Posaconazole: An Oral Triazole with an Extended Spectrum of Activity

2008 ◽  
Vol 42 (10) ◽  
pp. 1429-1438 ◽  
Author(s):  
Erik J Rachwalski ◽  
Jeffrey T Wieczorkiewicz ◽  
Marc H Scheetz
Keyword(s):  
English Language ◽  
Fungal Infections ◽  
Data Extraction ◽  
Treatment Options ◽  
Drug Application ◽  
Invasive Fungal Infections ◽  
Therapeutic Drug ◽  
Hematopoietic Stem ◽  
Yeasts And Molds

Objective: To summarize the published clinical data on posaconazole, critically review the New Drug Application data submitted to the Food and Drug Administration, and provide information critical for evaluation and formulary positioning. Data Sources: Reported investigations were identified from MEDLINE (1966-June 30, 2008), bibliographies of manuscripts, www.clinicaltrials.gov , and www.fda.gov . Study Selection and Data Extraction: English-language articles were selected. AN available in vitro, animal, clinical, and human studies describing the pharmacology, pharmacokinetics, pharmacodynamics, efficacy, safety, and adverse events of posaconazole were reviewed. Data Synthesis: Posaconazole is an oral broad-spectrum triazole with activity against many yeasts and molds. Resistance to posaconazole has been reported, but has been rare to date. Posaconazole, in doses of 200 mg 3 limes daily, reduced breakthrough invasive fungal infections (OR 0.30; 95% CI 0.12 to 0.71) and aspergillosis incidence (OR 0.31; 95% CI 0.13 to 0.75) in patients receiving hematopoietic stem-cell transplants compared with those receiving fluconazole. Similarly, the same regimen of posaconazole reduced invasive fungal infections (95% CI -9.7 to -2.5) and aspergillosis (CI not reported, p < 0.001) when compared with fluconazole and itraconazole in neutropenic patients. Posaconazole is non-inferior to fluconazole for treatment of oropharyngeal candidiasis (95% CI -6.6 to 5.0), but necessity for this indication remains unclear, as many other treatment options exist. Smaller investigations have analyzed use of posaconazole for patients requiring salvage or alternative treatment for zygomycosis, fusarbsis, cryptococcal meningitis, coccidioidomycosis, and histoplasmosis. Studies are needed to clarify efficacy for such expanded use, and therapeutic drug monitoring may improve outcomes. The most common adverse effects associated with the use of posaconazole include headache, fever, nausea, vomiting, and diarrhea. Conclusions: Posaconazole appears to be a valuable and promising addition to the antifungal armamentarium for prophylaxis and treatment of various fungal processes. At this time, posaconazole should probably be reserved for prophylaxis in patients at high risk for invasive fungal infection, as salvage therapy in refractory or resistant infections, or for patients with intolerance to other therapies.

Telavancin: A Novel Lipoglycopeptide Antibiotic

2009 ◽  
Vol 43 (5) ◽  
pp. 928-938 ◽  
Author(s):  
Lisa Charneski ◽  
Priti N Patel ◽  
Donna Sym
Keyword(s):  
English Language ◽  
Data Extraction ◽  
Anaerobic Bacteria ◽  
Drug Application ◽  
Qtc Interval ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Complicated Skin

Objective To review the pharmacology, antimicrobial activity, pharmacokinetics, clinical applications, and safety of telavancin, a new lipoglycopeptide antibiotic. Data Sources Literature was obtained from MEDLINE (1966–April 2009) and International Pharmaceutical Abstracts (1971–April 2009) using the search terms telavancin and TD-6424, and also from Theravance, Inc., and Astellas Pharma US, Inc. Study Selection And Data Extraction Available English-language articles were reviewed, as well as information obtained from Theravance, Inc., and Astellas Pharma US, Inc. Data Synthesis Telavancin has rapid bactericidal activity against gram-positive aerobic and anaerobic bacteria through multiple mechanisms of action. In vitro and Phase 2 in vivo data support the efficacy of telavancin against antibiotic-resistant gram-positive organisms. On March 4, 2008, the Food and Drug Administration (FDA) accepted as complete for review Theravance's response to the October 19, 2007, New Drug Application approvable letter for telavancin to be used as treatment for complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria. QTc interval prolongation has been reported, although the clinical impact of this has not been determined. Drug interactions have not been identified as of yet. Conclusions Telavancin is currently under review by the FDA for the treatment of cSSSIs caused by gram-positive bacteria. The completion of Phase 3 trials will determine whether telavancin will have a role in the treatment of other infections caused by resistant gram-positive bacteria.

scholarly journals 1733. Voriconazole Prophylaxis Following Allogeneic Hematopoietic Stem Cell Transplant: How Much Is Enough, Are Low Voriconazole Levels Associated With Opportunistic Infections, and What Are the Reasons for Discontinuation?

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S635-S635
Author(s):  
Giorgos Hadjivassiliou ◽  
Claire Rummage ◽  
Craig Hoesley ◽  
Matthew L Brown
Keyword(s):  
Stem Cell ◽  
Therapeutic Drug Monitoring ◽  
Hematopoietic Stem Cell ◽  
Drug Monitoring ◽  
Fungal Infections ◽  
Invasive Fungal Infections ◽  
Therapeutic Drug ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Subtherapeutic Level

Abstract Background Patients who undergo allogeneic hematopoietic stem cell transplantation (alloHSCT) are at increased risk for invasive fungal infections with associated high morbidity and mortality that necessitates the use of prophylactic antifungals. Voriconazole is commonly used for prophylaxis, but there are no recommendations for therapeutic drug monitoring. The purpose of this study was to characterize voriconazole therapeutic drug monitoring and associated outcomes in this patient population. Methods AlloHSCT patients receiving voriconazole prophylaxis at the University of Alabama at Birmingham Hospital between March 2015 and March 2018 were included in the analysis. Serum voriconazole levels (SVL) were evaluated to determine what percentage of patients achieved prophylactic or therapeutic concentrations. Incidence of invasive fungal infections (IFI) and voriconazole discontinuation was also assessed. Results Voriconazole prophylaxis was used in 151 of 162 alloHSCT patients, and 120 patients (79%) had SVL drawn correctly (≥4 days after initiation of course). We found that 35 (29%) patients achieved a subtherapeutic level (<0.5 μg/mL), 17 (14%) prophylactic level (0.5 to 1 μg/mL), 68 (57%) therapeutic level (1 to 5.5 μg/mL), and no patients achieved a supratherapeutic level (level ≥5.5 μg/mL). Voriconazole prophylaxis was discontinued early in 60 of 151 patients. Most common etiologies for discontinuation included liver function test abnormalities (44%) and encephalopathy (21%). The average SVL was 1.2 μg/mL in those requiring discontinuation. Four patients (3%) developed an IFI while receiving prophylactic voriconazole, of which only 1 had subtherapeutic level. Conclusion Even though approximately one-third of patients achieved a subtherapeutic SVL, there was no correlation with breakthrough IFI. There was also no linear correlation between SVL and risk of adverse effects requiring discontinuation. Our observational data do not support a need for therapeutic drug monitoring in alloHSCT patients receiving prophylactic voriconazole. Disclosures All authors: No reported disclosures.

scholarly journals Software for Dosage Individualization of Voriconazole for Immunocompromised Patients

2013 ◽  
Vol 57 (4) ◽  
pp. 1888-1894 ◽  
Author(s):  
William W. Hope ◽  
Michael VanGuilder ◽  
J. Peter Donnelly ◽  
Nicole M. A. Blijlevens ◽  
Roger J. M. Brüggemann ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Cell Transplant ◽  
Multiple Model ◽  
Pharmacokinetic Variability ◽  
Hematopoietic Stem ◽  
Wide Range

ABSTRACTThe efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.

Treatment Options for Rheumatoid Arthritis: Celecoxib, Leflunomide, Etanercept, and Infliximab

2000 ◽  
Vol 34 (6) ◽  
pp. 743-760 ◽  
Author(s):  
Brigitte T Luong ◽  
Barbara S Chong ◽  
Dionne M Lowder
Keyword(s):  
Rheumatoid Arthritis ◽  
English Language ◽  
Data Extraction ◽  
Treatment Options ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Antiinflammatory Drugs ◽  
Safety And Efficacy ◽  
Medline Search ◽  
Pertinent Data

OBJECTIVE: To review new pharmacologic agents approved for use in the management of rheumatoid arthritis (RA). DATA SOURCES: A MEDLINE search (1966–January 2000) was conducted to identify English-language literature available on the pharmacotherapy of RA, focusing on celecoxib, leflunomide, etanercept, and infliximab. These articles, relevant abstracts, and data provided by the manufacturers were used to collect pertinent data. STUDY SELECTION: All controlled and uncontrolled trials were reviewed. DATA EXTRACTION: Agents were reviewed with regard to mechanism of action, efficacy, drug interactions, pharmacokinetics, dosing, precautions/contraindications, adverse effects, and cost. DATA SYNTHESIS: Traditional pharmacologic treatments for RA have been limited by toxicity, loss of efficacy, or both. Increasing discoveries into the mechanisms of inflammation in RA have led to the development of new agents in hopes of addressing these limitations. With the development of celecoxib, a selective cyclooxygenase-2 inhibitor, the potential exists to minimize the gastrotoxicity associated with nonsteroidal antiinflammatory drugs. Leflunomide has been shown to be equal to or less efficacious than methotrexate, and may be beneficial as a second-line disease-modifying antirheumatic drug (DMARD). The biologic response modifiers, etanercept and infliximab, are alternatives that have shown benefit alone or in combination with methotrexate. However, they should be reserved for patients who fail to respond to DMARD therapy. Further studies should be conducted to evaluate the long-term safety and efficacy of these agents as well as their role in combination therapy. CONCLUSIONS: Celecoxib, leflunomide, etanercept, and infliximab are the newest agents approved for RA. Clinical trials have shown that these agents are beneficial in the treatment of RA; however, long-term safety and efficacy data are lacking.

Therapeutic Drug Monitoring of Voriconazole in the Management of Invasive Fungal Infections: A Critical Review

2015 ◽  
Vol 54 (12) ◽  
pp. 1223-1235 ◽  
Author(s):  
Hazem Elewa ◽  
Eman El-Mekaty ◽  
Ahmed El-Bardissy ◽  
Mary H. H. Ensom ◽  
Kyle John Wilby
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Critical Review ◽  
Fungal Infections ◽  
Invasive Fungal Infections ◽  
Therapeutic Drug

scholarly journals Cost Analysis of the Use of Voriconazole, Posaconazole and Micafungin in the Primary Prophylaxis of Invasive Fungal Infections in Recipients of Allogeneic Hematopoietic Stem Cell Transplants

10.36469/9832 ◽  
2015 ◽  
Vol 3 (2) ◽  
pp. 153-161
Author(s):  
Santiago Grau ◽  
Carlos Solano ◽  
Carol García-Vidal ◽  
Isidro Jarque ◽  
Jon A. Barrueta ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cost Analysis ◽  
Hematopoietic Stem Cell ◽  
Fungal Infections ◽  
Primary Prophylaxis ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Efficacy Rate ◽  
Hematopoietic Stem ◽  
The Cost

Objectives: Compare the cost of the primary prophylaxis of invasive fungal infections (IFI) with voriconazole, posaconazole, and micafungin in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in hospitals of the National Health System (NHS) in Spain. Methods: A cost analysis was made for 100 days and 180 days of prophylaxis and a decision tree model was developed. The efficacy rate of IFI prophylaxis and survival rate with liposomal amphotericin B treatment of prophylaxis failures were obtained from randomized trials and a meta-analysis of mixed treatment comparisons. The model simulation was interrupted with IFI treatment (prophylaxis failures). The costs of medication and its intravenous administration in the hospital (in the case of micafungin) were considered. Results: In the non-modeled analysis, the savings per patient of prophylaxis with voriconazole ranged from €1,709 to €9,655 compared with posaconazole oral solution, from €1,811 to €9,767 compared with posaconazole gastro-resistant tablets and from €3,376 to €7,713 compared with micafungin. In the modeled analysis, the mean cost per patient of the prophylaxis and treatment of IFIs was €6,987 to €7,619 with voriconazole, €7,749 with posaconazole, and €22,424 with micafungin. Therefore, the savings per patient of prophylaxis with voriconazole was €130 to €3,664 and €11,132 to €30,374 compared with posaconazole and micafungin, respectively. The result remained stable after modification of the number of days of antifungal prophylaxis and the cost of antifungal treatment of failures. Conclusion: Taking into account this model, antifungal prophylaxis with voriconazole in recipients of hematopoietic progenitor transplants, compared with posaconazole or micafungin, may represent savings for hospitals in Spain.

scholarly journals Recent Advances in Therapeutic Drug Monitoring of Voriconazole, Mycophenolic Acid, and Vancomycin: A Literature Review of Pediatric Studies

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 1991
Author(s):  
Matylda Resztak ◽  
Joanna Sobiak ◽  
Andrzej Czyrski
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Mycophenolic Acid ◽  
Drug Monitoring ◽  
Pediatric Patients ◽  
Fungal Infections ◽  
Cord Blood Transplantation ◽  
Active Form ◽  
Therapeutic Drug ◽  
Hematopoietic Stem ◽  
Acute Kidney Disease

The review includes studies dated 2011–2021 presenting the newest information on voriconazole (VCZ), mycophenolic acid (MPA), and vancomycin (VAN) therapeutic drug monitoring (TDM) in children. The need of TDM in pediatric patients has been emphasized by providing the information on the differences in the drugs pharmacokinetics. TDM of VCZ should be mandatory for all pediatric patients with invasive fungal infections (IFIs). Wide inter- and intrapatient variability in VCZ pharmacokinetics cause achieving and maintaining therapeutic concentration during therapy challenging in this population. Demonstrated studies showed, in most cases, VCZ plasma concentrations to be subtherapeutic, despite the updated dosages recommendations. Only repeated TDM can predict drug exposure and individualizing dosing in antifungal therapy in children. In children treated with mycophenolate mofetil (MMF), similarly as in adult patients, the role of TDM for MMF active form, MPA, has not been well established and is undergoing continued debate. Studies on the MPA TDM have been carried out in children after renal transplantation, other organ transplantation such as heart, liver, or intestine, in children after hematopoietic stem cell transplantation or cord blood transplantation, and in children with lupus, nephrotic syndrome, Henoch-Schönlein purpura, and other autoimmune diseases. MPA TDM is based on the area under the concentration–time curve; however, the proposed values differ according to the treatment indication, and other approaches such as pharmacodynamic and pharmacogenetic biomarkers have been proposed. VAN is a bactericidal agent that requires TDM to prevent an acute kidney disease. The particular group of patients is the pediatric one. For this group, the general recommendations of the dosing may not be valid due to the change of the elimination rate and volume of distribution between the subjects. The other factor is the variability among patients that concerns the free fraction of the drug. It may be caused by both the patients’ population and sample preconditioning. Although VCZ, MMF, and VAN have been applied in pediatric patients for many years, there are still few issues to be solve regarding TDM of these drugs to ensure safe and effective treatment. Except for pharmacokinetic approach, pharmacodynamics and pharmacogenetics have been more often proposed for TDM.

Meropenem/Vaborbactam, the First Carbapenem/β-Lactamase Inhibitor Combination

2018 ◽  
Vol 52 (8) ◽  
pp. 769-779 ◽  
Author(s):  
Jonathan C. Cho ◽  
Monika T. Zmarlicka ◽  
Kristy M. Shaeer ◽  
Joe Pardo
Keyword(s):  
English Language ◽  
Clinical Success ◽  
Data Extraction ◽  
Phase Iii ◽  
Klebsiella Pneumoniae Carbapenemase ◽  
Preclinical Phase ◽  
Study Selection ◽  
Tract Infections ◽  
Lactamase Inhibitor

Objective: To review the pharmacology, spectrum of activity, pharmacokinetics, pharmacodynamics, safety, efficacy, administration, and considerations for clinical use of meropenem/vaborbactam (M/V). Data Sources: A literature search using PubMed and clinicaltrials.gov (June 2013 to December 2017) was conducted using the search terms meropenem, vaborbactam, RPX7009, biapenem, RPX2003, and carbavance. References from relevant articles and conference abstracts were also reviewed. Study Selection and Data Extraction: Preclinical, phase I studies, and phase III studies written in the English language were evaluated. Data Synthesis: M/V is a novel carbapenem/β-lactamase inhibitor antimicrobial with in vitro activity against nearly 99% of Klebsiella pneumoniae carbapenemase–producing Enterobacteriaceae. M/V is approved for the treatment of adults with complicated urinary tract infections (cUTIs), including pyelonephritis. In a phase III cUTI trial (TANGO I), 98.4% of patients treated with M/V experienced overall clinical success compared with 94% of patients treated with piperacillin/tazobactam (95% CI = 0.7 to 9.1). When compared with best available therapy for carbapenem-resistant Enterobacteriaceae (CRE) infections in TANGO II, patients receiving M/V were more likely to achieve clinical cure at both the end of therapy (64.3% vs 33.3%, P = 0.04) as well as at the test of cure (57.1% vs 26.7%, P = 0.04). The most common adverse effects associated with M/V were headache, infusion-site reactions, and diarrhea. Conclusion: M/V has a valuable role in the treatment of CRE and should be used judiciously to preserve its use for resistant infections.

The Contact System

2002 ◽  
Vol 126 (11) ◽  
pp. 1382-1386 ◽  
Author(s):  
Craig S. Kitchens
Keyword(s):  
Antiphospholipid Syndrome ◽  
English Language ◽  
Case Reports ◽  
Data Extraction ◽  
Meta Analysis ◽  
Factor Xii ◽  
Activity Levels ◽  
Medline Search ◽  
Apparent Association

Abstract Objectives.—To review the literature for conditions, diseases, and disorders that affect activity of the contact factors, and further to review the literature for evidence that less than normal activity of any of the contact factors may be associated with thrombophilia. Data Sources.—MEDLINE search for English-language articles published from 1988 to 2001 and pertinent references contained therein, as well as search of references in recent relevant articles and reviews. Study Selection.—Relevant clinical and laboratory information was extracted from selected articles. Meta-analysis was not feasible because of heterogeneity of reports. Data Extraction and Synthesis.—Evidence for association of altered levels of the contact factors and thrombophilia was sought. A wide variety of disorders is associated with decreased activity of the contact factors; chief among these disorders are liver disease, hepatic immaturity of newborns, the antiphospholipid syndrome, and, for factor XII, being of Asian descent. These disorders are more common than homozygous deficiency. The few series and case reports of thrombophilic events in patients homozygous for deficiency of contact factors are not persuasive enough to support causality. The apparent association between levels consistent with heterozygosity (40%–60% of normal) of any of the contact factors (but especially factor XII) in persons with antiphospholipid antibodies appears to be due to falsely decreased in vitro activity levels of these factors, which are normal on antigenic testing. The apparent association with thrombosis is better explained by the antiphospholipid syndrome than by the modest reduction of the levels of contact factors. Conclusions.—Presently, it is not recommended to measure activity of contact factors during routine evaluation of patients who have suffered venous or arterial thromboembolism or acute coronary syndromes.

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