Dataset Information

Concentration-Dependent Antagonism and Culture Conversion in Pulmonary Tuberculosis.

ABSTRACT:

Background

There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion.

Methods

One hundred patients with pulmonary tuberculosis (65% human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7-8 weeks of therapy, and PK parameters determined using nonlinear mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5-6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 0- to 24-hour area under the curve (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC (%TMIC).

Results

Twenty-six percent of patients had Cmax of rifampicin <8 mg/L, pyrazinamide <35 mg/L, and isoniazid <3 mg/L. No relationship was found between PK exposures and 2-month culture conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was <4.6 mg/L and rifampicin Cmax/MIC <28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax >4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion.

Conclusions

PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.

SUBMITTER: Rockwood N

PROVIDER: S-EPMC5411399 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Concentration-Dependent Antagonism and Culture Conversion in Pulmonary Tuberculosis.

Rockwood Neesha N Pasipanodya Jotam G JG Denti Paolo P Sirgel Frederick F Lesosky Maia M Gumbo Tawanda T Meintjes Graeme G McIlleron Helen H Wilkinson Robert J RJ

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20170501 10

<h4>Background</h4>There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion.<h4>Methods</h4>One hundred patients with pulmonary tuberculosis (65% human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7-8 weeks of therapy, and PK parameters determined ...[more]

PMID: 28205671

Similar Datasets

Project description:BackgroundTuberculosis Trials Consortium Study 28, was a double blind, randomized, placebo-controlled, phase 2 clinical trial examining smear positive pulmonary Mycobacterium tuberculosis. Over the course of intensive phase therapy, patients from African sites had substantially delayed and lower rates of culture conversion to negative in liquid media compared to non-African patients. We explored potential explanations of this finding.MethodsIn TBTC Study 28, protocol-correct patients (n = 328) provided spot sputum specimens for M. tuberculosis culture in liquid media, at baseline and weeks 2, 4, 6 and 8 of study therapy. We compared sputum culture conversion for African and non-African patients stratified by four baseline measures of disease severity: AFB smear quantification, extent of disease on chest radiograph, cavity size and the number of days to detection of M. tuberculosis in liquid media using the Kaplan-Meier product-limit method. We evaluated specimen processing and culture procedures used at 29 study laboratories serving 27 sites.ResultsAfrican TB patients had more extensive disease at enrollment than non-African patients. However, African patients with the least disease by the 4 measures of disease severity had conversion rates on liquid media that were substantially lower than conversion rates in non-African patients with the greatest extent of disease. HIV infection, smoking and diabetes did not explain delayed conversion in Africa. Some inter-site variation in laboratory processing and culture procedures within accepted practice for clinical diagnostic laboratories was found.ConclusionsCompared with patients from non-African sites, African patients being treated for TB had delayed sputum culture conversion and lower sputum conversion rates in liquid media that were not explained by baseline severity of disease, HIV status, age, smoking, diabetes or race. Further investigation is warranted into whether modest variation in laboratory processes substantially influences the efficacy outcomes of phase 2 TB treatment trials or if other factors (e.g., nutrition, host response) are involved.Trial registrationClinicalTrials.gov NCT00144417.

Project description:Novel tuberculosis (TB) prevention and control strategies are urgently required. Utilising specimens from the Improving Retreatment Success (NCT02114684) trial we assessed the associations between inflammatory markers, measured during active TB, with treatment response and disease severity in HIV-infected and uninfected individuals. Multiplex immunoassays and ELISA were used to measure plasma expression of 24 cytokines/chemokines. Cytokines were log transformed to adjust for skewness. We conducted a nested, un-matched, case (n= 31) - control (n=101) study with cases defined as those participants who failed to sputum culture convert within 8-weeks of TB treatment initiation. Additionally, we examined the association between the measured cytokines and time to culture conversion and presence of lung cavitation using cox proportional hazards and logistic regression models, respectively. Multivariable analyses adjusted for a wide range of baseline clinical and demographic variables. IP-10 expression during active TB was associated with increased odds of sputum culture conversion by 8-weeks overall (aOR 4.255, 95% CI 1.025 - 17.544, p=0.046)) and among HIV-infected individuals (OR 10.204, 95% CI 1.247 - 83.333, p=0.030). Increased MCP-3 (aHR 1.723, 95% CI 1.040 - 2.855, p=0.035) and IL-6 (aHR 1.409, 95% CI 1.045 - 1.899, p=0.024) expression was associated with a shorter time to culture conversion in the total cohort. Higher plasma expression of IL-6 (aHR 1.783, 95% CI 1.128 - 2.820, p=0.013), IL-1RA (aHR 2.595, 95% CI 1.136 - 5.926, p=0.024), IP-10 (aHR 2.068, 95% CI 1.034 - 4.137, p=0.040) and IL-1α (aHR 2.008, 95% CI 1.053 - 3.831, p=0.035) were significantly associated with shorter time to culture conversion among HIV-infected individuals. Increased IL-6 and IL-1RA expression was significantly associated with the presence of lung cavitation during active TB in the total cohort (OR 2.543, 95% CI 1.254 - 5.160, p=0.010), (OR 4.639, 95% CI 1.203 - 21.031, p=0.047) and in HIV-infected individuals (OR 2.644, 95% CI 1.062 - 6.585, p=0.037), (OR 7.795, 95% CI 1.177 - 51.611, p=0.033) respectively. Our results indicate that inflammatory cytokines/chemokines play an important role in TB disease outcome. Importantly, the observed associations were stronger in multivariable models highlighting the impact of behavioural and clinical variables on the expression of immune markers as well as their potential effects on TB outcome.

Dataset Information

Concentration-Dependent Antagonism and Culture Conversion in Pulmonary Tuberculosis.

Background

Methods

Results

Conclusions

Publications

Concentration-Dependent Antagonism and Culture Conversion in Pulmonary Tuberculosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets