Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-11 (of 11 Records) |
Query Trace: Peloquin CA[original query] |
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Implementation of BPaL in the United States: Experience using a novel all-oral treatment regimen for treatment of rifampin-resistant or rifampin-intolerant TB disease
Haley CA , Schechter MC , Ashkin D , Peloquin CA , Cegielski JP , Andrino BB , Burgos M , Caloia LA , Chen L , Colon-Semidey A , DeSilva MB , Dhanireddy S , Dorman SE , Dworkin FF , Hammond-Epstein H , Easton AV , Gaensbauer JT , Ghassemieh B , Gomez ME , Horne D , Jasuja S , Jones BA , Kaplan LJ , Khan AE , Kracen E , Labuda S , Landers KM , Lardizabal AA , Lasley MT , Letzer DM , Lopes VK , Lubelchek RJ , Macias CP , Mihalyov A , Misch EA , Murray JA , Narita M , Nilsen DM , Ninneman MJ , Ogawa L , Oladele A , Overman M , Ray SM , Ritger KA , Rowlinson MC , Sabuwala N , Schiller TM , Schwartz LE , Spitters C , Thomson DB , Tresgallo RR , Valois P , Goswami ND . Clin Infect Dis 2023 77 (7) 1053-1062 BACKGROUND: Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons initiate treatment and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, six-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200 mg linezolid. After U.S. FDA approval in 2019, some U.S. clinicians rapidly implemented BPaL using an initial linezolid 600 mg dose adjusted by serum drug concentrations and clinical monitoring. METHODS: Data from U.S. patients treated with BPaL between 10/14/2019 and 4/30/2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider-driven, and most had linezolid adjusted by therapeutic drug monitoring (TDM). RESULTS: Of 70 patients starting BPaL, two changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and two of these 68 (2.9%) patients relapsed after completion. Using an initial 600 mg linezolid dose daily adjusted by TDM and careful clinical and laboratory monitoring for side effects, supportive care, and expert consultation throughout BPaL treatment, three (4.4%) patients with hematologic toxicity and four (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months. CONCLUSIONS: BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in ATS/CDC/ERS/IDSA 2019 guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the U.S. is feasible. |
Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA Clinical Practice Guideline
Nahid P , Mase SR , Migliori GB , Sotgiu G , Bothamley GH , Brozek JL , Cattamanchi A , Cegielski JP , Chen L , Daley CL , Dalton TL , Duarte R , Fregonese F , Horsburgh CR Jr , Ahmad Khan F , Kheir F , Lan Z , Lardizabal A , Lauzardo M , Mangan JM , Marks SM , McKenna L , Menzies D , Mitnick CD , Nilsen DM , Parvez F , Peloquin CA , Raftery A , Schaaf HS , Shah NS , Starke JR , Wilson JW , Wortham JM , Chorba T , Seaworth B . Am J Respir Crit Care Med 2019 200 (10) e93-e142 Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided.Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB. |
Elevated Plasma Moxifloxacin Concentrations and SLCO1B1 g.-11187G>A Polymorphism in Adults with Pulmonary Tuberculosis.
Weiner M , Gelfond J , Johnson-Pais TL , Engle M , Peloquin CA , Johnson JL , Sizemore EE , Mac Kenzie WR . Antimicrob Agents Chemother 2018 62 (5) Moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and bactericidal activity against Mycobacterium tuberculosis However, moxifloxacin plasma concentrations are variable between patients. We evaluated whether human gene polymorphisms affect moxifloxacin plasma concentrations in tuberculosis patients from two geographic regions. We enrolled a convenience sample of 49 adults with drug-sensitive pulmonary tuberculosis from Africa and the United State s enrolled in two treatment trials of moxifloxacin as part of multidrug therapy. Pharmacokinetic parameters were evaluated by noncompartmental techniques. Human single-nucleotide polymorphisms of transporter genes were evaluated with analysis of covariance on moxifloxacin exposure and peak concentration (Cmax). Moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC0-24) and Cmax were significantly increased by drug mg/kg dosage and genotype of variant g.-11187G>A in the SLCO1B1 gene (rs4149015), but not by geographic region. Median moxifloxacin AUC0-24 was 46% higher and Cmax 30% higher in 4 (8% of) participants who had the SLCO1B1 g.-11187 AG genotype compared with 45 participants who had the wild type GG genotype (median from model, AUC0-24 34.4 vs. 23.6 mug*h/mL, P =.005; Cmax 3.5 vs. 2.7 mug/mL, P =.009, ANCOVA). Because moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals, and prolonged QTc intervals are associated with cardiac arrhythmia, further study is needed to evaluate risk associated with the SLCO1B1 g.-11187G>A variant. |
Population pharmacokinetics of pyrazinamide in patients with tuberculosis
Alsultan A , Savic R , Dooley KE , Weiner M , Whitworth W , Mac Kenzie WR , Peloquin CA . Antimicrob Agents Chemother 2017 61 (6) 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 TB treatment duration, if optimized. The goals of this study were (a) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK sub-studies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28, and (b) to determine covariates that affect PZA PK. We also (c) performed simulations and target attainment analysis using the proposed targets of Cmax >35 mcg/ml or AUC >363 mcg*hr/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the sub-studies. The mean (standard deviation, SD) maximum plasma concentration (Cmax) was 30.8 (7.4) mcg/ml, and the area under the concentration-versus-time curve (AUC0-24) was 307 mcg*hr/ml (83). A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower V/F compared to men, and both Cl/F and V/F increased with body weight. Our simulations show that higher doses for PZA (>50mg/kg) are needed to achieve the therapeutic target of AUC/MIC >11.3 in >80% of patients, while doses >80mg/kg are needed for 90% target attainment, given specific assumptions about MIC determinations. For the therapeutic targets of Cmax >35 mcg/ml and/or AUC >363 mcg*hr/ml, doses in the range of 30-40 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 for PZA.Reference in this manuscript to any specific commercial product, process, service, manufacturer, or company does not constitute endorsement or recommendation by the U.S. Government or CDC. The findings and conclusions are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. |
Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase 2 clinical trials
Savic RM , Weiner M , Mac Kenzie WR , Engle M , Whitworth WC , Johnson JL , Nsubuga P , Nahid P , Nguyen NV , Peloquin CA , Dooley KE , Dorman SE . Clin Pharmacol Ther 2017 102 (2) 321-331 Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses. |
Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of drug-susceptible tuberculosis
Nahid P , Dorman SE , Alipanah N , Barry PM , Brozek JL , Cattamanchi A , Chaisson LH , Chaisson RE , Daley CL , Grzemska M , Higashi JM , Ho CS , Hopewell PC , Keshavjee SA , Lienhardt C , Menzies R , Merrifield C , Narita M , O'Brien R , Peloquin CA , Raftery A , Saukkonen J , Schaaf HS , Sotgiu G , Starke JR , Migliori GB , Vernon A . Clin Infect Dis 2016 63 (7) 853-67 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. |
Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of drug-susceptible tuberculosis
Nahid P , Dorman SE , Alipanah N , Barry PM , Brozek JL , Cattamanchi A , Chaisson LH , Chaisson RE , Daley CL , Grzemska M , Higashi JM , Ho CS , Hopewell PC , Keshavjee SA , Lienhardt C , Menzies R , Merrifield C , Narita M , O'Brien R , Peloquin CA , Raftery A , Saukkonen J , Schaaf HS , Sotgiu G , Starke JR , Migliori GB , Vernon A . Clin Infect Dis 2016 63 (7) e147-e195 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. |
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
Mase SR , Jereb JA , Gonzalez D , Martin F , Daley CL , Fred D , Loeffler A , Menon L , Morris SB , Brostrom R , Chorba T , Peloquin CA . Pediatr Infect Dis J 2015 35 (4) 414-21 BACKGROUND: 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. 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 levofloxacin Cmax, elimination half-life (t1/2), and area under the curve from 0 to 24 hours (AUC0-24 hours * microg/mL) were correlated to determine optimal dosage and to examine associations. Population PK and target attainment were modeled. With results from FSM, dosages were increased in RMI toward the target maximal drug concentration (Cmax) for Mycobacterium tuberculosis, 8-12 microg/ml. RESULTS: Cmax correlated linearly with per-weight dosage. Neither Cmax nor t1/2 was associated with gender, age, body mass index, concurrent medications, or pre-dose meals. At levofloxacin dosage of 15-20 mg/kg, Cmax ≥ 8 microg/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 microg/ml and a high target attainment across fAUCss,0-24/MIC values in children ≥2 years of age. |
Rifapentine pharmacokinetics and tolerability in children and adults treated once weekly with rifapentine and isoniazid for latent tuberculosis infection
Weiner M , Savic RM , Mac Kenzie WR , Wing D , Peloquin CA , Engle M , Bliven E , Prihoda TJ , Gelfond JAL , Scott NA , Abdel-Rahman SM , Kearns GL , Burman WJ , Sterling TR , Villarino ME . J Pediatric Infect Dis Soc 2014 3 (2) 132-145 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 concentrationtime 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. |
Protein binding of rifapentine and the 25-desacetyl metabolite in patients with pulmonary tuberculosis
Egelund EF , Weiner M , Singh RP , Prihoda TJ , Gelfond JA , Derendorf H , Mac Kenzie WR , Peloquin CA . Antimicrob Agents Chemother 2014 58 (8) 4904-10 Rifapentine is highly protein bound in blood, but the free, unbound drug is the microbiologically active fraction. In this exploratory study, we characterized the free plasma fraction of rifapentine in 41 patients with tuberculosis. We found lower total rifapentine concentration but significantly higher free rifapentine in African patients of Black race compared to non-Africans. These data support larger pharmacokinetic/pharmacodynamic studies to confirm these findings and assess free rifapentine in relation to microbiological and clinical outcomes. |
Pharmacokinetic interaction of rifapentine and raltegravir in healthy volunteers
Weiner M , Egelund EF , Engle M , Kiser M , Prihoda TJ , Gelfond JA , Mac Kenzie W , Peloquin CA . J Antimicrob Chemother 2014 69 (4) 1079-85 OBJECTIVES: Latent tuberculosis infection and tuberculosis disease are prevalent worldwide. However, antimycobacterial rifamycins have drug interactions with many antiretroviral drugs. We evaluated the effect of rifapentine on the pharmacokinetic properties of raltegravir. METHODS: In this open-label, fixed-sequence, three-period study, 21 healthy volunteers were given: raltegravir alone (400 mg every 12 h for 4 days) on days 1-4 of Period 1; rifapentine (900 mg once weekly for 3 weeks) on days 1, 8 and 15 of Period 2 and raltegravir (400 mg every 12 h for 4 days) on days 12-15 of Period 2; and rifapentine (600 mg once daily for 10 scheduled doses) on days 1, 4-8 and 11-14 of Period 3 and raltegravir (400 mg every 12 h for 4 days) on days 11-14 of Period 3. Plasma raltegravir concentrations were measured. ClinicalTrials.gov database: NCT00809718. RESULTS: In 16 subjects who completed the study, coadministration of raltegravir with rifapentine (900 mg once weekly; Period 2) compared with raltegravir alone resulted in the geometric mean of the raltegravir AUC from 0 to 12 h (AUC0-12) being increased by 71%; the peak concentration increased by 89% and the trough concentration decreased by 12%. Coadministration of raltegravir with rifapentine in Period 3 did not change the geometric mean of the raltegravir AUC0-12 or the peak concentration, but it decreased the trough concentration by 41%. Raltegravir coadministered with rifapentine was generally well tolerated. CONCLUSIONS: The increased raltegravir exposure observed with once-weekly rifapentine was safe and tolerable. Once-weekly rifapentine can be used with raltegravir to treat latent tuberculosis infection in patients who are infected with HIV. |
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