Predictors of Prolonged TB Treatment in a Dutch Outpatient Setting

Introduction Standard treatment duration for drug-susceptible tuberculosis (TB) treatment is 6 months. Treatment duration is often extended-and for various different reasons. The aim of this study was to determine the prevalence and to assess risk factors associated with extended TB treatment. Methods A cross-sectional study was conducted. Data including demographic, clinical, radiological and microbiological information from the Netherlands TB Register (NTR) of 90 patients with smear and culture positive pulmonary TB of the region Haaglanden, The Netherlands, was eligible for analysis. Results Treatment was extended to >= 200 days by 46 (51%) patients. Extended TB treatment was associated with a higher frequency of symptoms, presumed to be due to adverse drug reactions (ADR; OR 2.39 95% CI: 1.01-5.69), drug-induced liver injury (DILI) (OR: 13.51; 95% CI: 1.66-109.82) and longer than 2 month smear and culture conversion rate (OR: 11.00; 95% CI: 1.24-97.96 and OR: 8.56; 95% CI: 1.53-47.96). In the multivariable logistic analysis, development of DILI emerged as the single statistically strong risk factor necessitating extension of TB treatment. Conclusion This finding will need further confirmation in a prospective study, exploring the possible mutual role of pharmacokinetic and pharmacogenetic determinants of DILI among TB patients

Pharmacokinetics of Levofloxacin in Multidrug-and Extensively Drug-Resistant Tuberculosis Patients

Pharmacodynamics are important in treatment of especially multidrug- and extensively resistant tuberculosis (M/XDR-TB). The free area under the concentration time curve in relation to minimal inhibitory concentration (fAUC/MIC) is the most relevant pharmacokinetic (PK)-pharmacodynamic (PD) parameter to predict the efficacy of levofloxacin (LFX). The objective of our study was to assess LFX PK variability in M/XDR-TB patients and its potential consequence for fAUC/MIC ratios. Patients with pulmonary M/XDR-TB received LFX as part of treatment regimen at a dose of 15 mg/kg once daily. Blood samples obtained at steady state before- and 1, 2, 3, 4, 7, and 12 hrs after drug administration were measured by validated a liquid chromatography-tandem mass spectrometry. MIC values of LFX were determined by the agar dilution method on Middlebrook 7H10 and the MGIT960 system. Twenty patients with a mean age of 31 (IQR; 27-35) years were enrolled in this study. The median AUC0-24h was 98.8 mg/h/L (IQR; 84.8-159.6). The MIC median value for LFX was 0,5 mg/L with a range of 0.25 to 2.0 mg/L and the median fAUC0-24/MIC ratio was 109.5 (IQR; 48.5-399.4). In four of the 20 patients the value was below the target value of ≥100. When a MIC of 0.25, 0.5, 1.0 and 2.0 mg/L were applicable, 19, 18, 3 and no patients, respectively, had a fAUC/MIC ratio that exceeded 100. We observed a large variability in AUC. A fAUC0-24/MIC of ≥ 100 was only observed in case MIC values for LFX were 0.25-0.5 mg/L. Dosages exceeding 15mg/kg should be considered for target attainment if exposures are assumed to be safe

Population Pharmacokinetic Model and Limited Sampling Strategies for Personalized Dosing of Levofloxacin in Tuberculosis Patients

Levofloxacin is an antituberculosis drug with substantial interindividual pharmacokinetic variability; therapeutic drug monitoring (TDM) could therefore be helpful to improve treatment results. TDM would be more feasible with limited sampling strategies (LSSs), a method to estimate the area under the concentration curve for the 24-h dosing interval (AUC(0-24)) by using a limited number of samples. This study aimed to develop a population pharmacokinetic (popPK) model of levofloxacin in tuberculosis patients, along with LSSs using a Bayesian and multiple linear regression approach. The popPK model and Bayesian LSS were developed using data from 30 patients and externally validated with 20 patients. The LSS based on multiple linear regression was internally validated using jackknife analysis. Only clinically suitable LSSs (maximum time span, 8 h; minimum interval, 1 h; 1 to 3 samples) were tested. Performance criteria were root-mean-square error (RMSE) of 0.95. A one-compartment model with lag time best described the data while only slightly underestimating the AUC(0-24) (mean, -7.9%; standard error [SE], 1.7%). The Bayesian LSS using 0- and 5-h postdose samples (RMSE, 8.8%; MPE, 0.42%; r(2=)0.957) adequately estimated the AUC(0-24), with a mean underestimation of -4.4% (SE, 2.7%). The multiple linear regression LSS using 0- and 4-h postdose samples (RMSE, 7.0%; MPE, 5.5%; r(2)=0.977) was internally validated, with a mean underestimation of -0.46% (SE, 2.0%). In this study, we successfully developed a popPK model and two LSSs that could be implemented in clinical practice to assist TDM of levofloxacin