High Frequency of Resistance, Lack of Clinical Benefit, and Poor Outcomes in Capreomycin Treated South African Patients with Extensively Drug-Resistant Tuberculosis

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.

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Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study

The Lancet Respiratory Medicine ◽

10.1016/s2213-2600(18)30235-2 ◽

2018 ◽

Vol 6 (9) ◽

pp. 699-706 ◽

Cited By ~ 82

Author(s):

Kathryn Schnippel ◽

Norbert Ndjeka ◽

Gary Maartens ◽

Graeme Meintjes ◽

Iqbal Master ◽

...

Keyword(s):

Cohort Study ◽

South African ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Resistant Tuberculosis ◽

African Patients

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Treatment outcomes of patients with multidrug and extensively drug-resistant tuberculosis in Zhejiang, China

European Journal of Medical Research ◽

10.1186/s40001-021-00502-0 ◽

2021 ◽

Vol 26 (1) ◽

Author(s):

Ming-Wu Zhang ◽

Lin Zhou ◽

Yu Zhang ◽

Bin Chen ◽

Ying Peng ◽

...

Keyword(s):

Treatment Outcomes ◽

Treatment Success ◽

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Resistant Tuberculosis ◽

Extensively Drug Resistant ◽

Cavitary Disease ◽

Referral Hospitals ◽

Baseline Weight ◽

Poor Outcomes

Abstract Background The aim of this study was to assess the treatment outcomes of multidrug and extensively drug-resistant tuberculosis (M/XDR-TB) in Zhejiang, China and to evaluate possible risk factors associated with poor outcomes of M/XDR-TB. Methods Two-hundred-and-sixty-two patients having M/XDR-TB who received the diagnosis and treatment at nine referral hospitals from 1 January 2016 to 31 December 2016 in Zhejiang, China were included. All patients received second-line regimens recommended by WHO under the DOTS-Plus strategy. Results Among the 262 patients, the treatment success rate was 55.34% (n = 145) with 53.44% (n = 140) cured and 1.91% (n = 5) who completed treatment, 62 (23.66%) failed, 27 (10.31%) died, 16 (6.11%) defaulted and 12 (4.58%) transferred out. Forty (64.52%) of the 62 M/XDR-TB patients who failed treatment were due to adverse effects in the first 10 months of treatment. Eighteen patients (6.37%) had XDR-TB. Treatment failure was significantly higher among patients with XDR-TB at 50% than that among patients with non-XDR-TB at 21.72% (P = 0.006). Failure outcomes were associated with a baseline weight less than 50 kg (OR, 8.668; 95% CI 1.679–44.756; P = 0.010), age older than 60 years (OR, 9.053; 95% CI 1.606–51.027; P = 0.013), hemoptysis (OR, 8.928; 95% CI 1.048–76.923; P = 0.045), presence of cavitary diseases (OR, 10.204; 95% CI 2.032–52.631; P = 0.005), or treatment irregularity (OR, 47.619; 95% CI 5.025–500; P = 0.001). Conclusion Treatment outcomes for M/XDR-TB under the DOTS-Plus strategy in Zhejiang, China were favorable but still not ideal. Low body weight (< 50 kg), old age (> 60 years), severe symptoms of TB including cavitary disease, hemoptysis and irregular treatment were independent prognostic factors for failure outcomes in patients with M/XDR-TB.

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Long-term bedaquiline-related treatment outcomes in patients with extensively drug-resistant tuberculosis from South Africa

European Respiratory Journal ◽

10.1183/13993003.00544-2018 ◽

2018 ◽

Vol 51 (5) ◽

pp. 1800544 ◽

Cited By ~ 30

Author(s):

Olatunde Olayanju ◽

Jason Limberis ◽

Aliasgar Esmail ◽

Suzette Oelofse ◽

Phindile Gina ◽

...

Keyword(s):

Outcome Data ◽

Favourable Outcome ◽

Cd4 Count ◽

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Treatment Regimens ◽

Resistant Tuberculosis ◽

Extensively Drug Resistant ◽

African Patients

Optimal treatment regimens for patients with extensively drug-resistant tuberculosis (XDR-TB) remain unclear. Long-term prospective outcome data comparing XDR-TB regimens with and without bedaquiline from an endemic setting are lacking.We prospectively followed-up 272 South African patients (49.3% HIV-infected; median CD4 count 169 cells·µL−1) with newly diagnosed XDR-TB between 2008 and 2017. Outcomes were compared between those who had not received bedaquiline (pre-2013; n=204) and those who had (post-2013; n=68; 80.9% received linezolid in addition).The 24-month favourable outcome rate was substantially better in the bedaquiline versus the non-bedaquiline group (66.2% (45 out of 68) versus 13.2% (27 out of 204); p<0.001). In addition, the bedaquiline group exhibited reduced 24-month rates of treatment failure (5.9% versus 26.0%; p<0.001) and default (1.5% versus 15.2%; p<0.001). However, linezolid was withdrawn in 32.7% (18 out of 55) of patients in the bedaquiline group because of adverse events. Admission weight >50 kg, an increasing number of anti-TB drugs and bedaquiline were independent predictors of survival (the bedaquiline survival effect remained significant in HIV-infected persons, irrespective of CD4 count).XDR-TB patients receiving a backbone of bedaquiline and linezolid had substantially better favourable outcomes compared to those not using these drugs. These data inform the selection of XDR-TB treatment regimens and roll-out of newer drugs in TB-endemic countries.

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