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1
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Fernández-Ruiz M. Pharmacological management of invasive mold infections in solid organ transplant recipients. Expert Opin Pharmacother 2024; 25:239-254. [PMID: 38436619 DOI: 10.1080/14656566.2024.2326507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 02/29/2024] [Indexed: 03/05/2024]
Abstract
INTRODUCTION Solid organ transplant (SOT) recipients face an increased susceptibility to invasive fungal infection (IFI) due to filamentous fungi. Post-transplant invasive aspergillosis (IA) and mucormycosis are related to exceedingly high mortality rates and graft loss risk, and its management involve a unique range of clinical challenges. AREAS COVERED First, the current treatment recommendations for IA and mucormycosis among SOT recipients are critically reviewed, including the supporting evidence. Next, we discussed particular concerns in this patient population, such as drug-drug interactions (DDIs) between triazoles and post-transplant immunosuppression or treatment-related toxicity. The role for immunomodulatory and host-targeted therapies is also considered, as well as the theoretical impact of the intrinsic antifungal activity of calcineurin inhibitors. Finally, a personal opinion is made on future directions in the pharmacological approach to post-transplant IFI. EXPERT OPINION Despite relevant advances in the treatment of mold IFIs in the SOT setting, such as the incorporation of isavuconazole (with lower incidence of DDIs and better tolerability than voriconazole), there remains a large room for improvement in areas such as the position of combination therapy or the optimal strategy for the reduction of baseline immunosuppression. Importantly, future studies should define the specific contribution of newer antifungal agents and classes.
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Affiliation(s)
- Mario Fernández-Ruiz
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
- Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
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Li H, Zhang M, Jiao X, Zhu Y, Liu Y, Zeng L, Wang H, Zhang L, Zhang W, Zhang L. Using disproportionality analysis to explore the association between periostitis and triazole antifungals in the FDA Adverse Event Reporting System Database. Sci Rep 2023; 13:4475. [PMID: 36934109 PMCID: PMC10024698 DOI: 10.1038/s41598-023-27687-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 01/05/2023] [Indexed: 03/19/2023] Open
Abstract
Though triazole antifungals are the first choice for preventing and treating invasive fungal infections, periostitis caused by voriconazole has been described in emerging case reports; however, no studies exist on this association in real-world clinical settings. Our study aimed to identify the association between periostitis and triazole antifungals by analyzing data from the FDA Adverse Event Reporting System (FAERS). We extracted and analyzed reports on the association between periostitis and triazole antifungals in FAERS from the first quarter of 2004 to the second quarter of 2022 using OpenVigil 2.1. Disproportionality analysis was performed to evaluate the association between periostitis and triazole antifungals, and chi-squared (χ2), relative reporting ratio (RRR), reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural networks (BCPNN) of information components (IC) were reported. In total, 143 patients experienced periostitis while using voriconazole. Disproportionality analysis identified an association between periostitis and voriconazole (χ2 = 82,689.0, RRR = 583.6, 95%CI [472.4, 721.1], PRR = 1808.9, 95%CI [1356.0, 2412.9], ROR = 1831.7, 95%CI [1371.6, 2446.3], IC = 9.2, 95%CI [8.6, 9.8]). However, no safety signals were observed between periostitis and other triazole antifungals. When stratified by sex and age, disproportionality analysis identified positive signals between periostitis and voriconazole. The possible association between periostitis and voriconazole should attract sufficient attention in clinical practice. Alternative treatment with other triazole antifungals can be considered, and causality needs to be verified in further prospective studies.
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Affiliation(s)
- Hailong Li
- Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, China
- Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- NMPA Key Laboratory for Technical Research On Drug Products In Vitro and In Vivo Correlation, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Miao Zhang
- Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, China
- Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- NMPA Key Laboratory for Technical Research On Drug Products In Vitro and In Vivo Correlation, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Xuefeng Jiao
- Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, China
- Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- NMPA Key Laboratory for Technical Research On Drug Products In Vitro and In Vivo Correlation, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Yu Zhu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yan Liu
- Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, China
- Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- NMPA Key Laboratory for Technical Research On Drug Products In Vitro and In Vivo Correlation, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Linan Zeng
- Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, China
- Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- NMPA Key Laboratory for Technical Research On Drug Products In Vitro and In Vivo Correlation, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Huiqing Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Lei Zhang
- College of Computer Science, Sichuan University, Chengdu, China
| | - Wei Zhang
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China.
- Medical Big Data Center, Sichuan University, Chengdu, China.
| | - Lingli Zhang
- Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, China.
- Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China.
- NMPA Key Laboratory for Technical Research On Drug Products In Vitro and In Vivo Correlation, Chengdu, China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China.
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Chau MM, Daveson K, Alffenaar JWC, Gwee A, Ho SA, Marriott DJE, Trubiano JA, Zhao J, Roberts JA. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy and haemopoietic stem cell transplant recipients, 2021. Intern Med J 2021; 51 Suppl 7:37-66. [PMID: 34937141 DOI: 10.1111/imj.15587] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Antifungal agents can have complex dosing and the potential for drug interaction, both of which can lead to subtherapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy and haemopoietic stem cell transplant recipients. Antifungal agents can also be associated with significant toxicities when drug concentrations are too high. Suboptimal dosing can be minimised by clinical assessment, laboratory monitoring, avoidance of interacting drugs, and dose modification. Therapeutic drug monitoring (TDM) plays an increasingly important role in antifungal therapy, particularly for antifungal agents that have an established exposure-response relationship with either a narrow therapeutic window, large dose-exposure variability, cytochrome P450 gene polymorphism affecting drug metabolism, the presence of antifungal drug interactions or unexpected toxicity, and/or concerns for non-compliance or inadequate absorption of oral antifungals. These guidelines provide recommendations on antifungal drug monitoring and TDM-guided dosing adjustment for selected antifungal agents, and include suggested resources for identifying and analysing antifungal drug interactions. Recommended competencies for optimal interpretation of antifungal TDM and dose recommendations are also provided.
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Affiliation(s)
- Maggie M Chau
- Pharmacy Department, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Kathryn Daveson
- Department of Infectious Diseases and Microbiology, The Canberra Hospital, Garran, Australian Capital Territory, Australia
| | - Jan-Willem C Alffenaar
- Faculty of Medicine and Health, School of Pharmacy, University of Sydney, Camperdown, New South Wales, Australia.,Pharmacy Department, Westmead Hospital, Westmead, New South Wales, Australia.,Marie Bashir Institute of Infectious Diseases and Biosecurity, University of Sydney, Camperdown, New South Wales, Australia
| | - Amanda Gwee
- Infectious Diseases Unit, The Royal Children's Hospital, Parkville, Victoria, Australia.,Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.,Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Su Ann Ho
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Deborah J E Marriott
- Department of Clinical Microbiology and Infectious Diseases, St Vincent's Hospital, Darlinghurst, New South Wales, Australia.,Faculty of Science, University of Technology, Ultimo, New South Wales, Australia.,Faculty of Medicine, The University of New South Wales, Kensington, New South Wales, Australia
| | - Jason A Trubiano
- Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia.,Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia
| | - Jessie Zhao
- Department of Haematology, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Jason A Roberts
- The University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Department of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.,Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France
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Guarascio AJ, Bhanot N, Min Z. Voriconazole-associated periostitis: Pathophysiology, risk factors, clinical manifestations, diagnosis, and management. World J Transplant 2021; 11:356-371. [PMID: 34631468 PMCID: PMC8465512 DOI: 10.5500/wjt.v11.i9.356] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/19/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
Voriconazole use has been associated with osteoarticular pain and periostitis, likely due to high fluoride content in the drug formulation. This phenomenon has been described primarily with high dosage or prolonged course of voriconazole therapy in immunocompromised and transplant patient populations. Patients typically present with diffuse bony pains associated with elevated serum alkaline phosphatase and plasma fluoride levels in conjunction with radiographic findings suggestive of periostitis. We provide a comprehensive review of the literature to highlight salient characteristics commonly associated with voriconazole-induced periostitis.
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Affiliation(s)
- Anthony J Guarascio
- Department of Pharmacy, Duquesne University School of Pharmacy, Pittsburgh, PA 15282, United States
| | - Nitin Bhanot
- Division of Infectious Disease, Medicine Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, United States
| | - Zaw Min
- Division of Infectious Disease, Medicine Institute, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA 15212, United States
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Spectrum of Voriconazole-Induced Periostitis With Review of the Differential Diagnosis. AJR Am J Roentgenol 2018; 212:157-165. [PMID: 30403528 DOI: 10.2214/ajr.18.19991] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
OBJECTIVE Voriconazole is an antifungal medication used primarily for the treatment of Candida and Aspergillus infections. A fairly newly described side effect of long-term voriconazole use is periostitis. The purpose of this article is to describe the main differential consideration-hypertrophic osteoarthropathy-and other differential diagnoses, including venous stasis, thyroid acropachy, and hypervitaminosis A. CONCLUSION With knowledge of imaging appearance, clinical manifestations, and outcomes, radiologists can make an accurate diagnosis of voriconazole-induced periostitis, and clinical teams can initiate appropriate management.
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7
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Job KM, Olson J, Stockmann C, Constance JE, Enioutina EY, Rower JE, Linakis MW, Balch AH, Yu T, Liu X, Thorell EA, Sherwin CMT. Pharmacodynamic studies of voriconazole: informing the clinical management of invasive fungal infections. Expert Rev Anti Infect Ther 2017; 14:731-46. [PMID: 27355512 DOI: 10.1080/14787210.2016.1207526] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
INTRODUCTION Voriconazole is a broad-spectrum antifungal agent commonly used to treat invasive fungal infections (IFI), including aspergillosis, candidiasis, Scedosporium infection, and Fusarium infection. IFI often occur in immunocompromised patients, leading to increased morbidity and mortality. AREAS COVERED The objective of this review is to summarize the pharmacodynamic properties of voriconazole and to provide considerations for potential optimal dosing strategies. Studies have demonstrated superior clinical response when an AUC/MIC >25 or Cmin/MIC >1 is attained in adult patients, correlating to a trough concentration range as narrow as 2-4.5 mg/L; however, these targets are poorly established in the pediatric population. Topics in this discussion include voriconazole use in multiple age groups, predisposing patient factors for IFI, and considerations for clinicians managing IFI. Expert commentary: The relationship between voriconazole dosing and exposure is not well defined due to the large inter- and intra-subject variability. Development of comprehensive decision support tools for individualizing dosing, particularly in children who require higher dosing, will help to increase the probability of achieving therapeutic efficacy and decrease sub-therapeutic dosing and adverse events.
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Affiliation(s)
- Kathleen M Job
- a Division of Clinical Pharmacology , University of Utah , Salt Lake City , UT , USA
| | - Jared Olson
- b Pharmacy, Primary Children's Hospital, Intermountain Healthcare , University of Utah , Salt Lake City , UT , USA
| | - Chris Stockmann
- c Division of Pediatric Infectious Diseases, Department of Pediatrics , University of Utah , Salt Lake City , UT , USA
| | - Jonathan E Constance
- a Division of Clinical Pharmacology , University of Utah , Salt Lake City , UT , USA
| | - Elena Y Enioutina
- a Division of Clinical Pharmacology , University of Utah , Salt Lake City , UT , USA.,d Division of Microbiology and Immunology, Department of Pathology , University of Utah , Salt Lake City , UT , USA
| | - Joseph E Rower
- a Division of Clinical Pharmacology , University of Utah , Salt Lake City , UT , USA
| | - Matthew W Linakis
- a Division of Clinical Pharmacology , University of Utah , Salt Lake City , UT , USA
| | - Alfred H Balch
- a Division of Clinical Pharmacology , University of Utah , Salt Lake City , UT , USA
| | - Tian Yu
- a Division of Clinical Pharmacology , University of Utah , Salt Lake City , UT , USA
| | - Xiaoxi Liu
- a Division of Clinical Pharmacology , University of Utah , Salt Lake City , UT , USA
| | - Emily A Thorell
- c Division of Pediatric Infectious Diseases, Department of Pediatrics , University of Utah , Salt Lake City , UT , USA
| | - Catherine M T Sherwin
- a Division of Clinical Pharmacology , University of Utah , Salt Lake City , UT , USA.,e Department of Pharmacology and Toxicology, College of Pharmacy , University of Utah , Salt Lake City , UT , USA
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8
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Sircar M, Kotton C, Wojciechowski D, Safa K, Gilligan H, Heher E, Williams W, Thadhani R, Tolkoff-Rubin N. Voriconazole-Induced Periostitis & Enthesopathy in Solid Organ Transplant Patients: Case Reports. ACTA ACUST UNITED AC 2016; 4:8-17. [PMID: 27990445 PMCID: PMC5158005 DOI: 10.4236/jbm.2016.411002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background Voriconazole is frequently used to treat fungal infections in solid organ transplant patients. Recently, there have been reports suggesting that prolonged voriconazole therapy may lead to periostitis. Aim Here we present two cases of voriconazole-induced periostitis in solid organ transplant patients. Case Presentation Voriconazole was given to two transplant patients-one with a liver transplant and the second with a heart transplant, to treat their fungal infections. Both developed voriconazole-induced toxicity. While undergoing voriconazole therapy, they had incapacitating bone pain. The liver transplant patient had to be taken off voriconazole, and the heart transplant patient succumbed to non-voriconazole related causes. Conclusions Voriconazole therapy in two solid organ transplant patients resulted in periostitis. We provide potential etiologies underlying voriconazole-induced periostitis, including fluoride toxicity, abnormalities in the pulmonary vascular bed leading to the production of downstream inflammatory mediators, and abnormal pharmacokinetics of hepatic drug metabolism. In addition to monitoring blood voriconazole trough levels, we suggest careful assessment for musculoskeletal pain in patients undergoing voriconazole treatment for two months or more, particularly if their daily dosages of voriconazole exceed 500 mg per day. Appropriate workup should include measurement of alkaline phosphatase, voriconazole trough and fluoride levels as well as a bone scan. Overall, early recognition of voriconazole-induced musculoskeletal toxicity is important for better morbidity outcomes.
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Affiliation(s)
- Monica Sircar
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Camille Kotton
- Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - David Wojciechowski
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; MGH Transplant Center, Departments of Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Kassem Safa
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; MGH Transplant Center, Departments of Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Hannah Gilligan
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; MGH Transplant Center, Departments of Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Eliot Heher
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; MGH Transplant Center, Departments of Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Winfred Williams
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; MGH Transplant Center, Departments of Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Ravi Thadhani
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Nina Tolkoff-Rubin
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; MGH Transplant Center, Departments of Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
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9
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Voriconazole-induced periostitis: a new rheumatic disorder. Clin Rheumatol 2016; 36:609-615. [DOI: 10.1007/s10067-016-3341-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 06/22/2016] [Accepted: 06/22/2016] [Indexed: 02/04/2023]
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10
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Adwan MH. An update on drug-induced arthritis. Rheumatol Int 2016; 36:1089-97. [DOI: 10.1007/s00296-016-3462-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 03/09/2016] [Indexed: 12/17/2022]
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Husain S, Sole A, Alexander BD, Aslam S, Avery R, Benden C, Billaud EM, Chambers D, Danziger-Isakov L, Fedson S, Gould K, Gregson A, Grossi P, Hadjiliadis D, Hopkins P, Luong ML, Marriott DJ, Monforte V, Muñoz P, Pasqualotto AC, Roman A, Silveira FP, Teuteberg J, Weigt S, Zaas AK, Zuckerman A, Morrissey O. The 2015 International Society for Heart and Lung Transplantation Guidelines for the management of fungal infections in mechanical circulatory support and cardiothoracic organ transplant recipients: Executive summary. J Heart Lung Transplant 2016; 35:261-282. [DOI: 10.1016/j.healun.2016.01.007] [Citation(s) in RCA: 124] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 01/10/2016] [Indexed: 01/10/2023] Open
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Chau MM, Kong DCM, van Hal SJ, Urbancic K, Trubiano JA, Cassumbhoy M, Wilkes J, Cooper CM, Roberts JA, Marriott DJE, Worth LJ. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014. Intern Med J 2015; 44:1364-88. [PMID: 25482746 DOI: 10.1111/imj.12600] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Antifungal agents may be associated with significant toxicity or drug interactions leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy. These risks may be minimised by clinical assessment, laboratory monitoring, avoidance of particular drug combinations and dose modification. Specific measures, such as the optimal timing of oral drug administration in relation to meals, use of pre-hydration and electrolyte supplementation may also be required. Therapeutic drug monitoring (TDM) of antifungal agents is warranted, especially where non-compliance, non-linear pharmacokinetics, inadequate absorption, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Recommended indications for voriconazole and posaconazole TDM in the clinical management of haematology patients are provided. With emerging knowledge regarding the impact of pharmacogenomics upon metabolism of azole agents (particularly voriconazole), potential applications of pharmacogenomic evaluation to clinical practice are proposed.
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Affiliation(s)
- M M Chau
- Pharmacy Department, The Royal Melbourne Hospital, Melbourne Health, Parkville, Victoria
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Abstract
History A 74-year-old woman presented with multifocal bone pain, including pain in multiple ribs, bilateral shoulders, and bilateral hips. The pain began several months before presentation and was quite severe, ultimately necessitating control with narcotics. At examination, strength in both lower extremities was slightly reduced, sensation and reflexes were intact, and range of motion was full, though painful. There were no notable constitutional symptoms of fever or weight loss. Laboratory work-up was remarkable for elevated alkaline phosphatase level (277 U/L [4.6 mkat/L]). The patient had undergone left lung transplantation 8 years prior for pulmonary fibrosis. A thorough pulmonary work-up for the cause of fibrosis, which included gathering an exposure, occupational, allergy, and previous infectious history, and a rheumatoid work-up were negative. The patient's posttransplantation course was complicated by bronchiolitis obliterans from chronic rejection and by recent pulmonary embolism, for which she was undergoing anticoagulation therapy at the time of presentation. Additionally, the patient experienced repeated pulmonary infections with Aspergillus, leading to multiple hospitalizations and long-term antifungal prophylaxis with voriconazole. A bone scan from an outside hospital was reviewed, and further imaging was performed.
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Affiliation(s)
- Tina D Tailor
- From the Department of Radiology, University of Washington Medical Center, 1959 Pacific St, Box 357115, Seattle, WA 98195-7115
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Skaug M, Spak C, Oza U. Painful periostitis in the setting of chronic voriconazole therapy. Proc (Bayl Univ Med Cent) 2014; 27:350-2. [PMID: 25484509 DOI: 10.1080/08998280.2014.11929156] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
A 72-year-old woman on chronic voriconazole therapy for recurrent histoplasmosis developed a painful forearm mass. Laboratory and imaging findings were consistent with a diffuse periostitis. Her symptoms resolved after discontinuation of voriconazole. To our knowledge, this is the first case of voriconazole-induced periostitis to be reported in a patient with chronic histoplasmosis.
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Affiliation(s)
- Margaret Skaug
- Department of Radiology (Skaug, Oza) and Division of Infectious Diseases, Department of Internal Medicine (Spak), Baylor University Medical Center at Dallas
| | - Cedric Spak
- Department of Radiology (Skaug, Oza) and Division of Infectious Diseases, Department of Internal Medicine (Spak), Baylor University Medical Center at Dallas
| | - Umesh Oza
- Department of Radiology (Skaug, Oza) and Division of Infectious Diseases, Department of Internal Medicine (Spak), Baylor University Medical Center at Dallas
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Voriconazole-induced periostitis causing arthralgias mimicking a flare of granulomatosis with polyangiitis. J Clin Rheumatol 2014; 19:444-5. [PMID: 24263147 DOI: 10.1097/rhu.0000000000000045] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
We describe a case of voriconazole-induced periostitis that occurred in a 68-year-old woman with granulomatosis with polyangiitis. Our patient presented with months of severe hip pain limiting her daily activities, which was initially felt to be a flare of her granulomatosis with polyangiitis. However, upon further review, she had an elevated alkaline phosphatase and periostitis on her hip radiograph; voriconazole was held, and within 2 days she had marked improvement in her pain. Although this clinical syndrome is well documented in transplant patients, it is a rare complication in patients with autoimmune disorders. However, it is important because it may cause severe arthralgias that can mimic a flare of rheumatic diseases.
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Raghavan M, Hayes A. Voriconazole-associated soft tissue ossification: an undescribed cause of glenohumeral joint capsulitis. Skeletal Radiol 2014; 43:1301-5. [PMID: 24699891 DOI: 10.1007/s00256-014-1865-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 02/07/2014] [Accepted: 03/05/2014] [Indexed: 02/02/2023]
Abstract
Voriconazole-related periostitis has been increasingly described in the literature over the last several years as a recognizable disease entity, especially in lung transplant patients. This relationship should be considered when approaching immunosuppressed patients presenting with diffuse bone pain and imaging findings of periostitis. We present a case of voriconazole-associated periostitis, capsular and enthesial ossification and glenuhumeral capsulitis in a patient with a hematologic malignancy. To the authors' knowledge, soft tissue ossification associated with voriconazole has not been described in the radiology literature.
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Affiliation(s)
- Meera Raghavan
- Department of Diagnostic Imaging, Musculoskeletal Radiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA,
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Moon WJ, Scheller EL, Suneja A, Livermore JA, Malani AN, Moudgal V, Kerr LE, Ferguson E, Vandenberg DM. Plasma fluoride level as a predictor of voriconazole-induced periostitis in patients with skeletal pain. Clin Infect Dis 2014; 59:1237-45. [PMID: 24992954 DOI: 10.1093/cid/ciu513] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Voriconazole is a triazole antifungal medication used for prophylaxis or to treat invasive fungal infections. Inflammation of the periosteum resulting in skeletal pain, known as periostitis, is a reported side effect of long-term voriconazole therapy. The trifluorinated molecular structure of voriconazole suggests a possible link between excess fluoride and periostitis, as elevated blood fluoride has been reported among patients with periostitis who received voriconazole. METHODS Two hundred sixty-four patients from Michigan were impacted by the multistate outbreak of fungal infections as a result of contaminated methylprednisolone injections. A retrospective study was conducted among 195 patients who received voriconazole therapy at St Joseph Mercy Hospital during this outbreak. Twenty-eight patients who received both bone scan and plasma fluoride measurements for skeletal pain were included in the statistical analyses. Increased tracer uptake on bone scan was considered positive for periostitis. The primary outcome measure was the correlation between plasma fluoride and bone scan results. RESULTS Blood fluoride (P < .001), alkaline phosphatase (P = .020), daily voriconazole dose (P < .001), and cumulative voriconazole dose (P = .027) were significantly elevated in patients who had periostitis compared with those who did not. Discontinuation or dose reduction of voriconazole resulted in improvement of pain in 89% of patients. CONCLUSIONS High plasma fluoride levels coupled with skeletal pain among patients who are on long-term voriconazole therapy is highly suggestive of periostitis. Initial measurement of fluoride may be considered when bone scan is not readily available. Early detection should be sought, as discontinuation of voriconazole is effective at reversing the disease.
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Affiliation(s)
- Woo J Moon
- Department of Internal Medicine, St Joseph Mercy Hospital
| | - Erica L Scheller
- Department of Molecular and Integrative Physiology, University of Michigan
| | - Anupam Suneja
- Department of Internal Medicine, St Joseph Mercy Hospital
| | | | - Anurag N Malani
- Department of Internal Medicine, St Joseph Mercy Hospital Section of Infectious Diseases
| | - Varsha Moudgal
- Department of Internal Medicine, St Joseph Mercy Hospital Section of Infectious Diseases
| | - Lisa E Kerr
- Department of Pharmacy, St Joseph Mercy Hospital, Ann Arbor, Michigan
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Hirota K, Yasoda A, Fujii T, Inagaki N. Voriconazole-induced periostitis in a patient with overlap syndromes. BMJ Case Rep 2014; 2014:bcr-2013-203485. [PMID: 24599432 DOI: 10.1136/bcr-2013-203485] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
A 52-year-old woman with overlap syndrome and interstitial pneumonia underwent immunosuppressive therapy and she was suspected to suffer from pulmonary aspergillosis. Oral voriconazole was initiated, and a rapid elevation of alkaline phosphatase (ALP) occurred after 4 weeks. After 2 months, the patient presented diffuse pain in bilateral skeletal regions, and bone scintigraphy revealed bilateral multiple areas of increased radiotracer uptake. We suspected the skeletal involvement as voriconazole-induced periostitis. Actually, the plasma fluoride level was increased. Voriconazole was replaced with itraconazole, and after 3 weeks, the patient stopped complaining of bone pain concomitant with the decrease in ALP. Voriconazole-induced periostitis is a rare condition but had previously been reported in solid organ or patients with bone marrow transplant who received a long-term voriconazole therapy. Our present case is distinctive of previous ones, because it occurred in a patient with connective tissue disease which had its rapid progression.
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Affiliation(s)
- Keisho Hirota
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Bucknor MD, Gross AJ, Link TM. Voriconazole-induced periostitis in two post-transplant patients. J Radiol Case Rep 2013; 7:10-7. [PMID: 24421948 DOI: 10.3941/jrcr.v7i8.1458] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
While drug-related periostitis has been known of for many years, the specific association of diffuse periostitis with voriconazole (most frequently in transplant patients) has only been recently explicitly addressed in the literature. Recognition of the radiologic and clinical manifestations of voriconazole-related periostitis is important for helping to narrow an otherwise broad differential diagnosis. We present two cases that illustrate different radiologic presentations of this painful cause of diffuse periostitis. Case 1 features a 60 year-old woman with a history of orthotopic heart transplant who was hospitalized for "full body pain" with progressively worsening bone tenderness involving the humeri, knees, femurs, hips, and hands. Case 2 describes a 48 year-old man with a history of acute lymphoblastic leukemia status post stem cell transplant who presented with diffuse arthralgias involving bilateral ankles, knees, wrists, and elbows.
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Affiliation(s)
- Matthew D Bucknor
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA
| | - Andrew J Gross
- Department of Internal Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, CA, USA
| | - Thomas M Link
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA
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Tedja R, El-Sherief A, Olbrych T, Gordon S. Multifocal periostitis as a complication of chronic use of voriconazole in a lung transplant recipient. Transpl Infect Dis 2013; 15:424-9. [PMID: 23663268 DOI: 10.1111/tid.12088] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Revised: 10/18/2012] [Accepted: 12/08/2012] [Indexed: 01/30/2023]
Abstract
Fungal infections are common in solid organ transplantation. An increasing number of transplant recipients receive antifungal therapy for prolonged duration owing to invasive fungal infections. Herein, we describe a diagnosis of periostitis as a complication of chronic use of voriconazole in a lung transplant recipient. The patient was diagnosed with probable pulmonary aspergillosis and was treated with oral voriconazole for a total of 9 months. Evidence of multifocal periostitis was observed in the axial and appendicular skeleton. Early recognition of this phenomenon is important to prevent unnecessary tests and procedures. Prompt discontinuation of voriconazole should result in improvement of symptoms.
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Affiliation(s)
- R Tedja
- Department of Infectious Disease, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
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Lustenberger DP, Granata JD, Scharschmidt TJ. Periostitis secondary to prolonged voriconazole therapy in a lung transplant recipient. Orthopedics 2011; 34:e793-6. [PMID: 22049971 DOI: 10.3928/01477447-20110922-35] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
This article reports a case of perostitis deformans in a lung transplantation patient taking the fluoride-containing medication voriconazole, a relatively new and potent anti-fungal. The patient had a normal range of motion in all joints and a normal gait. On radiographs at presentation, multifocal areas of periostitis were visualized involving the left-hand first, second, and third proximal phalanx shafts. Similar periostitis was present on the left-hand third, fourth, and fifth middle phalanx shafts. Plain radiographs of the right hand also demonstrated multifocal periostitis of the third and fourth proximal and middle phalanges. Aggressive periostitis at the level of the right fourth proximal and middle phalanges was also present. Given her long-term treatment with voriconazole and a presentation consistent with periostitis deformans, voriconazole was presumed to be the offending agent and was replaced with itraconazole. The patient's symptoms resolved shortly after withdrawal of voriconazole.Voriconazole-associated periostitis has only recently been reported in the literature. Food and Drug Administration-approved in 2002, voriconazole is efficacious in treating serious, invasive fungal infections that are generally seen in immunocompromised patients. Due to the novel nature of voriconazole and the uncommon indications for its long-term use, the periostitis deformans described in this article may be unfamiliar to the orthopedic surgeon. Consequently, a patient presenting with bone pain and periosteal involvement on plain radiographs may provoke a broad, expensive, and ultimately unnecessary diagnostic evaluation. The clinical case and imaging findings presented here can help to promote understanding of this benign condition and its simple cure: voriconazole discontinuation.
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Skiles JL, Imel EA, Christenson JC, Bell JE, Hulbert ML. Fluorosis because of prolonged voriconazole therapy in a teenager with acute myelogenous leukemia. J Clin Oncol 2011; 29:e779-82. [PMID: 21969513 DOI: 10.1200/jco.2011.35.9604] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Jodi L Skiles
- Indiana University School of Medicine, Indianapolis, IN, USA.
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