitted drug resistance was a rare event. However, more recent work using molecular typing has shown transmission events occurring in the context of DR-TB [3]. Understanding the risk of transmission, infection and progression to disease in the context of DR-TB is important to guide control measures and help predict the evolution and magnitude of the multidrug-resistant (MDR)-TB epidemic. Hence, we performed a systematic review and meta-analysis to assess whether M. tuberculosis transmission and progression to TB disease (risk/rate of M. tuberculosis infection in all contacts, risk/rate of TB disease in all contacts and risk/rate of TB disease in infected contacts) differ between DR- and DS-TB

High intrapulmonary rifampicin and isoniazid concentrations are associated with rapid sputum bacillary clearance in patients with pulmonary tuberculosis

This work was supported by a Wellcome Trust Clinical PhD Fellowship [grant number 105392/B/14/Z to A.D.M. and L69AGB to JM]. ELC was supported by Wellcome [200901/Z/16/Z]. The Malawi-Liverpool-Wellcome Clinical Research Programme is supported by a strategic award from the Wellcome Trust [206545/Z/17/Z]. We also acknowledge infrastructural support for bioanalysis from the Liverpool Biomedical Research Centre funded by Liverpool Health Partners.Background Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modelling bacillary clearance in sputum in adult patients on first-line treatment in Malawi. Methods Bacillary elimination rates (BER) were estimated using linear mixed-effects modelling of serial time-to-positivity in mycobacterial growth indicator tubes for sputum collected during the intensive phase of treatment (weeks 0 to 8) for microbiologically confirmed TB. Population pharmacokinetic models used plasma and intrapulmonary drug levels at 8 and 16 weeks. Pharmacokinetic-pharmacodynamic relationships were investigated using individual-level measures of drug exposure (AUC and Cmax) for rifampicin, isoniazid, pyrazinamide, and ethambutol, in plasma, epithelial lining fluid, and alveolar cells as covariates in the bacillary elimination models. Results Among 157 participants (58% HIV co-infected), drug exposure in plasma or alveolar cells was not associated with sputum bacillary clearance. Higher peak concentrations (Cmax) or exposure (AUC) to rifampicin or isoniazid in epithelial lining fluid was associated with more rapid bacillary elimination and shorter time to sputum negativity. More extensive disease on baseline chest radiograph was associated with slower bacillary elimination. Clinical outcome was captured in 133 participants, with 15 (11%) unfavourable outcomes recorded (recurrent TB, failed treatment, or death). No relationship between BER and late clinical outcome was identified. Conclusions Greater intrapulmonary drug exposure to rifampicin or isoniazid in the epithelial lining fluid was associated with more rapid bacillary clearance. Higher doses of rifampicin and isoniazid may result in sustained high intrapulmonary drug exposure, rapid bacillary clearance, shorter treatment duration and better treatment outcomes.Publisher PDFPeer reviewe