scholarly journals Linezolid Pharmacokinetics in South African Patients with Drug-Resistant Tuberculosis and a High Prevalence of HIV Coinfection

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Sean Wasserman ◽  
Paolo Denti ◽  
James C. M. Brust ◽  
Mahmoud Abdelwahab ◽  
Siphokazi Hlungulu ◽  
...  
Keyword(s):  
South African ◽  
Critical Concentration ◽  
Therapeutic Index ◽  
World Health ◽  
Drug Resistant ◽  
Target Attainment ◽  
Time Curve ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
African Patients

ABSTRACT The World Health Organization (WHO) recently recommended that linezolid be prioritized in treatment regimens for drug-resistant tuberculosis (TB), but there are limited data on its pharmacokinetics (PK) in patients with this disease. We conducted an observational study to explore covariate effects on linezolid PK and to estimate the probability of PK/pharmacodynamic target attainment in South African patients with drug-resistant TB. Consecutive adults on linezolid-based regimens were recruited in Cape Town and underwent intensive PK sampling at steady state. Noncompartmental analysis was performed. Thirty participants were included: 15 HIV positive, 26 on the initial dose of 600 mg daily, and 4 participants on 300 mg daily after dose reduction for linezolid-related toxicity. There was a negative correlation between body weight and exposure, with 17.4% (95% confidence interval [CI], 0.1 to 31.7) decrease in area under the concentration-time curve from 0 to 24 h (AUC0–24) per 10-kg weight increment after adjustment for other covariates. Age was an independent predictor of trough concentration, with an estimated 43.4% (95% CI, 5.9 to 94.2) increase per 10-year increment in age. The standard 600-mg dose achieved the efficacy target of free AUC/MIC of >119 at wild-type MIC values (≤0.5 mg/liter), but the probability of target attainment dropped to 61.5% (95% CI, 40.6 to 79.8) at the critical concentration of 1 mg/liter. When dosed at 600 mg daily, trough concentrations were above the toxicity threshold of 2 mg/liter in 57.7% (95% CI, 36.9 to 76.6). This confirms the narrow therapeutic index of linezolid, and alternative dosing strategies should be explored.

scholarly journals Linezolid population pharmacokinetics in South African adults with drug-resistant tuberculosis.

2021 ◽  
Author(s):  
Mahmoud Tareq Abdelwahab ◽  
Sean Wasserman ◽  
James C.M. Brust ◽  
Keertan Dheda ◽  
Lubbe Wiesner ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
South African ◽  
Drug Exposure ◽  
Controlled Trial ◽  
Therapeutic Index ◽  
Drug Resistant ◽  
Concentration Data ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Daily Dose

BACKGROUND Linezolid is widely used for drug-resistant tuberculosis (DR-TB) but has a narrow therapeutic index. To inform dose optimisation, we aimed to characterise the population pharmacokinetics of linezolid in South African participants with DR-TB and explore the effect of covariates, including HIV-co-infection, on drug exposure. METHODS Data were obtained from pharmacokinetic sub-studies in a randomised controlled trial and an observational cohort study, both of which enrolled adults with drug-resistant pulmonary tuberculosis. Participants underwent intensive and sparse plasma sampling. We analyzed linezolid concentration data using non-linear mixed-effects modelling and performed simulations to estimate attainment of putative efficacy and toxicity targets. RESULTS 124 participants provided 444 plasma samples; 116 were on the standard daily dose of 600 mg, while 19 had dose reduction to 300 mg due to adverse events. Sixty-one participants were female, 71 were HIV-positive, and median weight was 56 kg (IQR 50 - 63). In the final model, typical values for clearance and central volume were 3.57 L/h and 40.2 L, respectively. HIV co-infection had no significant effect on linezolid exposure. Simulations showed that 600 mg dosing achieved the efficacy target ( f AUC 0-24h /MIC > 119 at MIC level of 0.5 mg/L) with 96% probability but had 56% probability of exceeding safety target ( trough 24h > 2 mg/L ). The 300 mg dose did not achieve adequate efficacy exposures. CONCLUSION Our model characterised population pharmacokinetics of linezolid in South African patients with DR-TB and supports the 600 mg daily dose with safety monitoring.

scholarly journals Outcomes of Multi-Drug Resistant Tuberculosis (MDR-TB) among a Cohort of South African Patients with High HIV Prevalence

PLoS ONE ◽  
2011 ◽  
Vol 6 (7) ◽  
pp. e20436 ◽  
Author(s):  
Jason E. Farley ◽  
Malathi Ram ◽  
William Pan ◽  
Stacie Waldman ◽  
Gail H. Cassell ◽  
...  
Keyword(s):  
South African ◽  
Hiv Prevalence ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Multi Drug Resistant Tuberculosis ◽  
Mdr Tb ◽  
African Patients

Exploring patient-provider factors for risk of developing Multi-drug Resistance Tuberculosis in Southern Ethiopia: Qualitative Operation Research (Preprint)

2019 ◽  
Author(s):  
Yitagesu Habtu ◽  
Tesema Bereku ◽  
Girma Alemu ◽  
Ermias Abera
Keyword(s):  
Phenomenological Study ◽  
Treatment Success ◽  
World Health ◽  
Multi Drug Resistance ◽  
Southern Ethiopia ◽  
Drug Resistant ◽  
Related Factors ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Multi Drug Resistant Tuberculosis

BACKGROUND Ethiopia is one of among thirty high burden countries of multi-drug resistant tuberculosis (MDR-TB) in the regions of world health organization. Contextual evidence on the emergence of the disease is limited at a program level. OBJECTIVE The aim of the study is to explore patient-provider factors that may facilitate the emergence of multi-drug resistant tuberculosis. METHODS We used a phenomenological study design of qualitative approach from June to July, 2015. We conducted ten in-depth interviews and 4 focus group discussions with purposely selected patients and providers. We designed and used an interview guide to collect data. Verbatim transcribes were exported to open code 3.4 for emerging thematic analysis. Domain summaries were used to support core interpretation. RESULTS The study explored patient-provider factors facilitating the emergence of multi-drug resistant tuberculosis. These factors as underlying, health system and patient-related factors. Especially, the a shows conflicting finding between having a history of discontinuing drug-susceptible tuberculosis and emergence of multi-drug resistant tuberculosis. CONCLUSIONS The patient-provider factors may result in poor early case identification, adherence to and treatment success in drug sensitive or multi-drug resistant tuberculosis. Our study implies the need for awareness creation about multi-drug resistant tuberculosis for patients and further familiarization for providers. This study also shows that patients developed multi-drug resistant tuberculosis though they had never discontinued their drug-susceptible tuberculosis treatment. Therefore, further studies may require for this discording finding.

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