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Since its approval by the United States Food and Drug Administration in 2002, voriconazole has become a key component in the successful treatment of many invasive fungal infections, including the most common, aspergillosis and candidiasis. Despite voriconazole’s widespread use, optimizing its treatment in an individual can be challenging due to significant interpatient variability in plasma concentrations of the drug. Variability is due to nonlinear pharmacokinetics and the influence of patient characteristics such as age, sex, weight, liver disease, and genetic polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) encoding for the CYP2C19 enzyme, the primary enzyme responsible for metabolism of voriconazole. CYP2C19 polymorphisms account for the largest portion of variability in voriconazole exposure, posing significant difficulty to clinicians in targeting therapeutic concentrations. In this review, we discuss the role of CYP2C19 polymorphisms and their influence on voriconazole’s pharmacokinetics, adverse effects, and clinical efficacy. Given the association between CYP2C19 genotype and voriconazole concentrations, as well as the association between voriconazole concentrations and clinical outcomes, particularly efficacy, it seems reasonable to suggest a potential role for CYP2C19 genotype to guide initial voriconazole dose selection followed by therapeutic drug monitoring to increase the probability of achieving efficacy while avoiding toxicity.

Background In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults. Methods Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentration-time curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME). Results There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all ≥18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed. Conclusions A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults.

Rifampin is an essential component of short-course chemotherapy for tuberculosis (TB).1 Findings from randomized clinical studies demonstrate that the addition of rifampin to treatment regimens during the induction and the continuation phases of TB treatment reduce rates of treatment failure and relapse.2,3 In vitro studies suggest that rifampin demonstrates concentration-dependent killing of Mycobacterium tuberculosis, with the rifampin area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) ratio identified as the best parameter that correlated best with reduction in bacterial counts.4, 5 In the hollow-fiber model of TB, maximal microbial killing was achieved by rifampin daily AUC0-24h/MIC ratio of 24.14 and rifampin prevented resistance to itself at peak concentration (Cmax) to MIC ratio of ≥ 175.4 Clinically, low plasma exposure to the rifamycins has been associated with TB treatment failure and emergence of rifamycin resistance.6-8 The organic anion transporter polypeptide 1B1 (OATP1B1) encoded by the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene mediates the hepatic uptake and elimination of a range of drugs, including rifampin.9 Data from recent studies show that SLCO1B1 c.463C→A and rs4149032 polymorphisms are associated with low rifampin plasma concentrations.10, 11 While these findings are novel, they are yet to be replicated or confirmed in other studies. Taken together, genetic testing and clinical information may be used to identify patients at risk of low rifampin plasma exposure and could enable individualized dosing designed to optimize treatment outcomes. Concomitant administration of rifampin with efavirenz-containing antiretroviral therapy in HIV and TB co-infected patients is necessary to reduce mortality rates.12-14 Rifampin is a potent inducer of hepatic cytochrome P450 enzyme activity, and concomitant administration with efavirenz results in reduced efavirenz concentrations in some, but not all patients.15-17 The variable effect of rifampin on efavirenz plasma pharmacokinetics may be due, in part, to inter-individual variations in rifampin plasma concentrations or uptake of rifampin into hepatocytes, but this hypothesis has not been previously evaluated, to the best of our knowledge. Using stored samples and data from subjects in a previous drug-drug interaction study,16 we sought to identify factors associated with variable rifampin pharmacokinetics. In addition, we explored the relationship between variable rifampin pharmacokinetics and change in efavirenz plasma exposure and clearance.

Background Bedaquiline and delamanid are new and much-needed treatment options for drug-resistant tuberculosis (TB); however, there are limited data guiding their use and no direct comparison of the two drugs. We thus sought to compare the clinical outcomes of patients with drug-resistant tuberculosis receiving either a bedaquiline- or delamanid-based treatment regimen. Methods This is a prospective observational study among patients with drug-resistant pulmonary TB in the country of Georgia from 2015 to 2017. Patients receiving bedaquiline or delamanid were eligible to be enrolled. Monthly sputum cultures and MIC testing on Mycobacterium tuberculosis isolates were performed. Clinical outcomes included time to culture conversion, rate of acquired drug resistance and treatment outcomes. Results Among 156 patients with MDR-TB who were approached, 100 were enrolled, and 95 were receiving a bedaquiline (n = 64) or delamanid (n = 31) based regimen and included in the study. Patients receiving bedaquiline or delamanid were similar with regards to age, BMI, substance use, comorbidities, rate of cavitary disease, and extensively drug-resistant (XDR) TB. Rates of additional Class A drug use including linezolid (78 vs. 81%) and a fluoroquinolone (39 vs. 36%) were similar and the mean effective drugs received per group was 4 (IQR 3–4, P = 0.33). Median drug duration was 171 days for bedaquiline and 182 days for delamanid; no patient discontinued due to QTC prolongation. Adjusted cumulative culture conversion rates at 60 days (64% vs. 48%, P = 0.14) and 180 days (95% vs. 77%, P = 0.02) were higher in patients receiving bedaquiline compared with delamanid (see figure). Rates of acquired drug resistance were higher in patients receiving delamanid compared with bedaquiline (35 vs. 12%, P < 0.01). Lastly, patients receiving a bedaquiline-based regimen had higher rates of favorable outcomes as compared with patients receiving delamanid (94% vs. 67%, P < 0.01). Conclusion Patients receiving bedaquiline- and delamanid-based treatment regimens for drug-resistant TB had similar characteristics and those receiving bedaquiline had better clinical outcomes. Our results provide an important first comparison of bedaquiline vs. delamanid containing regimens. Disclosures All Authors: No reported Disclosures.

Rationale: High-dose levofloxacin (L) (1,000 mg) was as active as moxifloxacin (M) (400 mg) in an early bactericidal activity trial, suggesting these fluoroquinolones could be used interchangeably. Whether pyrazinamide (Z) contributes sterilizing activity beyond the first 2 months in fluoroquinolone-containing second-line regimens remains unknown. Objectives: We compared the efficacy of M and high-dose L alone or in combination with ethionamide (Et), amikacin (A), and Z given for 2 or 7 months. Methods: A pharmacokinetic study was performed to determine the L dose equivalent to 1,000 mg in humans. Treatment started 2 weeks after aerosol infection with Mycobacterium tuberculosis H37Rv. Mice received M or L alone or in combination with 2 months of EtZA followed by 5 months of Et or EtZ. Measurements and Main Results: After 2 months of treatment, lung colony-forming unit (CFU) counts were similar in mice receiving either fluoroquinolone alone, but, after 4 and 5 months, CFU counts were 2 log10 lower in mice receiving M. Mice receiving 2MEtZA/3MEt and 2LEtZA/3LEt had 1.0 and 2.7 log10 lung CFUs, respectively. When Z was given throughout, both regimens rendered mice culture negative by 5 months, and most mice did not relapse after 7 months of treatment, with fewer relapses observed in the M group after 6 and 7 months of treatment. Conclusions: In murine tuberculosis, M had superior efficacy compared with L despite lower serum drug exposures and may remain the fluoroquinolone of choice for second-line regimens. Z contributed substantial sterilizing activity beyond 2 months in fluoroquinolone-containing second-line regimens, largely compensating for L’s weaker activity.

Posaconazole is a triazole antifungal agent used as adjuvant or salvage therapy for the treatment of zygomycosis, an invasive fungal infection associated with high mortality. Oral posaconazole absorption is highly variable. We describe the pharmacokinetics of oral posaconazole in a 2-year-old boy with rhino-cerebral-orbital zygomycosis. Seven days after induction therapy for acute lymphoblastic leukemia, he was brought to the emergency department because of left eyelid swelling and was admitted to the hospital. Zygomycosis was diagnosed 12 days later. After we conducted a literature search and consulted with antifungal drug experts, a triple-antifungal regimen consisting of liposomal amphotericin B, caspofungin, and posaconazole was started. Given the severity of the disease, we aimed for posaconazole plasma trough concentrations greater than 1.25 µg/ml; the dosage necessary to achieve this goal was posaconazole 200 mg 4 times/day. After a difficult 105-day stay in the hospital and stabilization of the fungal infection, the patient was discharged. Caspofungin was discontinued at time of discharge, but the patient continued to receive amphotericin B lipid complex 7.5 mg/kg/day intravenously and posaconazole 200 mg orally 4 times/day. This is one of the few case reports describing posaconazole pharmacokinetics in a child younger than 8 years. In patients with extensive zygomycosis, a triple-antifungal regimen, combined with therapeutic drug monitoring of posaconazole, may be helpful.

High-resolution measurement of medication adherence is essential to personalized drug therapy. A US Food and Drug Administration (FDA)-cleared device, using an edible ingestion sensor (IS), external wearable patch, and paired mobile device can detect and record ingestion events. Oral medications must be combined with an IS to generate precise "digitized-medication" ingestion records. We developed a Good Manufacturing Practice protocol to repackage oral medications with the IS within certified Capsugel capsules, termed co-encapsulation (CoE). A randomized bioequivalence study of CoE-IS-Rifamate (Isoniazid/Rifampin 150/300 mg) vs. native-Rifamate was conducted in 12 patients with active Mycobacterium tuberculosis and demonstrated bioequivalence using the population method ratio test (95% confidence interval). Subsequently, CoE-IS-medications across all biopharmaceutical classes underwent in vitro dissolution testing utilizing USP and FDA guidelines. CoE-IS medications tested met USP dissolution specifications and were equivalent to their native formulations. CoE combines oral medications with the IS without altering the quality of the native formulation, generating "digitized" medications for remote capture of dosing histories.

The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten the TB treatment duration, if treatment is optimized. The goals of this study were (i) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK substudies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28 and (ii) to determine covariates that affect PZA PK. (iii) We also performed simulations and target attainment analysis using the proposed targets of a maximum plasma concentration ( C max ) of >35 μg/ml or an area under the concentration-versus-time curve (AUC) of >363 μg · h/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the substudies. The mean (standard deviation [SD]) C max was 30.8 (7.4) μg/ml, and the mean (SD) AUC from time zero to 24 h (AUC 0–24 ) was 307 (83) μg · h/ml. A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower volume of distribution ( V / F ) than men, and both clearance (CL/ F ) and V / F increased with body weight. Our simulations show that higher doses of PZA (>50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of >11.3 in >80% of patients, while doses of >80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of a C max of >35 μg/ml and/or an AUC of >363 μg · h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in >90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.

Tuberculosis (TB) is the most prevalent opportunistic infection among HIV patients, and the leading cause of death among HIV patients worldwide. Simultaneous treatment of both diseases is recommended by current guidelines, but can be challenging due to the potential for drug-drug interactions, overlapping toxicities, difficulty adhering to medications, and an increased risk for immune reconstitution inflammatory syndrome (IRIS). Clinical manifestations of TB can also vary between HIV-infected patients and uninfected patients, which can increase the risk for delayed diagnosis. Areas covered: Topics covered in this review include the following: the inter-related pathophysiology of HIV and TB; clinical manifestations and diagnosis; drug-drug interactions, particularly the rifamycins with the antiretrovirals; IRIS presentation and treatment, as well as a discussion on overlapping toxicity between the two disease states. Expert commentary: The complexity of managing these two disease states simultaneously requires a multidisciplinary approach to care and dedicated resources. If properly funded, TB/HIV co-infection will continue to decline over the coming years.

AZD5847 is an oxazolidinone antibiotic with in vitro activity against Mycobacterium tuberculosis . The objective of this study was to evaluate the antimycobacterial activity, safety, and pharmacokinetics of AZD5847 in patients with pulmonary tuberculosis. Groups of 15 treatment-naive, sputum smear-positive adults with pulmonary tuberculosis were randomly assigned to receive AZD5847 at one of four doses (500 mg once daily, 500 mg twice daily, 1,200 mg once daily, and 800 mg twice daily) or daily standard chemotherapy. The primary efficacy endpoint was the mean daily rate of change in the log 10 number of CFU of M. tuberculosis per milliliter of sputum, expressed as the change in log 10 number of CFU per milliliter of sputum per day. The mean 14-day activity of the combination of isoniazid, rifampin, ethambutol, and pyrazinamide (−0.163 log 10 CFU/ml sputum/day; 95% confidence interval [CI], −0.193, −0.133 log 10 CFU/ml sputum/day) was consistent with that found in previous studies. AZD5847 at 500 mg twice daily significantly decreased the number of CFU on solid medium (−0.039; 95% CI, −0.069, −0.009; P = 0.0048). No bactericidal activity was detected at doses of AZD5847 of 500 mg once daily (mean early bactericidal activity [EBA], 0.02 [95% CI, −0.01, 0.05]), 1,200 mg once daily (mean EBA, 0.02 [95% CI, −0.01, 0.05]), and 800 mg twice daily (mean EBA, 0.02 [95% CI, −0.01, 0.05]). AZD5847 at doses of both 500 mg and 800 mg twice daily also showed an increase in the time to a positive culture in MGIT liquid culture medium. Two serious adverse events (grade 4 thrombocytopenia and grade 4 hyperbilirubinemia) occurred in patients receiving AZD5847 at higher doses. AZD5847 dosed twice daily kills tubercle bacilli in the sputum of patients with pulmonary tuberculosis and has modest early bactericidal activity. (This study has been registered at ClinicalTrials.gov under registration no. NCT01516203.)

This report describes the pharmacokinetic profiles of chronically administered oral isoniazid and rifampin in one adult male and one adult female Asian elephant ( Elephas maximus ) that were asymptomatically infected with Mycobacterium tuberculosis . Rifampin's half-life was reduced when compared to previous single-dose pharmacokinetic profiles of healthy uninfected Asian elephants. Both elephants experienced delayed absorption of isoniazid and rifampin as compared to previous pharmacokinetic studies in this species. The altered pharmacokinetics of both drugs in repeated-dosing clinical situations underscores the need for individual therapeutic drug monitoring for tuberculosis treatment.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

The goal of this article is to review the use of rifapentine in the treatment of latent tuberculosis infection (LTBI). Controlling LTBI is an important part of the global strategy to end the spread of tuberculosis. Rifapentine's potent sterilizing effect against Mycobacterium tuberculosis combined with its long half-life make it an attractive LTBI treatment option. Areas covered: A systematic literature search of Pubmed using the terms 'rifapentine' and 'tuberculosis' was performed. Articles identified were cross-referenced for other relevant publications. The mechanisms of action and resistance, pharmacokinetic and pharmacodynamics, potential drug interactions and side effects are discussed. Expert commentary: Rifapentine in combination with isoniazid for twelve weeks is the best available option for treating latent TB in the majority of patients in the United States due to its favorable safety profile and the increased likelihood of completing therapy. Currently, rifapentine is not registered or available in other countries.

BACKGROUND: Evidence has existed for decades that higher doses of rifampin may be more effective, but potentially more toxic, than standard doses used in tuberculosis treatment. Whether increased doses of rifampin could safely shorten treatment remains an open question. METHODS/DESIGN: The HIRIF study is a phase II randomized trial comparing rifampin doses of 20 and 15 mg/kg/day to the standard 10 mg/kg/day for the first 2 months of tuberculosis treatment. All participants receive standard doses of companion drugs and a standard continuation-phase treatment (4 months, 2 drugs). They are followed for 6 months post treatment. Study participants are adults with newly diagnosed, previously untreated, smear positive (≥2+) pulmonary tuberculosis. The primary outcome is rifampin area under the plasma concentration-time curve (AUC0-24) after at least 14 days of study treatment/minimum inhibitory concentration. 180 randomized participants affords 90 % statistical power to detect a difference of at least 14 mcg/mL*hr between the 20 mg/kg group and the 10 mg/kg group, assuming a loss to follow-up of up to 17 %. DISCUSSION: Extant evidence suggests the potential for increased doses of rifampin to shorten tuberculosis treatment duration. Early studies that explored this potential using intermittent, higher dosing were derailed by toxicity. Given the continued large, global burden of tuberculosis with nearly 10 million new cases annually, shortened regimens with existing drugs would offer an important advantage to patients and health systems. TRIAL REGISTRATION: This trial was registered with clinicaltrials.gov (registration number: NCT01408914 ) on 2 August 2011.

Tuberculosis has been and remains arguably the most important infectious disease of all time. However, when compared to other diseases of similar human impact, relatively little progress has been made. Although there are many new drugs being developed for the first time in decades, it is unclear what role each of these new drugs will play.The history of current therapy is reviewed as are the challenges associated with medications currently in use. Drugs that have recently been added to the armamentarium of therapy are reviewed as well as new candidate drugs.Developing new drugs to treat tuberculosis is of critical importance but even more important is developing strategies that ensure that there is no further amplification of drug resistance around the world especially in high burden low resource settings. Directly observed therapy is the cornerstone of protecting existing and future regimens and new technologies will potentially extend the reach of monitored therapy. Challenges remain including maintaining an adequate drug supply but the greatest challenge may be the issue of persistent organisms that require prolonged therapy. By discovering the triggers of persistence and identifying new drug targets can it be possible to radically shorten therapy.

Item does not contain fulltext OBJECTIVES: Extensive but fragmented data from existing studies were used to describe the drug-drug interaction between rifabutin and HIV PIs and predict doses achieving recommended therapeutic exposure for rifabutin in patients with HIV-associated TB, with concurrently administered PIs. METHODS: Individual-level data from 13 published studies were pooled and a population analysis approach was used to develop a pharmacokinetic model for rifabutin, its main active metabolite 25-O-desacetyl rifabutin (des-rifabutin) and drug-drug interaction with PIs in healthy volunteers and patients who had HIV and TB (TB/HIV). RESULTS: Key parameters of rifabutin affected by drug-drug interaction in TB/HIV were clearance to routes other than des-rifabutin (reduced by 76%-100%), formation of the metabolite (increased by 224% in patients), volume of distribution (increased by 606%) and distribution to the peripheral compartment (reduced by 47%). For des-rifabutin, clearance was reduced by 35%-76% and volume of distribution increased by 67%-240% in TB/HIV. These changes resulted in overall increased exposure to rifabutin in TB/HIV patients by 210% because of the effects of PIs and 280% with ritonavir-boosted PIs. CONCLUSIONS: Given together with non-boosted or ritonavir-boosted PIs, rifabutin at 150 mg once daily results in similar or higher exposure compared with rifabutin at 300 mg once daily without concomitant PIs and may achieve peak concentrations within an acceptable therapeutic range. Although 300 mg of rifabutin every 3 days with boosted PI achieves an average equivalent exposure, intermittent doses of rifamycins are not supported by current guidelines.

Low circulating serum levels of 25-hydroxyvitamin D (referred to hereafter as vitamin D) have been correlated with many health conditions, including chronic pain. Recent clinical practice guidelines define vitamin D levels20 ng/ml as deficient and levels of 21-29 ng/ml as insufficient. Vitamin D insufficiency, including the most severe levels of deficiency, is more prevalent in black Americans. Ethnic and race group differences have been reported in both clinical and experimental pain, with black Americans reporting increased pain. The purpose of this study was to examine whether variations in vitamin D levels contribute to race differences in knee osteoarthritis pain.The sample consisted of 94 participants (74% women), including 45 blacks and 49 whites with symptomatic knee osteoarthritis. Their average age was 55.8 years (range 45-71 years). Participants completed a questionnaire on knee osteoarthritis symptoms and underwent quantitative sensory testing, including measures of sensitivity to heat-induced and mechanically induced pain.Blacks had significantly lower levels of vitamin D compared to whites, demonstrated greater clinical pain, and showed greater sensitivity to heat-induced and mechanically induced pain. Low levels of vitamin D predicted increased experimental pain sensitivity, but did not predict self-reported clinical pain. Group differences in vitamin D levels significantly predicted group differences in heat pain and pressure pain thresholds at the index knee and ipsilateral forearm.These data demonstrate that race differences in experimental pain are mediated by differences in the vitamin D level. Vitamin D deficiency may be a risk factor for increased knee osteoarthritis pain in black Americans.

Item does not contain fulltext Rationale: Currently recommended multidrug treatment regimens for Mycobacterium avium complex (MAC) lung disease yield limited cure rates. This results, in part, from incomplete understanding of the pharmacokinetics and pharmacodynamics of the drugs. Objectives: To study pharmacokinetics, pharmacodynamics, and drug interactions of multidrug treatment regimens in a large cohort of patients with MAC lung disease. Methods: We retrospectively collected pharmacokinetic data of all patients treated for MAC lung disease in the Adult Care Unit at National Jewish Health, Denver, Colorado, in the January 2006 to January 2010 period; we retrospectively calculated areas under the time-concentration curve (AUC). Minimum inhibitory concentrations (MIC) of their MAC isolates were retrieved for pharmacodynamic calculations. Measurements and Main Results: We included 531 pharmacokinetic analyses, performed for 481 patients (84% females; mean age, 63 yr; mean body mass index, 21.6). Peak serum concentrations (C(max)) below target range were frequent for ethambutol (48% of patients); clarithromycin (56%); and azithromycin (35%). Concurrent administration of rifampicin led to 68%, 23%, and 10% decreases in C(max) of clarithromycin, azithromycin, and moxifloxacin. C(max)/MIC or AUC/MIC ratios associated with bactericidal activity were seldom met; 57% of patients achieved target ratios for ethambutol, versus 42% for clarithromycin, 19% for amikacin, 18% for rifampicin, and 11% for moxifloxacin. Conclusions: Currently recommended regimens for MAC lung disease yield important pharmacologic interactions and low concentrations of key drugs including macrolides. Pharmacodynamic indices for rifampicin, clarithromycin, amikacin, and moxifloxacin are seldom met. This may partly explain the poor outcomes of currently recommended treatment regimens. Trials of new drugs and new dosing strategies are needed.

In previous experiments, replacing the 10-mg/kg of body weight daily dose of rifampin with 7.5 to 10 mg/kg of rifapentine in combinations containing isoniazid and pyrazinamide reduced the duration of treatment needed to cure tuberculosis in BALB/c mice by approximately 50% due to rifapentine's more potent activity and greater drug exposures obtained. In the present study, we performed dose-ranging comparisons of the bactericidal and sterilizing activities of rifampin and rifapentine, alone and in combination with isoniazid and pyrazinamide with or without ethambutol, in BALB/c mice and in C3HeB/FeJ mice, which develop necrotic lung granulomas after infection with Mycobacterium tuberculosis . Each rifamycin demonstrated a significant increase in sterilizing activity with increasing dose. Rifapentine was roughly 4 times more potent in both mouse strains. These results reinforce the rationale for ongoing clinical trials to ascertain the highest well-tolerated doses of rifampin and rifapentine. This study also provides an important benchmark for the efficacy of the first-line regimen in C3HeB/FeJ mice, a strain in which the lung lesions observed after M. tuberculosis infection may better represent the pathology of human tuberculosis.

Objectives Vancomycin-resistant enterococci (VRE) have emerged as an important nosocomial pathogen in medical centres worldwide. This study evaluated the impact of front-loading of linezolid on bacterial killing and suppression of resistance against VRE strains with defined genetic mutations. Methods Time-killing experiments over 48 h assessed the concentration effect relationship of linezolid against eight strains of vancomycin-resistant Enterococcus faecalis. A hollow fibre infection model (HFIM) simulated traditional and front-loaded human therapeutic linezolid regimens against VRE strains at 10(6) cfu/mL over 240 h. Translational modelling was performed using S-ADAPT and NONMEM. Results Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity with >2 log(10) cfu/mL killing for all strains with an MIC of 4 and minimal activity against VRE with MICs of 16 and 64 mg/L. Against one strain with no resistant alleles (MIC 4 mg/L), 600 mg of linezolid every 12 h achieved maximal reductions of 0.96 log(10) cfu/mL over 240 h in the HFIM, whereas front-loaded 1200 mg of linezolid every 12 h ×10 doses or 2400 mg of linezolid every 12 h ×10 doses followed by 600 mg of linezolid every 12 h provided significantly improved killing with maximal reductions of 3.02 and 3.46 log(10) cfu/mL. Front-loaded regimens suppressed amplification of resistant subpopulations against VRE strains with no resistant alleles (MIC 4 mg/L) and postponed regrowth of resistant subpopulations against a VRE with 3.2 resistant alleles (MIC 4 mg/L). Modelling yielded excellent population fits (r = 0.934) and identified the number of sensitive alleles as a critical covariate. Conclusions Early, high-dose regimens of linezolid provided promising killing against selected susceptible strains and may be clinically beneficial if early bactericidal activity is necessary.

Novel oral regimens composed of new drugs with potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ≥ clofazimine ≥ rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further.

Tuberculosis (TB) has survived for millennia due to its unique physiochemical properties and its ability to persist in a "dormant" state. Because of these unique properties, the treatment of TB involves multiple drugs for half of a year or longer. Although the incidence of TB has declined in most developing countries, it remains poorly controlled in much of the developing world. This is partly driven by co-infection with HIV in these settings. Concern about this dual epidemic has renewed interest in anti-tuberculosis drugs, and this in turn has led to increasing amounts of pharmacokinetic data regarding TB drugs. Population pharmacokinetics has proven useful for many disease states, providing a valuable tool with which to explore data and predict future events. It not only generates pharmacokinetic parameter estimates, but it includes patient characteristics (covariates) that may alter those parameters. We review the population pharmacokinetic studies undertaken with anti-TB medications. In addition to the primary medications used in TB treatment (rifampin, isoniazid, pyrazinamide, and ethambutol) we discuss the fluoroquinolones, various software packages, and the covariates that were found to be significant in each study.

PA-824 is one of two nitroimidazoles in phase II clinical trials to treat tuberculosis. In mice, it has dose-dependent early bactericidal and sterilizing activity. In humans with tuberculosis, PA-824 demonstrated early bactericidal activity (EBA) at doses ranging from 200 to 1,200 mg per day, but no dose-response effect was observed. To better understand the relationship between drug exposure and effect, we performed a dose fractionation study in mice. Dose-ranging pharmacokinetic data were used to simulate drug exposure profiles. Beginning 2 weeks after aerosol infection with Mycobacterium tuberculosis , total PA-824 doses from 144 to 4,608 mg/kg were administered as 3, 4, 8, 12, 24, or 48 divided doses over 24 days. Lung CFU counts after treatment were strongly correlated with the free drug T >MIC ( R 2 = 0.87) and correlated with the free drug AUC/MIC ( R 2 = 0.60), but not with the free drug C max /MIC ( R 2 = 0.17), where T >MIC is the cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions and AUC is the area under the concentration-time curve. When the data set was limited to regimens with dosing intervals of ≤72 h, both the T >MIC and the AUC/MIC values fit the data well. Free drug T >MIC of 22, 48, and 77% were associated with bacteriostasis, a 1-log kill, and a 1.59-log kill (or 80% of the maximum observed effect), respectively. Human pharmacodynamic simulations based on phase I data predict 200 mg/day produces free drug T >MIC values near the target for maximal observed bactericidal effect. The results support the recently demonstrated an EBA of 200 mg/day and the lack of a dose-response between 200 and 1,200 mg/day. T >MIC , in conjunction with AUC/MIC, is the parameter on which dose optimization of PA-824 should be based.

Rifampin has concentration-dependent activity against Mycobacterium tuberculosis . However, marked intersubject variation of rifampin concentrations occurs. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of the human transporter genes SLCO1B1 , SLCO1B3 , and MDR1 . Seventy-two adults with pulmonary tuberculosis from Africa, North America, and Spain were evaluated during multidrug intensive-phase therapy, and their results were compared to those from 16 healthy controls from North America. Rifampin pharmacokinetic values were similar between tuberculosis patients and controls (geometric mean [GM] area under the concentration-time curve from 0 to 24 h [AUC 0-24 ] of 40.2 versus 40.9 μg·h/ml; P = 0.9). However, in multivariable analyses, the rifampin AUC 0-24 was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in the SLCO1B1 gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC 0-24 was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC 0-24 was also 36% lower among participants with SLCO1B1 genotype c.463CA than that among participants with SLCO1B1 genotype c.463CC (adjusted GM, 29.8 versus 46.7 μg·h/ml; P = 0.001). Polymorphisms in the SLCO1B1 gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC 0-24 values was observed, but the mean values of the AUC 0-24 did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the SLCO1B1 c.463C>A gene. When adjusted for the patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis, which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease.

Objectives In this study, we sought to compare the sterilizing activity of human-equivalent doses of the ‘Denver regimen’ against acute tuberculosis (TB) infection in the standard mouse model and in the guinea pig. Methods Pharmacokinetic studies in guinea pigs were used to establish human-equivalent doses for rifampicin, isoniazid and pyrazinamide. Guinea pigs and mice were aerosol-infected with Mycobacterium tuberculosis CDC1551 and treatment was started 2 weeks later with rifampicin/isoniazid/pyrazinamide for up to 6 months. For the first 2 weeks of therapy, the dosing frequency was 5 days/week, and for the remaining period, twice weekly. Treatment was discontinued in groups of 30 mice and 10 guinea pigs at 5 months and at 6 months, and these animals were held for a further 3 months in order to assess relapse rates. Results Guinea pig lungs became culture-negative after 3 months of predominantly twice-weekly treatment and relapse rates were 0% (0/10) both after 5 months and after 6 months of treatment. In contrast, all mice remained culture-positive despite 6 months of the same treatment, and 93% (28/30) and 69% (20/29) of mice relapsed after treatment for 5 and 6 months, respectively. Conclusions Treatment with rifampicin/isoniazid/pyrazinamide administered at human-equivalent doses is much more potent against acute TB infection in guinea pigs than in mice. Our findings have important implications for the use of alternative animal models in testing novel TB drug regimens and for modelling M. tuberculosis persistence.

This study evaluates the serum concentrations of rifampin (RMP), isoniazid (INH), and intestinal barrier function in patients with multidrug-resistant tuberculosis (MDR-TB), drug susceptible tuberculosis (DS-TB), and health volunteers (HC; controls). Peak serum concentrations of RMP were significantly lower in MDR-TB and DS-TB as compared with HC (odds ratio [OR] = 3.125, confidence interval [CI] [1.037-9.418] and OR = 4.025, CI [1.207-13.418], respectively). The INH peak serum concentration was not significantly different between MDR-TB versus DS-TB or DS-TB versus HC. The percent of mannitol excretion was significantly lower in the MDR-TB group compared with DS-TB (13.18 versus 16.03, analysis of covariance [ANCOVA], P = 0.0369) and compared with HC (13.18 versus 16.61, ANCOVA, P = 0.0291) the other study groups. These data suggested a lower peak serum concentration of RMP for both MDR-TB and DS-TB as compared with the HC group. The data also showed a lower intestinal area of absorption in patients with tuberculosis and even worse in MDR-TB.

Background. We explored the association between antituberculosis drug pharmacokinetics and treatment outcomes among patients with pulmonary tuberculosis in Botswana. Methods. Consenting outpatients with tuberculosis had blood samples collected 1, 2, and 6 h after simultaneous isoniazid, rifampin, ethambutol, and pyrazinamide ingestion. Maximum serum concentrations (Cmax) and areas under the serum concentration time curve were determined. Clinical status was monitored throughout treatment. Results. Of the 225 participants, 36 (16%) experienced poor treatment outcome (treatment failure or death); 155 (69%) were infected with human immunodeficiency virus (HIV). Compared with published standards, low isoniazid Cmax occurred in 84 patients (37%), low rifampin Cmax in 188 (84%), low ethambutol Cmax in 87 (39%), and low pyrazinamide Cmax in 11 (5%). Median rifampin and pyrazinamide levels differed significantly by HIV status and CD4 cell count category. Only pyrazinamide pharmacokinetics were significantly associated with treatment outcome; low pyrazinamide Cmax was associated with a higher risk of documented poor treatment outcome, compared with normal Cmax (50% vs. 16%; ). HIV-infected patients with a CD4 cell count !200 cells/mL P ! .01 had a higher risk of poor treatment outcome (27%) than did HIV-uninfected patients (11%) or HIV-infected patients with a CD4 cell count 200 cells/mL (12%; ). After adjustment for HIV infection and CD4 cell P p .01 count, patients with low pyrazinamide Cmax were 3 times more likely than patients with normal pyrazinamide Cmax to have poor outcomes (adjusted risk ratio, 3.38; 95% confidence interval, 1.84‐6.22). Conclusions. Lower than expected antituberculosis drug Cmax occurred frequently, and low pyrazinamide Cmax was associated with poor treatment outcome. Exploring the global prevalence and significance of these findings may suggest modifications in treatment regimens that could improve tuberculosis cure rates.

PURPOSE. To formulate rifampicin, an anti-tuberculosis antibiotic, for aerosol delivery in a dry powder ‘porous nanoparticle-aggregate particle’ (PNAP) form suited for shelf stability, effective dispersibility and extended release with local lung and systemic drug delivery. METHODS. Rifampicin was encapsulated in PLGA nanoparticles by a solvent evaporation process, spray dried into PNAPs containing varying amounts of nanoparticles, and characterized for physical and aerosol properties. Pharmacokinetic studies were performed with formulations delivered to guinea pigs by intratracheal insufflation and compared to oral and intravenous delivery of rifampicin. RESULT. The PNAP formulations possessed properties suitable for efficient deposition in the lungs. In vitro release showed an initial burst of rifampicin, with the remainder available for release beyond eight hours. PNAPs delivered to guinea pigs by insufflation achieved systemic levels of rifampicin detected for six to eight hours. Moreover, rifampicin concentrations remained detectable in lung tissue and cells up to and beyond eight hours. Conversely, after pulmonary delivery of an aerosol without nanoparticles, rifampicin could not be detected in the lungs at eight hours. CONCLUSIONS. Our results indicate that rifampicin can be formulated into an aggregated nanoparticle form that, once delivered to animals, achieves systemic exposure and extends levels of drug in the lungs.

We formulated PA-824, a nitroimidazopyran with promise for the treatment of tuberculosis, for efficient aerosol delivery to the lungs in a dry powder porous particle form. The objectives of this study were to prepare and characterize a particulate form of PA-824, assess the stability of this aerosol formulation under different environmental conditions, and determine the pharmacokinetic parameters for the powder after pulmonary administration. The drug was spray dried into porous particles containing a high drug load and possessing desirable aerosol properties for efficient deposition in the lungs. The physical, aerodynamic, and chemical properties of the dry powder were stable at room temperature for 6 months and under refrigerated conditions for at least 1 year. Pharmacokinetic parameters were determined in guinea pigs after the pulmonary administration of the PA-824 powder formulation at three doses (20, 40, and 60 mg/kg of body weight) and compared to those after the intravenous (20 mg/kg) and oral (40 mg/kg) delivery of the drug. Oral and inhaled delivery of PA-824 achieved equivalent systemic delivery at the same body dose within the first 12 h of dosing. However, animals dosed by the pulmonary route showed drug loads that remained locally in the lungs for 32 h postexposure, whereas those given the drug orally cleared the drug more rapidly. Therefore, we expect from these pharmacokinetic data that pulmonary delivery may achieve the same efficacy as oral delivery at the same body dose, with a potential improvement in efficacy related to pulmonary infection. This may translate into the ability to deliver lower body doses of this drug for the treatment of tuberculosis by aerosol.

Linezolid, the first oxazolidinone approved for clinical use, has effective in vitro and promising in vivo activity against Mycobacterium tuberculosis.To evaluate the early and extended early bactericidal activity of linezolid in patients with pulmonary tuberculosis.Randomized open label trial. Thirty patients with newly diagnosed smear-positive pulmonary tuberculosis (10 per arm) were assigned to receive isoniazid (300 mg daily) and linezolid (600 mg twice daily or 600 mg once daily) for 7 days. Sputum for quantitative culture was collected for 2 days before and then daily during 7 days of study drug administration. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (early bactericidal activity) and the last 5 days of study drug administration (extended early bactericidal activity).The mean early bactericidal activity of isoniazid (0.67 log10 cfu/ml/d) was greater than that of linezolid twice and once daily (0.26 and 0.18 log10 cfu/ml/d, respectively). The extended early bactericidal activity of linezolid between Days 2 and 7 was minimal.Linezolid has modest early bactericidal activity against rapidly dividing tubercle bacilli in patients with cavitary pulmonary tuberculosis during the first 2 days of administration, but little extended early bactericidal activity. Clinical trial registered with www.clinicaltrials.gov (NCT00396084).

Moxifloxacin- and rifapentine-based regimens are under investigation for the treatment of tuberculosis. However, rifapentine may induce enzymes that metabolize moxifloxacin, resulting in decreased moxifloxacin concentrations. In this phase I, two-period, sequential-design study, 13 subjects received 400 mg moxifloxacin daily for 4 days followed by daily moxifloxacin coadministered with 900 mg rifapentine thrice weekly. Pharmacokinetic analyses were performed after the 4th and 19th doses of moxifloxacin and after the 1st and 7th doses of rifapentine. For moxifloxacin, the mean area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) decreased by 17.2% ( P = 0.0006) when the drug was coadministered with rifapentine, and the mean half-life ( t 1/2 ) decreased from 11.1 to 8.9 h ( P = 0.0033). For rifapentine, the mean AUC 0-48 after seven thrice-weekly doses decreased by 20.3% ( P = 0.0035) compared to the AUC 0-48 after the first dose, and the mean t 1/2 decreased from 18.5 to 14.8 h ( P = 0.0004). The AUC 0-48 for the 25-desacetyl-rifapentine metabolite diminished 21%. Two days after completing the study drugs, one subject developed a fever and hepatitis, and another developed a flu-like illness with a rash. In conclusion, rifapentine modestly reduced moxifloxacin concentrations. Changes consistent with rifapentine autoinduction of metabolism were seen. Adverse reactions in two subjects may have represented rifamycin hypersensitivity syndrome, although some features were atypical.

Concomitant administration of azole antifungal agents and rifamycins is contraindicated because an interaction between these drugs results in subtherapeutic azole concentrations. We describe a 30-year-old woman with severe pulmonary disease associated with Mycobacterium xenopi and Aspergillus fumigatus, necessitating simultaneous antimycobacterial and antifungal therapy. She was treated with rifabutin-the rifamycin with the least cytochrome P450 (CYP) enzyme induction-and therapeutic drug monitoring was performed so that target serum concentrations of all antimicrobial agents could be achieved. As a result of this monitoring, the frequency of voriconazole 300 mg needed to be increased from twice/day to 3 times/day. The patient's clinical outcome improved dramatically. She was discharged from the hospital and continued treatment for her mycobacterial infection while remaining free of the Aspergillus infection. We believe that careful drug selection combined with therapeutic monitoring of antimicrobial drug serum concentrations is a practical model that clinicians can use to manage coexisting mycobacterial and fungal infections.

Previous structure-based design studies resulted in the discovery of alkyl substituted diphenyl ether inhibitors of InhA, the enoyl reductase from Mycobacterium tuberculosis. Compounds such as 5-hexyl-2-phenoxyphenol 19 are nM inhibitors of InhA and inhibit the growth of both sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis with MIC(90) values of 1-2 microg/mL. However, despite their promising in vitro activity, these compounds have ClogP values of over 5. In efforts to reduce the lipophilicity of the compounds, and potentially enhance compound bioavailability, a series of B ring analogues of 19 were synthesized that contained either heterocylic nitrogen rings or phenyl rings having amino, nitro, amide, or piperazine functionalities. Compounds 3c, 3e, and 14a show comparable MIC(90) values to that of 19, but have improved ClogP values.

The objective of this study was to determine the population pharmacokinetic parameters of levofloxacin, gatifloxacin, and moxifloxacin following multiple oral doses. Twenty-nine patients with tuberculosis at the University Hospital in Vitória, Brazil, participated. Subjects received multiple doses of one drug (levofloxacin, 1,000 mg daily, or gatifloxacin or moxifloxacin, 400 mg daily) as part of a 7-day study of early bactericidal activity. Serum samples were collected over 24 h after the fifth dose and assayed using validated high-performance liquid chromatography assays. Concentration-time data were analyzed using noncompartmental, compartmental, and population methods. The three drugs were well tolerated. Levofloxacin produced the highest maximum plasma concentrations (median, 15.55 μg/ml; gatifloxacin, 4.75 μg/ml; moxifloxacin, 6.13 μg/ml), largest volume of distribution (median, 81 liters; gatifloxacin, 79 liters; moxifloxacin, 63 liters), and longest elimination half-life (median, 7.4 h; gatifloxacin, 5.0 h; moxifloxacin, 6.5 h). A one-compartment model, with or without weight as a covariate, adequately described the data. Postmodeling simulations using median population parameter estimates closely approximated the median values from the original data. Area under the concentration-time curve/MIC ratios for free drug were high. All three quinolones showed favorable pharmacokinetic and pharmacodynamic indices, with the most favorable results in this population being seen with levofloxacin at the comparative doses used.

Objectives Use of proton pump inhibitors in HIV-infected patients is common. The purpose of this study was to determine the steady-state pharmacokinetics of once-daily (qd) fosamprenavir/ritonavir (FPV/r) and atazanavir/ritonavir (ATV/r) alone and in combination with 20 mg qd omeprazole (OMP) in healthy volunteers. Design and methods A prospective, open-label, single-site, two-period, crossover pharmacokinetic study was carried out in healthy volunteers. Subjects received either qd FPV/r 1400 mg/200 mg or ATV/r 300 mg/100 mg in the morning for 14 days and then 20 mg OMP in the evening for an additional 7 days. The pharmacokinetics were assessed over 24 h on days 14 and 21. Following a 2-week washout, subjects repeated the process with the other regimen. Trough protease inhibitor (PI) concentrations were taken on day 16 of each period to assess the impact of a single dose of OMP on ATV and amprenavir (APV) concentrations. Plasma ATV and APV pharmacokinetic parameters were assessed by noncompartmental analysis; geometric mean ratios (GMRs; PI+OMP/PI; 90% confidence interval) were calculated between days 14 and 21. Results Nineteen healthy, non-HIV-infected volunteers were evaluated. OMP reduced ATV exposure [area under the concentration curve at 0–24 h (AUC0–24 h)] and the minimum drug concentration (Cmin) by 27% each. In contrast, APV exposure and Cmin were decreased by 4 and 2%, respectively. Four subjects (21%) experienced greater than 50% declines in both ATV AUC0–24 h and Cmin after the addition of OMP; this was not observed in any subject following receipt of FPV/r. No alterations in APV or ATV trough concentrations were observed following a single dose of OMP. Conclusions The addition of 20 mg OMP administered in the evening has minimal effect on APV pharmacokinetics. In contrast, ATV pharmacokinetics were altered; a number of ATV-treated subjects experienced pronounced declines in exposures upon the addition of 20 mg OMP administered in the evening, whereas others experienced little to no change.

Treatment regimens combining moxifloxacin and rifampin for drug-susceptible tuberculosis are being studied intensively. However, rifampin induces enzymes that transport and metabolize moxifloxacin. We evaluated the effect of rifampin and the human multidrug resistance gene (MDR1) C3435T polymorphisms (P-glycoprotein) on moxifloxacin pharmacokinetic parameters. This was a single-center, sequential design study with 16 volunteers in which sampling was performed after four daily oral doses of moxifloxacin (400 mg) and again after 10 days of combined rifampin (600 mg) and moxifloxacin. After daily coadministration of rifampin, the area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) for moxifloxacin decreased 27%. Average bioequivalence between moxifloxacin coadministered with rifampin and moxifloxacin alone was not demonstrated: the ratio of geometric means (RGM) of the moxifloxacin AUC 0-24 was 73.3 (90% confidence intervals [CI], 64.3, 83.5) (total P value, 0.87 for two one-sided t tests). Peak moxifloxacin concentrations, however, were equivalent: the RGM of the maximum concentration of the drug in serum was 93.6 (90% CI, 80.2, 109.3) (total P value, 0.049). Concentrations of the sulfate conjugate metabolite of moxifloxacin were increased twofold following rifampin coadministration (AUC 0-24 , 1.29 versus 2.79 μg·h/ml). Concomitant rifampin administration resulted in a 27% decrease in the mean moxifloxacin AUC 0-24 and a marked increase in the AUC 0-24 of the microbiologically inactive M1 metabolite. Additional studies are required to understand the clinical significance of the moxifloxacin-rifampin interaction.

Received 22 May 2007; returned 15 June 2007; revised 25 June 2007; accepted 26 June 2007Objectives: Linezolid soft tissue penetration and serum antimicrobial activity were analysed in sixpatients with peripheral vascular disease and severe diabetic foot infections requiring surgical inter-vention.Methods: Blood draws (1, 3, 6, 9 and 12 h after initiation of a 1 h infusion) and a viable soft tissuesample at the site of infection were obtained in patients receiving linezolid (600 mg every 12 h) on theday of surgery. Concentrations of linezolid were determined by HPLC in both tissue (pre-treated withtissue lysis buffer) and serum. In addition, serum inhibitory and bactericidal activity (dilution titres1:2–1:32) of linezolid was determined in these patients against strains of methicillin-resistantStaphylococcus aureus (MRSA) with reduced susceptibility to vancomycin (vancomycin MICs 5 2, 4, 8,256 and >256 mg/L).Results: Linezolid concentrations in tissue were found to be 51% (range, 18% to 78%) of simultaneousserum concentrations. Rapid (1 h) and prolonged (12 h) inhibitory activity (titres 1:2) was observedfor linezolid against each of the study isolates. Furthermore, bactericidal activity (titres 1:2) wasobserved for at least 6 h (50% of the dosing interval) against four of these five strains.Conclusions: These findings suggest that linezolid could be effective in the treatment of multidrug-resistant MRSA even when concentrations at the infection site are diminished due to impaired blood flow.Keywords: pharmacokinetics, pharmacodynamics, diabetic foot infections

Background In the Federated States of Micronesia and then the Republic of the Marshall Islands (RMI), levofloxacin pharmacokinetics 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 disease or latent infection after multidrug-resistant tuberculosis exposure, to inform future dosing strategies. Methods Blood samples were collected at 0 (RMI only), 1, 2 and 6 hours (50 children, aged 6 months to 15 years) after oral levofloxacin at >6 weeks of treatment. Clinical characteristics and maximal drug concentration (Cmax) of levofloxacin, elimination half-life and area under the curve from 0 to 24 hours (AUC0-24 hours × μg/mL) were correlated to determine the optimal dosage and to examine associations. Population pharmacokinetics and target attainment were modeled. With results from the Federated States of Micronesia, dosages were increased in RMI toward the target Cmax for Mycobacterium tuberculosis, 8-12 µg/mL. Results Cmax correlated linearly with per-weight dosage. Neither Cmax nor half-life was associated with gender, age, body mass index, concurrent medications or predose meals. At levofloxacin dosage of 15-20 mg/kg, Cmax ≥8 µg/mL was observed, and modeling corroborated a high target attainment across the ratio of the area under the free concentration versus time curve to minimum inhibitory concentration (fAUCss,0-24/MIC) values. Conclusions Levofloxacin dosage should be 15-20 mg/kg for Cmax ≥8 µg/mL and a high target attainment across fAUCss,0-24/MIC values in children ≥2 years of age.

Background. Pharmacokinetic data on the first-line antituberculosis drugs using the World Health Organization (WHO) revised dosages for children are limited. We investigated the pharmacokinetics of these drugs in children who were mostly treated with revised dosages. Methods. Children with tuberculosis on first-line therapy for at least 4 weeks had blood samples collected at predose, 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography mass spectrometry methods, and pharmacokinetic parameters were calculated using noncompartmental analysis. Factors associated with plasma peak concentration (Cmax) and the area under the time–concentration curve 0–8 hours (AUC0–8h) of each drug was examined using univariate and multivariate analysis. Results. Of the 62 children, 32 (51.6%) were male, 29 (46.8%) wereyounger than 5 years old, and 28 (45.2%) had human immunodeficiency virus (HIV) coinfection. Three patients had undetectable pyrazinamide and ethambutol concentrations. The median (interquartile range) AUC0–8h for isoniazid was 17.7 (10.2–23.4) µg·h mL –1 , rifampin was 26.0 (15.3–36.1) µg·h mL –1 , pyrazinamide was 144.6 (111.5–201.2) µg·h mL –1 , and ethambutol was 6.7 (3.8–10.4) µg·h mL –1 . Of the children who received recommended weight-band dosages, 44/51 (86.3%), 46/56 (82.1%), 27/56 (48.2%), and 21/51 (41.2%) achieved target Cmax for isoniazid, pyrazinamide, ethambutol, and rifampin, respectively. In multivariate analysis, age, sex, HIV coinfection status, and drug dosage in milligrams per kilogram were associated with the drugs’ plasma drug Cmax or AUC0–8h. Conclusions. The revised dosages appeared to be adequate for isoniazid and pyrazinamide, but not for rifampin or ethambutol in this population. Higher dosages of rifampin and ethambutol than currently recommended may be required in most children.

The Columbia basin subpopulation of pygmy rabbit Brachylagus idahoensis was listed as endangered by the United States Fish and Wildlife Service in November 2001, and no pygmy rabbits have been seen in the wild since spring 2002. Captive propagation efforts have attempted to increase population size in preparation for reintroduction of animals into central Washington. Disseminated mycobacteriosis due to Mycobacterium avium has been the most common cause of death of adult captive pygmy rabbits. Between June 2002 and September 2004, mycobacteriosis was diagnosed in 28 captive adult pygmy rabbits (representing 29% of the captive population), in contrast to 18 adult pygmy rabbits dying of all other causes in the same time period. Antemortem and postmortem medical records were evaluated retrospectively to describe the clinical course of mycobacteriosis in pygmy rabbits, physical examination findings, and diagnostic test results in the diagnosis of mycobacteriosis in pygmy rabbits. Various treatment protocols, possible risk factors for mortality, and recommendations for prevention of mycobacteriosis were evaluated also. Compromised cell-mediated immunity appears to be the best explanation at this time for the observed high morbidity and mortality from mycobacterial infections in pygmy rabbits.

Drug-induced liver injury (DILI) is a problem of increasing significance, but has been a long-standing concern in the treatment of tuberculosis (TB) infection. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of DILI are presented, ranging from hepatic adaptation to hepatocellular injury. Knowledge of the metabolism of anti-TB medications and of the mechanisms of TB DILI is incomplete. Understanding of TB DILI has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demographic groups, and in those coinfected with HIV or hepatitis B or C virus are presented. Systematic steps for prevention and management of TB DILI are recommended. These include patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent TB infection (LTBI) alanine aminotransferase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT, have experienced prior isoniazid hepatitis, are pregnant or are within 3 months postpartum. During treatment of TB disease, in addition to these individuals, patients with HIV infection should have ALT monitoring. Some experts recommend biochemical monitoring for those older than 35 years. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or five times the ULN in the absence of symptoms. Priorities for future studies to develop safer treatments for LTBI and for TB disease are presented.

The creation of new chemotherapeutic regimens that permit shortening the duration of treatment is a major priority for antituberculosis drug development. In this study, we used the murine model of experimental tuberculosis therapy to determine whether incorporation of the investigational new nitroimidazopyran PA-824 into the standard first-line regimen has the potential to shorten the 6-month duration of treatment. As demonstrated previously, PA-824 alone had significant bactericidal activity over the first 2 months of treatment. Moreover, the substitution of PA-824 for isoniazid led to significantly lower lung CFU counts after 2 months of treatment and to more rapid culture-negative conversion compared to the standard regimen of rifampin, isoniazid, and pyrazinamide. Despite this, there was no difference in the proportion of mice relapsing after completing 6 months of therapy (2 of 19 mice treated with PA-824 in place of isoniazid relapsed versus 0 of 46 mice treated with the standard regimen). Meanwhile, no other PA-824-containing regimen tested was superior to the standard regimen on any assessment. Thus, we were unable to establish a clear role for PA-824 in a treatment-shortening regimen that includes two or more of the current first-line drugs. Future preclinical studies should include the evaluation of novel combinations of PA-824 with new drug candidates in addition to existing antituberculosis drugs for their potential to substantially improve the treatment of both drug-susceptible and multidrug-resistant tuberculosis.

Rationale: Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin. Methods: To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus isoniazid-based regimens to those of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single- and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined. Results: After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg). Conclusions: By virtue of the enhanced rifamycin exposure, twice-weekly regimens containing rifapentine (15 or 20 mg/kg) may permit shortening the current treatment duration by 2 mo. Such regimens warrant clinical investigation.

Background: Linezolid is being used increasingly for life-threatening vancomycin-resistant infections in critically ill patients. Limited data suggest that linezolid is cleared by intermittent hemodialysis. However, information on clearance of linezolid by continuous renal replacement therapy is limited. A patient undergoing continuous venovenous hemodiafiltration (CVVHDF) was evaluated to determine linezolid clearance through CVVHDF. Methods: A 33-year-old man with necrotizing fasciitis and acute-on-chronic renal failure requiring CVVHDF was treated with linezolid, 600 mg every 12 hours, for a vancomycin-resistant urinary tract infection. The study was performed on day 4 of therapy after a 1-hour infusion of linezolid. A series of blood samples and all urine and diafiltrate were collected during a 12-hour period. Linezolid concentrations were determined by using high-performance liquid chromatography assay. Linezolid clearance through CVVHDF was determined by using 2 methods. Method 1 evaluated the amount of drug recovered in diafiltrate. Method 2 evaluated plasma drug concentrations in prefilter and postfilter (PAN-10 Hemofilter; Asahi Medical Co, Tokyo, Japan) samples. Results: Clearance of linezolid through CVVHDF was 15.6 mL/min by method 1 and 21.6 mL/min by method 2. Total-body clearance was 189 mL/min. The amount of linezolid recovered in diafiltrate was 50 mg (8.3% of the dose). Conclusion: Clearance of linezolid through CVVHDF in this patient was marginal. It does not appear that supplemental dosing of linezolid is necessary in patients undergoing CVVHDF.

The objective of this article was to determine the current practice on amikacin dosing and monitoring in spinal cord injury patients from spinal cord physicians and experts. Physicians from spinal units and clinical pharmacologists were asked to provide protocol for dosing and monitoring of amikacin therapy in spinal cord injury patients. In a spinal unit in Poland, amikacin is administered usually 0.5 g twice daily. A once-daily regimen of amikacin is never used and amikacin concentrations are not determined. In Belgium, Southport (U.K.), Spain, and the VA McGuire Medical Center (Richmond, Virginia), amikacin is given once daily. Whereas peak and trough concentrations are determined in Belgium, only trough concentration is measured in Southport. In both these spinal units, modification of the dose is not routinely done with a nomogram. In Spain and the VA McGuire Medical Center, monitoring of serum amikacin concentration is not done unless a patient has renal impairment. In contrast, the dose/interval of amikacin is adjusted according to pharmacokinetic parameters at the Edward Hines VA Hospital (Hines, Illinois), where amikacin is administered q24h or q48h, depending on creatinine clearance. Spinal cord physicians from Denmark, Germany, and the Kessler Institute for Rehabilitation (West Orange, New Jersey) state that they do not use amikacin in spinal injury patients. An expert from Canada does not recommend determining serum concentrations of amikacin, but emphasizes the value of monitoring ototoxicity and nephrotoxicity. Experts from New Zealand recommend amikacin in conventionaltwice- orthrice-dailydosing because of the theoretical increased risk of neuromuscular blockade and apnea with larger daily doses in spinal cord injury patients. On the contrary, experts from Greece, Israel, and the U.S. recommend once-daily dosing and determining amikacin pharmacokinetic parameters for each patient. As there is considerable variation in clinical practice across spinal units and experts differ on ideal dosing and monitoring of amikacin therapy in spinal cord injury patients, there is an urgent need to develop best-practice guidelines.