Dataset Information

Longitudinal Pharmacokinetic-Pharmacodynamic Biomarkers Correlate With Treatment Outcome in Drug-Sensitive Pulmonary Tuberculosis: A Population Pharmacokinetic-Pharmacodynamic Analysis.

ABSTRACT: Background:This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions. Methods:Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing. Results:Higher isoniazid exposure correlated with increased bacillary killing in sputum (P?

SUBMITTER: Kloprogge F

PROVIDER: S-EPMC7378673 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Longitudinal Pharmacokinetic-Pharmacodynamic Biomarkers Correlate With Treatment Outcome in Drug-Sensitive Pulmonary Tuberculosis: A Population Pharmacokinetic-Pharmacodynamic Analysis.

Kloprogge Frank F Mwandumba Henry C HC Banda Gertrude G Kamdolozi Mercy M Shani Doris D Corbett Elizabeth L EL Kontogianni Nadia N Ward Steve S Khoo Saye H SH Davies Geraint R GR Sloan Derek J DJ

Open forum infectious diseases 20200606 7

<h4>Background</h4>This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions.<h4>Methods</h4>Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 ...[more]

PMID: 32733976

Similar Datasets

Project description:Fluoroquinolones are group A drugs in tuberculosis guidelines. We aim to compare the culture conversion between new-generation (levofloxacin and moxifloxacin) and old-generation (ciprofloxacin and ofloxacin) fluoroquinolones, develop pharmacokinetic models, and calculate target attainment for levofloxacin and moxifloxacin. We included three U.S. tuberculosis centers. Patients admitted between 1984 and 2015, infected with drug-resistant tuberculosis, and who had received fluoroquinolones for ≥28 days were included. Demographics, sputum cultures and susceptibility, treatment regimens, and serum concentrations were collected. A time-to-event analysis was conducted, and Cox proportional hazards model was used to compare the time to culture conversion. Using additional data from ongoing studies, pharmacokinetic modelling and Monte Carlo simulations were performed to assess target attainment for different doses. Overall, 124 patients received fluoroquinolones. The median age was 40 years, and the median weight was 60 kg. Fifty-six patients (45%) received old-generation fluoroquinolones. New-generation fluoroquinolones showed a faster time to culture conversion (median 16 versus 40 weeks, P = 0.012). After adjusting for isoniazid and clofazimine treatment, patients treated with new-generation fluoroquinolones were more likely to have culture conversion (adjusted hazards ratio, 2.16 [95% confidence interval, 1.28 to 3.64]). We included 178 patients in the pharmacokinetic models. Levofloxacin and moxifloxacin were best described by a one-compartment model with first-order absorption and elimination. At least 1,500 to 1,750 mg levofloxacin and 800 mg moxifloxacin may be needed for maximum kill at the current epidemiologic cutoff values. In summary, new-generation fluoroquinolones showed faster time to culture conversion compared to the old generation. For optimal target attainment at the current MIC values, higher doses of levofloxacin and moxifloxacin may be needed.

Project description:BackgroundTuberculosis (TB) is one of the leading causes of death worldwide. Radiology has an important role in the diagnosis of both drug-sensitive (DS) and rifampicin-resistant (RR) pulmonary TB (PTB). This study aimed to compare the chest x-ray (CXR) patterns of microbiologically confirmed DS and RR PTB cases stratified by HIV serostatus in Uganda.MethodsWe conducted a hospital-based retrospective study at the Mulago National Referral Hospital (MNRH) TB wards. All participants had a microbiologically confirmed diagnosis of PTB. CXR findings extracted included infiltrates, consolidation, cavity, fibrosis, bronchiectasis, atelectasis, and other non-lung parenchymal findings. All films were examined by two independent radiologists blinded to the clinical diagnosis.ResultsWe analyzed CXR findings of 165 participants: 139 DS- and 26 RR-TB cases. The majority (n = 118, 71.7%) of the participants were seronegative for HIV. Overall, 5/165 (3%) participants had normal CXR. There was no statistically significant difference in the proportion of participants with consolidations (74.8% versus 88.5%; p = 0.203), bronchopneumonic opacities (56.1% versus 42.3%, p = 0.207) and cavities (38.1% versus 46.2%, p = 0.514), across drug susceptibility status (DS versus RR TB). Among HIV-infected participants, consolidations were predominantly in the middle lung zone in the DS TB group and in the lower lung zone in the RR TB group (42.5% versus 12.8%, p = 0.66). HIV-infected participants with RR TB had statistically significantly larger cavity sizes compared to their HIV uninfected counterparts with RR TB (7.7 ± 6.8 cm versus 4.2 ± 1.3 cm, p = 0.004).ConclusionsWe observed that a vast majority of participants had similar CXR changes, irrespective of drug susceptibility status. However, HIV-infected RR PTB had larger cavities.The diagnostic utility of cavity sizes for the differentiation of HIV-infected and non-infected RR TB could be investigated further.

Project description:Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI) currently under review by the US Food and Drug Administration for marketing approval. The in vitro, protein-adjusted 90 % inhibitory concentration (IC90) of dolutegravir for wild-type virus is 0.064 ?g/ml, and it retains in vitro anti-HIV 1 activity across a broad range of viral phenotypes that are known to confer resistance to the currently marketed INSTIs, raltegravir and elvitegravir. Dolutegravir has a terminal elimination half-life of 13-14 h and maintains concentrations over the in vitro, protein-adjusted IC90 for more than 30 h following a single dose. Additionally, dolutegravir has low inter-subject variability compared with raltegravir and elvitegravir. A plasma exposure-response relationship has been well described, with antiviral activity strongly correlating with trough concentrations. Phase III trials have assessed the antiviral activity of dolutegravir compared with efavirenz and raltegravir in antiretroviral (ARV)-naive patients and found that dolutegravir achieved more rapid and sustained virologic suppression in both instances. Additionally, studies of dolutegravir activity in patients with known INSTI-resistant mutations have been favourable, indicating that dolutegravir retains activity in a variety of INSTI-resistant phenotypes. Much like currently marketed INSTIs, dolutegravir is very well tolerated. Because dolutegravir inhibits the renal transporter organic cation transporter 2, reduced tubular secretion of creatinine leads to non-progressive increases in serum creatinine. These serum creatinine increases have not been associated with a decreased glomerular filtration rate or progressive renal impairment. Dolutegravir's major and minor metabolic pathways are uridine diphosphate glucuronosyltransferase 1A1 and cytochrome P450 (CYP)-3A4, respectively, and it neither induces nor inhibits CYP isoenzymes. Thus dolutegravir has a modest drug interaction profile. However, antacids significantly decrease dolutegravir plasma exposure and should be separated by 2 h before, or 6 h after, a dolutegravir dose. In summary, dolutegravir is the first of the second-generation INSTIs and exhibits a predictable pharmacokinetic profile and a well-defined exposure-response relationship. Dolutegravir retains activity despite the presence of some class-resistant mutations and achieves rapid and sustained virologic suppression in ARV-naive and ARV-experienced patients. Clinically, dolutegravir is poised to become a commonly used component of antiretroviral regimens.

Dataset Information

Longitudinal Pharmacokinetic-Pharmacodynamic Biomarkers Correlate With Treatment Outcome in Drug-Sensitive Pulmonary Tuberculosis: A Population Pharmacokinetic-Pharmacodynamic Analysis.

Publications

Longitudinal Pharmacokinetic-Pharmacodynamic Biomarkers Correlate With Treatment Outcome in Drug-Sensitive Pulmonary Tuberculosis: A Population Pharmacokinetic-Pharmacodynamic Analysis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets