"La Fayette, intime"

Typewritten sheets in cover. Thesis (M.A.)--Boston University Bibliography: p. 1-8 at end

Peritoneal Dialysis Fluid Concentrations of Linezolid in the Treatment of Vancomycin‐Resistant Enterococcus faecium Peritonitis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90108/1/phco.23.12.1322.32702.pd

Therapeutic drug management: is it the future of multidrug-resistant tuberculosis treatment?

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Therapeutic drug monitoring in patients with tuberculosis and concurrent medical problems

Introduction Therapeutic drug monitoring (TDM) has been recommended for treatment optimization in tuberculosis (TB) but is only is used in certain countries e.g. USA, Germany, the Netherlands, Sweden and Tanzania. Recently, new drugs have emerged and PK studies in TB are continuing, which contributes further evidence for TDM in TB. The aim of this review is to provide an update on drugs used in TB, treatment strategies for these drugs, and TDM to support broader implementation. Areas covered This review describes the different drug classes used for TB, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), along with their pharmacokinetics, dosing strategies, TDM and sampling strategies. Moreover, the review discusses TDM for patient TB and renal or liver impairment, patients co-infected with HIV or hepatitis, and special patient populations - children and pregnant women. Expert opinion TB treatment has a long history of using 'one size fits all.' This has contributed to treatment failures, treatment relapses, and the selection of drug-resistant isolates. While challenging in resource-limited circumstances, TDM offers the clinician the opportunity to individualize and optimize treatment early in treatment. This approach may help to refine treatment and thereby reduce adverse effects and poor treatment outcomes. Funding, training, and randomized controlled trials are needed to advance the use of TDM for patients with TB

Gut Microbiota Composition and Diversity Before, During, and Two Months After Rifamycin-Based Tuberculosis Preventive Therapy

Tuberculosis (TB) preventive therapy (TPT) is an effective strategy to eliminate TB in low-incidence settings. Shorter TPT regimens incorporating the antimicrobial class of rifamycins are designed to improve adherence and completion rates but carry the risk of modifications to the gut microbiota. We enrolled six subjects diagnosed with latent TB infection (LTBI) who accepted to initiate TPT. We also enrolled six healthy volunteers unexposed to the rifamycins. We profiled the gut microbiota using 16S rRNA amplicon sequencing (V1-V2 region) to document the immediate effect of rifamycin-based TPT on the gut microbiota composition and tracked recovery to baseline two months after TPT. Overall, TPT accounted for 17% of the variance in gut microbial community dissimilarity. This rifamycin-based TPT induced dysbiosis was characterized by a depletion of butyrate-producing taxa (Clostridium-XIVa and Roseburia) and expansion of potentially pathogenic taxa within the Firmicutes and Proteobacteria phyla. Recovery of the gut microbial composition was incomplete two months after TPT. Robust clinical studies are necessary to comprehensively catalogue TPT-induced gut microbiota dysbiosis to inform strategies to mitigate potential long-term sequelae of this important TB control intervention

Linezolid Clearance During Continuous Venovenous Hemodiafiltration: A Case Report

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90207/1/phco.23.8.1071.32874.pd

Pharmacokinetic Modeling, Simulation, and Development of a Limited Sampling Strategy of Cycloserine in Patients with Multidrug-/Extensively Drug-Resistant Tuberculosis

BACKGROUND AND OBJECTIVE: Multidrug-resistant tuberculosis has much poorer treatment outcomes compared with drug-susceptible tuberculosis because second-line drugs for treating multidrug resistant tuberculosis are less effective and are frequently associated with side effects. Optimization of drug treatment is urgently needed. Cycloserine is a second-line tuberculosis drug with variable pharmacokinetics and thus variable exposure when programmatic doses are used. The objective of this study was to develop a population pharmacokinetic model of cycloserine to assess drug exposure and to develop a limited sampling strategy for cycloserine exposure monitoring. MATERIAL AND METHODS: Patients with multidrug-/extensively drug-resistant tuberculosis who were treated for > 7 days with cycloserine were eligible for inclusion. Patients received cycloserine 500 mg (body weight ≤ 50 kg) or 750 mg (body weight > 50 kg) once daily. MW/Pharm 3.83 (Mediware, Groningen, The Netherlands) was used to parameterize the population pharmacokinetic model. The model was compared with pharmacokinetic values from the literature and evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset. Monte Carlo simulations were used to develop a limited sampling strategy. RESULTS: Cycloserine plasma concentration vs time curves were obtained from 15 hospitalized patients (nine male, six female, median age 35 years). Mean dose/kg body weight was 11.5 mg/kg (standard deviation 2.04 mg/kg). Median area under the concentration-time curve over 24 h (AUC0-24 h) of cycloserine was 888 h mg/L (interquartile range 728-1252 h mg/L) and median maximum concentration of cycloserine was 23.31 mg/L (interquartile range 20.14-33.30 mg/L). The final population pharmacokinetic model consisted of the following pharmacokinetic parameters [mean (standard deviation)]: absorption constant Ka_po of 0.39 (0.31) h-1, distribution over the central compartment (Vd) of 0.54 (0.26) L/kg LBM, renal clearance as fraction of the estimated glomerular filtration rate of 0.092 (0.038), and metabolic clearance of 1.05 (0.75) L/h. The population pharmacokinetic model was successfully evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset of Chinese patients (difference of 14.6% and 19.5% in measured and calculated concentrations and AUC0-24 h, respectively). Root-mean-squared-errors found in predicting the AUC0-24 h using a one- (4 h) and a two- (2 h and 7 h) limited sampling strategy were 1.60% and 0.14%, respectively. CONCLUSIONS: This developed population pharmacokinetic model can be used to calculate cycloserine concentrations and exposure in patients with multidrug-/extensively drug-resistant tuberculosis. This model was successfully validated by internal and external validation methods. This study showed that the AUC0-24 h of cycloserine can be estimated in patients with multidrug-/extensively drug-resistant tuberculosis using a 1- or 2-point limited sampling strategy in combination with the developed population pharmacokinetic model. This strategy can be used in studies to correlate drug exposure with clinical outcome. This study also showed that good target attainment rates, expressed by time above the minimal inhibitory concentration, were obtained for cycloserine with a minimal inhibitory concentration of 5 and 10 mg/L, but low rates with a minimal inhibitory concentration of 20 and 32.5 mg/L

Pharmacokinetics and Dosing of Levofloxacin in Children Treated for Active or Latent Multidrug-resistant Tuberculosis, Federated States of Micronesia and Republic of the Marshall Islands

In the Federated States of Micronesia (FSM) and then the Republic of the Marshall Islands (RMI), levofloxacin pharmacokinetics (PK) were studied in children receiving directly observed once-daily regimens (10 mg/kg, age >5 years; 15–20 mg/kg, age ≤5 years) for either multidrug-resistant tuberculosis (MDR TB) disease or latent infection after MDR TB exposure, to inform future dosing strategies