Low drug AUCs are predictive of clinical outcomes in tuberculosis patients.

Evaluation of sources of pharmacokinetic variation can facilitate optimization of tuberculosis treatment regimens by identification of avoidable sources of variation and of risk factors for low or high drug concentrations in patients. Our objective was to describe the pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in a cohort of tuberculosis patients established on first-line treatment regimens and to evaluate the determinants of pharmacokinetic variation. Plasma concentration-time profiles were determined for each of the drugs in 142 patients with drug-sensitive pulmonary tuberculosis after 2 months of daily treatment in hospital. Pharmacokinetic measures were described by noncompartmental analysis. Multiple linear regression was used to evaluate the patient and the treatment factors associated with variation of the area under the concentration-time curve from 0 to 8 h. Several factors independently associated with variations in antituberculosis drug concentrations were identified: human immunodeficiency virus infection was associated with 39% and 27% reductions for rifampin and ethambutol, respectively; formulation factors were determinants of rifampin and isoniazid bioavailability; female patients had increased rifampin and isoniazid concentrations but reduced ethambutol concentrations; older patients had higher levels of isoniazid and ethambutol; patients with a history of previous antituberculosis treatment had lower ethambutol concentrations; and the dose per kilogram of body weight was associated with the concentrations of all four agents. Further studies are required to assess the implications of variations in antituberculosis drug concentrations for efficacy and safety before decisions are made to change the dosing strategy in patients at risk.

dIn tuberculosis treatment, susceptibility is defined by a critical concentration of 1.0 mg/liter for rifampin and 0.2 or 1.0 mg/liter for low-and high-level isoniazid resistance on the basis of an epidemiologic cutoff method that uses the distribution of the MICs for isolates. However, pharmacokinetics-pharmacodynamics-based clinical trial simulations suggested that the breakpoints should be 0.0625 mg/liter for rifampin and 0.0312 or 0.125 mg/liter for isoniazid. We examined the outcomes of 36 patients with drug-susceptible tuberculosis whose rifampin and isoniazid MICs were determined, whose plasma drug concentrations were also measured, and who were part of a prospective cohort study in Western Cape, South Africa. We performed classification and regression tree analysis to identify clinical and laboratory factors that predicted 2-month sputum conversion rates and longterm clinical outcomes. Poor long-term clinical outcomes were defined as microbiological failure, relapse, or death within a 2-year follow-up period. Peak drug concentrations and areas under the concentration-time curve were most predictive of outcomes and constituted the primary node, similar to our findings on the larger cohort. However, rifampin and isoniazid MICs improved the predictive capacity of the primary decision node by 20 and 17%, respectively, for these 36 patients. The rifampin MIC cutoff above which there was therapy failure was 0.125 mg/liter, while that of isoniazid was 0.0312 mg/liter; these are similar to those derived in clinical trial simulations. The critical concentrations used to define multidrug resistance for clinical decision making should take clinical outcomes into account.

Safety concerns persist for long-term pediatric fluoroquinolone use. Seventy children (median age, 2.1 years) treated with levofloxacin 10-20 mg/kg once daily for multidrug-resistant tuberculosis (median observation time, 11.8 months) had few musculoskeletal events, no levofloxacin-attributed serious adverse events, and no Fridericia-corrected QT interval >450 ms. Long-term levofloxacin was safe and well tolerated.

DECLARATIONBy submitting this thesis electronically, I declare that the entirety of the work contained therein is my own, original work, that I am the sole author thereof (save to the extent explicitly otherwise stated), that reproduction and publication thereof by Stellenbosch University will not infringe any third party rights and that I have not previously in its entirety or in part submitted it for obtaining any qualification. the most prevalent form of drug-resistant TB globally, and may be a risk factor for poor outcomes. HRRS-TB in children has been poorly described.Objective: To characterize the clinical presentation, treatment, and clinical and microbiological outcomes, and factors associated with poor outcomes among children with culture-confirmed HRRS-TB. Design:Retrospective hospital-based cohort study. Results:Of the 72 children included, median age 50.1 months (IQR 21.5-102.5), 42% were male. Forty-four (51%) had a potential source case; only 13 were confirmed HRRS-TB. Twelve of 66 tested (17%) were HIV-infected, and 36 of 60 (60%) with pulmonary TB had severe disease. Seventy had treatment data; median total duration was 11.3 months (IQR 9-12.3); 25 (36%) initiated treatment with a 3-drug intensive phase; 52 (74%) received a fluoroquinolone. Of 63 with known outcome, 55 (88%) had a favourable outcome; 1 died and 3 had treatment failure. Ten had positive follow-up cultures at ≥2 months after starting treatment (17% of all PTB and 27% of those with follow-up culture data); older age (p=0.008), previous TB treatment (p=0.023) and severe PTB (p=0.018) were associated with failure to cultureconvert at ≥2 months. Conclusions:Although overall outcomes were good, prolonged culture positivity and cases of treatment failure emphasize the need for additional attention to clinical management of children with HRRS-TB.Stellenbosch University https://scholar.sun.ac.za ACKNOWLEDGEMENTS