A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis.

BACKGROUND: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. METHODS: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. DISCUSSION: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. TRIAL REGISTRATION: DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

Clinical standards for the management of adverse effects during treatment for TB.

BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

First international quality control programme for laboratories measuring antimicrobial drugs to support dose individualization in critically ill patients.

OBJECTIVES: International quality control (proficiency testing) programmes are instituted to safeguard the analytical performance of laboratories and to aid these laboratories in identifying sources of error in their analytical methods. We describe the first international quality control programme for antimicrobial agents that are frequently used in critically ill patients. METHODS: Spiked plasma samples with ceftazidime, ciprofloxacin, flucloxacillin, piperacillin, sulfamethoxazole, N-acetyl sulfamethoxazole and trimethoprim were shipped to 22 laboratories from eight different countries. Acceptable accuracy by the performing laboratory was defined if measurements were within 80%-120% limits of the true weighed-in concentrations. RESULTS: A total of 81% of the measurements (ranging between 56% and 100%, dependent on drug) were within the 80%-120% limits of the true weighed-in concentrations. CONCLUSIONS: We found a relatively good performance of the participating laboratories in measuring eight different antimicrobial drugs. Nevertheless, some of the antimicrobial drugs were not measured properly as up to 44% of the measurements was inaccurate depending on the drug. Our results emphasize the need for and utility of an ongoing quality control programme.

Management of patients with multidrug-resistant tuberculosis.

The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDR-TB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDR-TB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDR-TB patients achieving a relapse-free cure.

Pharmacokinetics of pyrazinamide during the initial phase of tuberculous meningitis treatment.

Tuberculous meningitis (TBM) is the most severe manifestation of tuberculosis. Pyrazinamide (PZA) is a pivotal antituberculous drug, but its dose has not been optimised for TBM. The aims of this study were to describe the pharmacokinetics of PZA during TBM treatment, to identify predictors of PZA exposure and to assess relationships between PZA dose and exposures in plasma and CSF. Plasma PZA pharmacokinetic data were assessed on Days 2 and 10 of treatment in 52 adult TBM patients. A CSF-to-plasma concentration ratio was determined on Day 2. Predictors of plasma PZA exposure, correlation between plasma and CSF exposures, and prediction of CSF concentrations based on dose and plasma exposure were evaluated. The geometric mean plasma PZA exposure (AUC0-24) and peak concentration (Cmax) on Day 2 were 709 h·mg/L and 59 mg/L following a median dose of 33.3 mg/kg/day; AUC0-24 on Day 10 (523 h·mg/L) was lower (P < 0.001). Dose and BMI correlated with AUC0-24 and Cmax. The CSF concentration at 3-6 h was 42 mg/L and the CSF-to-plasma ratio was 90%. AUC0-24, Cmax and CSF concentration were highly correlated. CSF concentration could be predicted based on dose and various plasma exposure measures with <5% bias and <21% imprecision. Exposure to PZA decreases during the first days of TBM treatment, possibly due to the evolving inductive effect of rifampicin. PZA penetrates well in CSF. The association between PZA dose and exposures in plasma and CSF provides a rationale to study higher PZA doses for TBM.

Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis.

High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0-24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.).

Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis.

Objectives: The objectives of this study were to explore inter-study heterogeneity in the pharmacokinetics (PK) of orally administered rifampicin, to derive summary estimates of rifampicin PK parameters at standard dosages and to compare these with summary estimates for higher dosages. Methods: A systematic search was performed for studies of rifampicin PK published in the English language up to May 2017. Data describing the Cmax and AUC were extracted. Meta-analysis provided summary estimates for PK parameter estimates at standard rifampicin dosages. Heterogeneity was assessed by estimation of the I2 statistic and visual inspection of forest plots. Summary AUC estimates at standard and higher dosages were compared graphically and contextualized using preclinical pharmacodynamic (PD) data. Results: Substantial heterogeneity in PK parameters was evident and upheld in meta-regression. Treatment duration had a significant impact on the summary estimates for rifampicin PK parameters, with Cmax 8.98 mg/L (SEM 2.19) after a single dose and 5.79 mg/L (SEM 2.14) at steady-state dosing, and AUC 72.56 mg·h/L (SEM 2.60) and 38.73 mg·h/L (SEM 4.33) after single and steady-state dosing, respectively. Rifampicin dosages of at least 25 mg/kg are required to achieve plasma PK/PD targets defined in preclinical studies. Conclusions: Vast inter-study heterogeneity exists in rifampicin PK parameter estimates. This is not explained by the available modifying variables. The recommended dosage of rifampicin should be increased to improve efficacy. This study provides an important point of reference for understanding rifampicin PK at standard dosages as efforts to explore higher dosing strategies continue in this field.

Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis.

In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).

Study protocol on the role of intestinal microbiota in colorectal cancer treatment: a pathway to personalized medicine 2.0.

PURPOSE: Investigate in patients with metastatic and/or irresectable colorectal cancer treated with systemic treatment with capecitabine or TAS-102 whether: 1. Intestinal microbiota composition can act as a predictor for response. 2. Intestinal microbiota composition changes during systemic treatment and its relation to chemotoxicity. BACKGROUND: Gut microbiota and host determinants evolve in symbiotic and dependent relationships resulting in a personal ecosystem. In vitro studies showed prolonged and increased response to 5-fluorouracil, a fluoropyrimidine, in the presence of a favorable microbiota composition. Capecitabine and TAS-102 are both fluoropyrimidines used for systemic treatment in colorectal cancer patients. METHODS: An explorative prospective multicenter cohort study in the Maastricht University Medical Centre+ and Zuyderland Medical Centre will be performed in 66 patients. Before, during, and after three cycles of systemic treatment with capecitabine or TAS-102, fecal samples and questionnaires (concerning compliance and chemotoxicity) will be collected. The response will be measured by CT/MRI using RECIST-criteria. Fecal microbiota composition will be analyzed with 16S rRNA next-generation sequencing. The absolute bacterial abundance will be assessed with quantitative polymerase chain reaction. Multivariate analysis will be used for statistical analysis. CONCLUSIONS: We aim to detect a microbiota composition that predicts if patients with metastatic and/or irresectable colorectal cancer will respond to systemic treatment and/or experience zero to limited chemotoxicity. If we are able to identify a favorable microbiota composition, fecal microbiota transplantation might be the low-burden alternative to chemotherapy switch in the future.

Pediatric tuberculous meningitis: Model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children.

Pediatric tuberculous meningitis (TBM) is a highly morbid, often fatal disease. Standard treatment includes isoniazid, rifampin, pyrazinamide, and ethambutol. Current rifampin dosing achieves low cerebrospinal fluid (CSF) concentrations, and CSF penetration of ethambutol is poor. In adult trials, higher-dose rifampin and/or a fluoroquinolone reduced mortality and disability. To estimate optimal dosing of rifampin and levofloxacin for children, we compiled plasma and CSF pharmacokinetic (PK) and outcomes data from adult TBM trials plus plasma PK data from children. A population PK/pharmacodynamic (PD) model using adult data defined rifampin target exposures (plasma area under the curve (AUC)0-24 = 92 mg*h/L). Levofloxacin targets and rifampin pediatric drug disposition information were literature-derived. To attain target rifampin exposures, children require daily doses of at least 30 mg/kg orally or 15 mg/kg intravenously (i.v.). From our pediatric population PK model, oral levofloxacin doses needed to attain exposure targets were 19-33 mg/kg. Our results provide data-driven guidance to maximize pediatric TBM treatment while we await definitive trial results.

Limited sampling strategy for prolonged-release tacrolimus in renal transplant patients by use of the dried blood spot technique.

PURPOSE: The aim of this study was to develop a clinically applicable limited sampling strategy for ambulatory Caucasian kidney transplant patients to estimate area under the curve in a 24-h period (AUC0-24) of prolonged-release tacrolimus. METHODS: Twenty six kidney recipients, at least 6 months after transplantation, receiving prolonged-release tacrolimus, were enrolled. In each patient, seven blood samples were collected during a period of 24 h by use of the validated dried blood spot method. Best subset selection multiple linear regression was performed to derive limited sampling strategy (LSS). The equations were constrained to include a maximum of three samples collected within 4 h after the intake to maintain clinical applicability. To assess the predictive performance of LSS, residuals for each patient were calculated based on models fitted to a dataset where that patient was omitted. RESULTS: The prediction formula for the AUC(0-24) using the time points 0, 2, and 4 h after ingestion (C(0h)-C(2h)-C(4h)) provided the highest correlation with the AUC(0-24) (r(2) = 0.95): AUC0-24 = 44.9 + 8.9 × C(0h) + 2.1 × C(2h) + 7.6 × C(4h). Measures for bias and precision, i.e., median percentage prediction error (MPPE) and median absolute prediction error (MAPE), were 0.4 and 4.8%, respectively. For the same patients, the correlation between C(24h) and AUC0-24 was worse (r(2) = 0.77) while MPPE and MAPE were 6.2 and 7.2%, respectively. CONCLUSION: In the outpatient department, a LSS using C(0h)-C(2h)-C(4h) can be used for reliable estimation of the AUC(0-24) of prolonged-release tacrolimus.

Exposure to total and protein-unbound rifampin is not affected by malnutrition in Indonesian tuberculosis patients.

Nutritional status may have a profound impact on the pharmacokinetics of drugs, yet only few data are available for tuberculosis (TB) drugs. As malnutrition occurs frequently among TB patients, we assessed the effect of malnutrition on the steady-state pharmacokinetics of total and protein-unbound rifampin during the intensive phase of TB treatment. In a descriptive pharmacokinetic study in Bandung, Indonesia, patients received a fixed standard rifampin dose of 450 mg once daily during the intensive phase of TB treatment. A full pharmacokinetic curve for rifampin was recorded, and total and unbound concentrations of rifampin were analyzed in all samples. Rifampin pharmacokinetic parameters were compared between severely malnourished (BMI of <16.0 kg/m(2)), malnourished (BMI of <18.5 kg/m(2)), and well-nourished (BMI of ≥18.5 kg/m(2)) individuals. No difference in total and protein-unbound pharmacokinetic parameters between severely malnourished (n = 7), malnourished (n = 11), and well-nourished (n = 25) patients could be demonstrated. In addition, no significant correlation between BMI and exposure (area under the concentration-time curve from 0 to 24 h [AUC0-24] and maximum concentration of drug in serum [Cmax]) was found. Females had significantly higher total AUC0-24 (geometric mean, 59.2 versus 48.2 h · mg/liter; P = 0.02) and higher unbound AUC0-24 (geometric mean, 6.2 versus 4.8 h · mg/liter; P = 0.02) than males. Overall, a marked 2-fold interindividual variation in the free fraction was observed (7.6 to 15.0%; n = 36). Nutritional status and BMI do not appear to have a major effect on total and protein-unbound pharmacokinetic parameters of rifampin in Indonesian subjects. The large interindividual variability in the free fraction of rifampin suggests that protein-unbound rather than total rifampin concentrations should preferably be used to study exposure-response relationships.

Population pharmacokinetics and limited sampling strategy for first-line tuberculosis drugs and moxifloxacin.

Therapeutic drug monitoring (TDM) of tuberculosis (TB) drugs currently focuses on peak plasma concentrations, yet total exposure [area under the 24-h concentration-time curve (AUC0₋24)] is probably most relevant to the efficacy of these drugs. We therefore assessed population AUC0₋24 data for all four first-line TB drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) as well as moxifloxacin and developed limited sampling strategies to estimate AUC0₋24 values conveniently. AUC0₋24 and other pharmacokinetic (PK) parameters were determined following intensive PK sampling in two Dutch TB referral centres. Best subset selection multiple linear regression was performed to derive limited sampling equations. Median percentage prediction error and median absolute percentage prediction error were calculated via jackknife analysis to evaluate bias and imprecision of the predictions. Geometric mean AUC0₋24 values for rifampicin, isoniazid, pyrazinamide, ethambutol and moxifloxacin were 41.1, 15.2, 380, 25.5 and 33.6 hmg/L, respectively. Limited sampling at various fixed sampling points enabled an accurate and precise prediction of AUC0₋24 values of all drugs separately and simultaneously. In the absence of clinically validated target values for AUC0₋24, average AUC0₋24 values can be used as reference values in TDM. Limited sampling of AUC0₋24 is feasible in many settings and allows for TDM to be performed at a larger scale.

Five year results of an international proficiency testing programme for measurement of antifungal drug concentrations.

OBJECTIVES: Since 2007 the Dutch Association for Quality Assessment in Therapeutic Drug Monitoring (KKGT) has organized an international interlaboratory proficiency testing (PT) programme for measurement of antifungal drugs in plasma. We describe the 5 year results of the laboratories' performance. METHODS: Twice a year, laboratories received a set of blind plasma samples containing low or high concentrations of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole and flucytosine. Participating laboratories were asked to report their results within 6 weeks after dispatch and provide details of their analytical methods. Results deviating >20% from the weighed-in concentration were considered inaccurate. Four-way ANOVA was performed to assess the effect of antifungal drug measured, concentration, analytical method and performing laboratory on the absolute inaccuracy. In 2012, a questionnaire based on the CLSI guidelines was dispatched with the request to provide input on sources of error. RESULTS: Fifty-seven laboratories (13 countries) reported 2251 results (287 fluconazole, 451 itraconazole, 348 hydroxyitraconazole, 402 posaconazole, 652 voriconazole and 111 flucytosine) in 5 years. Analyses were performed using HPLC (55.0%), LC-MS(/MS) (43.4%), UPLC (1.4%) or GC-MS (0.2%). Overall, 432 (19.2%) analyses were inaccurate. The performing laboratory was the only factor clearly associated with inaccuracies. The questionnaire results indicated that laboratories encounter significant problems analysing low concentrations (15.4% of all inaccuracies). CONCLUSIONS: Results of the PT programme suggest that one out of five measurements is inaccurate. The performing laboratory is the main determinant of inaccuracy, suggesting that internal quality assurance is pivotal in preventing inaccuracies, irrespective of the antifungal drug measured, concentration and analytical equipment.

Pharmacokinetic studies in patients with nontuberculous mycobacterial lung infections.

Concentrations of antimycobacterial drugs are an intermediary link between doses administered and eventual response to the drugs. Few pharmacokinetic (PK) studies have focused on drug treatment for nontuberculous mycobacterial (NTM) disease, although a favourable treatment response occurs in just over 50% of patients despite drug treatment for ≥1 year. A prospective, descriptive PK study was performed to assess the plasma pharmacokinetics of rifampicin, ethambutol, clarithromycin, 14-OH-clarithromycin, azithromycin, isoniazid and moxifloxacin. Intensive PK sampling was performed in 14 patients with clinically relevant NTM lung disease. PK parameters were assessed and were compared with available data from the literature. Exposure to clarithromycin when combined with rifampicin was very low [area under the concentration-time curve over 12 h (AUC(0-12 h), geometric mean 2.6 h·mg/L, range 1.6-3.2 h·mg/L; peak concentration in plasma (C(max)), geometric mean 0.3 mg/L, range 0.1-0.7 mg/L]. The mean parent-to-metabolite ratios for clarithromycin to 14-OH-clarithromycin were 0.4 and 0.3 for AUC(0-12 h) and C(max), instead of the typical ratio of ca. 3, probably reflecting increased metabolism of clarithromycin to its (virtually inactive) 14-OH metabolite. Exposure to rifampicin was relatively high, with all patients having a rifampicin C(max) within the reference range. The majority of ethambutol C(max) values were within the reference range. The current study re-emphasises the relevant PK interaction between clarithromycin and rifampicin. This calls for a re-evaluation of dosing strategies in NTM lung disease, as suboptimal drug exposure may contribute to inadequate response to treatment of NTM disease.

Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age: supportive evidence for the implementation of revised WHO dosing recommendations.

OBJECTIVES: The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela. METHODS: Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1-15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined. RESULTS: 25 patients (83%) had an isoniazid Cmax below 3 mg/l and 23 patients (77%) had a rifampicin Cmax below 8 mg/l. One patient (3%) had a pyrazinamide Cmax below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01). CONCLUSION: We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.

Simultaneous determination of the azoles voriconazole, posaconazole, isavuconazole, itraconazole and its metabolite hydroxy-itraconazole in human plasma by reversed phase ultra-performance liquid chromatography with ultraviolet detection.

A reversed phase ultra-performance liquid chromatography method was developed for the simultaneous quantitative determination of the systemically administered azoles voriconazole, posaconazole, isavuconazole, itraconazole and its metabolite hydroxy-itraconazole in plasma. The method involved a simple liquid-liquid extraction followed by ultra-performance liquid chromatography with an Acquity UPLC BEH Phenyl column and ultraviolet detection set at a wavelength of 260 nm. The assay was validated over the concentration range of 0.050-10,000 mg/l for all four azoles and one metabolite. The accuracies for the assay were 97-104%, inter- and intra-day coefficients of variation were <7.5% and extraction recoveries were 98% for voriconazole, posaconazole, isavuconazole and the internal standard (UK115794), and 79% and 88% for itraconazole and hydroxy-itraconazole respectively. This method proved to be simple, accurate, precise and fast and is currently in use in our laboratory for the quantitative analysis of these azoles for Therapeutic Drug Monitoring and pharmacokinetic research.

Acute intoxication patients presenting to an emergency department in The Netherlands: admit or not? Prospective testing of two algorithms.

STUDY OBJECTIVE: After acute intoxication, most patients presenting to the emergency department (ED)--76% of them in The Netherlands--are admitted to hospital. Many will not need medical treatment on the ward. The authors tested two algorithms in the ED, based on vital parameters, ECG findings, and ingested substances, to identify patients who will receive treatment in hospital. METHODS: This prospective inception study enrolled patients aged 14 years and older presenting with acute intoxication between January 2006 and April 2008 to a Dutch university hospital. An algorithm was developed based on a previous retrospective study and the medical literature. In a second algorithm the clinical course during the stay in the ED was also taken into account. RESULTS: Of 313 patients presenting with acute intoxication to the ED, 134 (42.8%) were admitted to a ward for somatic care, but only 74 (23.6%) were treated on the ward. Algorithm 1 had 91.9% sensitivity (95% CI 82.6% to 96.7%) and 53.6% specificity (95% CI 47.0% to 60.0%). Algorithm 2 had 90.5% sensitivity (95% CI 80.9% to 95.8%) and 65.3% specificity (95% CI 58.8% to 71.2%). In line with hospital policy, several patients received N-acetylcysteine treatment for subtoxic paracetamol ingestion because they presented outside of office hours, when no measurements of blood paracetamol concentration are performed by the laboratory. When these patients are considered as untreated, both algorithms had 98.5% sensitivity (95% CI 90.6% to 99.9%). CONCLUSION: The algorithms had good sensitivity and better specificity than current clinical practice in most hospitals. It is too early to advocate their implementation, but results indicate that it is possible to use clinical parameters objectively to reduce unnecessary admissions to the ward.

Fluoroquinolones, the cornerstone of treatment of drug-resistant tuberculosis: a pharmacokinetic and pharmacodynamic approach.

Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-administered agents on these characteristics, for the currently used FQs (ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin) in TB treatment. Future FQs that are being developed may overcome the problems with FQs that are used in daily practice. Therefore PK and pharmacodynamic (PD) properties of novel FQs (clinafloxacin, garenoxacin, lomefloxacin, sitafloxacin, sparfloxacin, trovafloxacin, gemifloxacin, grepafloxacin and DC-159a) were evaluated in TB treatment as well. Integrating both excellent PK and PD properties, moxifloxacin, possibly at a higher dosage, may fulfil a far more important role in the treatment of multi-drug and early-generation FQ resistant TB than proposed in the current WHO guideline. Sparfloxacin, trovafloxacin and sitafloxacin are upcoming novel FQs that may be useful for drug-resistant TB based on their favourable PK properties or microbiological susceptibility against M. tuberculosis. Finally, the 8-methoxy moiety, as present in the chemical structure of MFX, will possibly provide DC- 159a with promising PK/PD characteristics and consequently this FQ may develop into a key FQ in future drug resistant TB treatment.