Mathieu S. Bolhuis

Efficacy and safety of meropenem–clavulanate added to linezolid-containing regimens in the treatment of MDR-/XDR-TB

Clinical experience on meropenem–clavulanate to treat tuberculosis (TB) is anecdotal (according to case reports on 10 patients). The aim of our case–control study was to evaluate the contribution of meropenem–clavulanate when added to linezolid-containing regimens in terms of efficacy and safety/tolerability in treating multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB cases after 3 months of second-line treatment. 37 cases with MDR-/XDR-TB were prescribed meropenem–clavulanate (3 g daily dose) in addition to a linezolid-containing regimen (dosage range 300–1200 mg·day−1), designed according to international guidelines, which was prescribed to 61 controls. The clinical severity of cases was worse than that of controls (drug susceptibility profile, proportion of sputum-smear positive and of re-treatment cases). The group of cases yielded a higher proportion of sputum-smear converters (28 (87.5%) out of 32 versus nine (56.3%) out of 16; p=0.02) and culture converters (31 (83.8%) out of 37 versus 15 (62.5%) out of 24; p=0.06). Excluding XDR-TB patients (11 (11.2%) out of 98), cases scored a significantly higher proportion of culture converters than controls (p=0.03). One case had to withdraw from meropenem–clavulanate due to increased transaminase levels. The results of our study provide: 1) preliminary evidence on effectiveness and safety/tolerability of meropenem–clavulanate; 2) reference to design further trials; and 3) a guide to clinicians for its rationale use within salvage/compassionate regimens.

Daily 300 mg dose of linezolid for multidrug-resistant and extensively drug-resistant tuberculosis: updated analysis of 51 patients

Conclusions: Our findings suggest that linezolid at a daily dose of 300 mg is effective against intractable MDR/XDR-TB, and may be associated with fewer neuropathic side effects than a daily dose of 600 or 1200 mg.

Dried Blood Spot Analysis for Therapeutic Drug Monitoring of Linezolid in Patients with Multidrug-Resistant Tuberculosis

ABSTRACT Linezolid is a promising antimicrobial agent for the treatment of multidrug-resistant tuberculosis (MDR-TB), but its use is limited by toxicity. Therapeutic drug monitoring (TDM) may help to minimize toxicity while adequate drug exposure is maintained. Conventional plasma sampling and monitoring might be hindered in many parts of the world by logistical problems that may be solved by dried blood spot (DBS) sampling. The aim of this study was to develop and validate a novel method for TDM of linezolid in MDR-TB patients using DBS sampling. Plasma, venous DBS, and capillary DBS specimens were obtained simultaneously from eight patients receiving linezolid. A DBS sampling method was developed and clinically validated by comparing DBS with plasma results using Passing-Bablok regression and Bland-Altman analysis. This study showed that DBS analysis was reproducible and robust. Accuracy and between- and within-day precision values from three validations presented as bias and coefficient of variation (CV) were less than 17.2% for the lower limit of quantification and less than 7.8% for other levels. The method showed a high recovery of approximately 95% and a low matrix effect of less than 8.7%. DBS specimens were stable at 37°C for 2 months and at 50°C for 1 week. The ratio of the concentration of linezolid in DBS samples to that in plasma was 1.2 (95% confidence interval [CI], 1.12 to 1.27). Linezolid exposure calculated from concentrations DBS samples and plasma showed good agreement. In conclusion, DBS analysis of linezolid is a promising tool to optimize linezolid treatment in MDR-TB patients. An easy sampling procedure and high sample stability may facilitate TDM, even in underdeveloped countries with limited resources and where conventional plasma sampling is not feasible.

Simultaneous determination of rifampicin, clarithromycin and their metabolites in dried blood spots using LC–MS/MS

INTRODUCTION Rifampicin (RIF) and clarithromycin (CLR) are common drugs for the treatment of infections like Mycobacterium tuberculosis and Mycobacterium ulcerans. Treatment for these diseases are long-term and the individual pharmacokinetic variation, drug-drug interactions or non-adherence may introduce sub-therapeutic exposure or toxicity. The application of therapeutic drug monitoring (TDM) can be used to ensure efficacy and avoid toxicity. With the use of dried blood spot (DBS), TDM may be feasible in rural areas. During DBS method development, unexpected interactions or matrix effects may be encountered due to endogenous components in the blood. Another complication compared to plasma analysis is that RIF can form chelate complexes with ferric ions or can bind with hemes, which are potentially present in the extracts of dried blood spots. METHODS The investigation focused on the interaction between RIF and the endogenous components of the DBS. The use of ethylenediaminetetraacetic acid (EDTA) and deferoxamine (DFX) as chelator agents to improve recoveries and matrix effects were investigated. A rapid analytical method was developed and validated to quantify RIF and CLR and their active metabolites desacetyl rifampicin (DAc-RIF) and 14-hydroxyclarythromcin (14OH-CLR) in DBS samples. A clinical application study was performed in tuberculosis patients by comparing DBS concentrations with plasma concentrations. RESULTS The interaction between RIF and the DBS matrix was avoided using the complexing agents EDTA and DFX, which improved recoveries and matrix effects. The developed sample procedure resulted in a simple and fast method for the simultaneous quantification of RIF, CLR and their metabolites in DBS samples. High stability was observed as all four substances were stable at ambient temperature for 2 months. Deming regression analysis of the clinical application study showed no significant differences for RIF, DAc-RIF, CLR and 14OH-CLR between patient plasma and DBS analysis. The slopes of the correlation lines between DBS and plasma concentrations of RIF, DAc-RIF, CLR and 14OH-CLR were 0.90, 0.99, 0.80 and 1.09 respectively. High correlations between plasma and DBS concentrations were observed for RIF (R(2)=0.9076), CLR (R(2)=0.9752) and 14OH-CLR (R(2)=0.9421). Lower correlation was found for DAc-RIF (R(2) of 0.6856). CONCLUSION The validated method is applicable for TDM of RIF, CLR and their active metabolites. The stability of the DBS at high temperatures can facilitate the TDM and pharmacokinetic studies of RIF and CLR even in resource limited areas. The role of EDTA and DFX as complexing agents in the extraction was well investigated and may provide a solution for potential applications to other DBS analytical methods.

Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients

The use of linezolid for the treatment of multidrug-resistant tuberculosis is limited by dose- and time-dependent toxicity. Recently, we reported a case of pharmacokinetic drug–drug interaction between linezolid and clarithromycin that resulted in increased linezolid exposure. The aim of this prospective pharmacokinetic study is to quantify the effect of clarithromycin on the exposure of linezolid. Subjects were included in an open-label, single-centre, single-arm, fixed-order pharmacokinetic interaction study. All subjects received 300 mg linezolid twice daily during the entire study, consecutively co-administered with 250 mg and 500 mg clarithromycin once daily. Steady-state serum curves of linezolid and clarithromycin were analysed using validated methods, and differences between pharmacokinetic parameters were calculated. Linezolid exposure increased by a median (interquartile range) of 44% (23–102%, p=0.043) after co-administration of 500 mg clarithromycin (n=5) compared to baseline, whereas 250 mg clarithromycin had no statistically significant effect. Co-administration was well tolerated by most patients; none experienced severe adverse effects. One patient reported common toxicity criteria grade 2 gastrointestinal adverse events. In this study, we showed that clarithromycin significantly increased linezolid serum exposure after combining clarithromycin with linezolid in multidrug-resistant tuberculosis patients. The drug–drug interaction is possibly P-glycoprotein-mediated. Due to large interpatient variability, therapeutic drug monitoring is advisable to determine individual effect size. Clarithromycin significantly increased linezolid serum exposure in multidrug-resistant tuberculosis patients http://ow.ly/oYGK1

Incorporating therapeutic drug monitoring into the World Health Organization hierarchy of tuberculosis diagnostics

Tuberculosis (TB), once considered as a disease of the past generally afflicting poor people, still claims 1.5 million lives annually [1]. Although 86% of patients with drug susceptible TB are cured with established first-line drugs, treatment is often longer than 6 months due to slow response, compliance problems or adverse drug reactions. In addition, emergence of drug-resistant Mycobacterium tuberculosis strains with an unacceptably low treatment success rate of 50% and TB–HIV co-infection have challenged the goals of global TB control and elimination [1]. Incorporating therapeutic drug monitoring into the WHO hierarchy of tuberculosis diagnostics http://ow.ly/YcRMw

Clarithromycin significantly increases linezolid serum concentrations

A 42-year-old male patient was admitted at our hospital for treatment of smear-positive pulmonary tuberculosis (TB). Drug sensitivity testing revealed extensively drug-resistant TB, and the isolate appeared only susceptible to cycloserine, linezolid, clarithromycin, and clofazimine. According to the WHO treatment guidelines for TB, the treatment regimen was composed of these four drugs, as no other options were available (11). Linezolid was the cornerstone of this regimen because of the high in vitro activity against Mycobacterium tuberculosis (MIC of 0.125 to 0.5 mg/liter) (1, 8). Linezolid is a toxic drug, and its labeled duration of administration is therefore limited to 28 days to prevent peripheral neuropathy and anemia. Dose reduction has been evaluated in TB patients as an attempt to reduce toxicity to allow prolonged treatment for 18 to 24 months (6, 7, 10). The serum linezolid concentration target in our hospital is to maintain an AUC (the area under the concentration-time curve over 24 h in the steady state)/MIC ratio of >100 and a percentage of time in excess of the MIC of 100%. These conditions are generally reached with a dosage of 300 mg twice daily (2). Serum drug concentrations are analyzed using a validated liquid chromatography-tandem mass spectrophotometry method (5). In this patient, we measured a considerable increase in the AUC of linezolid from 29 mg·h/liter to 108 mg·h/liter (Fig. ​(Fig.11).

Linezolid tolerability in multidrug-resistant tuberculosis: a retrospective study

Linezolid is used off-label to treat multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) [1, 2]. Recently, two systematic reviews and meta-analyses pointed out its promising efficacy [3, 4]. However, linezolid toxicity may outweigh its potential benefits. Indeed, adverse events were notified in almost 60% of the treated cases, with a high incidence of severe events such as anaemia, peripheral neuropathy, optic neuritis, and thrombocytopenia. Decreased linezolid doses were associated with significantly lowered toxicity [5]. Furthermore, therapeutic drug monitoring (TDM) has increasingly been recognised as an asset in the field of TB treatment [6, 7]. TDM may assess individual linezolid exposure, especially since the drug shows a large inter-individual variability [8] and important pharmacological interactions were observed [6]. However, there is no clear association between linezolid exposure and adverse events. Drug exposure is not routinely evaluated, either in prospective studies or in routine care. Unfortunately, TDM is not routinely incorporated into the study designs of research upon MDR-TB and linezolid [9, 10]. Therefore, we aimed to retrospectively investigate linezolid safety and tolerability in relation to linezolid exposure in MDR-TB patients. Linezolid for MDR-TB is well tolerated but peripheral neuropathy is related to cumulative dose and days of exposure http://ow.ly/Nx8wC

Current status and opportunities for therapeutic drug monitoring in the treatment of tuberculosis

ABSTRACT Introduction: Tuberculosis remains a global health problem and pharmacokinetic variability has been postulated as one of the causes of treatment failure and acquired drug resistance. New developments enable implementation of therapeutic drug monitoring, a strategy to evaluate drug exposure in order to tailor the dose to the individual patient, in tuberculosis treatment. Areas covered: Literature on pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs was explored to evaluate the effect of drug exposure in relation to drug susceptibility, toxicity and efficacy. New, down-sized strategies, like dried blood spot analysis and limited sampling strategies are reviewed. In addition, molecular resistance testing of Mycobacteria tuberculosis, combining a short turn-around time with relevant information on drug susceptibility of the causative pathogen was explored. Newly emerging host biomarkers provide information on the response to treatment. Expert opinion: Therapeutic drug monitoring can minimize toxicity and increase efficacy of tuberculosis treatment and prevent the development of resistance. Dried blood spot analysis and limited sampling strategies, can be combined to provide us with a more patient friendly approach. Furthermore, rapid information on drug susceptibility by molecular testing, and information from host biomarkers on the bacteriological response, can be used to further optimize tuberculosis treatment.

Role of therapeutic drug monitoring in pulmonary infections: use and potential for expanded use of dried blood spot samples

Respiratory tract infections are among the most common infections in men. We reviewed literature to document their pharmacological treatments, and the extent to which therapeutic drug monitoring (TDM) is needed during treatment. We subsequently examined potential use of dried blood spots as sample procedure for TDM. TDM was found to be an important component of clinical care for many (but not all) pulmonary infections. For gentamicin, linezolid, voriconazole and posaconazole dried blood spot methods and their use in TDM were already evident in literature. For glycopeptides, β-lactam antibiotics and fluoroquinolones it was determined that development of a dried blood spot (DBS) method could be useful. This review identifies specific antibiotics for which development of DBS methods could support the optimization of treatment of pulmonary infections.