Clinical
`Infectio ____
`Diseases
`
`(
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2097 - 1/13
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`

`
`Clini al
`
`1 March 2003
`Volume 36
`Number 5
`
`On the cover: detail from A Little Better, by George B. O'Neil
`(1828-1917). Sutcliffe Gallery, Harrogate, North Yorkshire,
`Great Britain. Photograph © Fine Art Photographic Library,
`London/ Art Resource, New York. Reproduced with
`permission.
`
`The complete work is reproduced above.
`
`This painting, titled A Little Better. is by George Bernard
`O'Neil (1828-1917). The date of the painting is uncertain,
`but it is representative of English genre paintings of the
`19th century, many of which depicted scenes of family life
`in intimate settings. Childhood illnesses were a common
`subject. These images had a direct emotional impact be(cid:173)
`cause of the experience of all families of the era with sudden
`deaths of children caused by infectious diseases. Here, the
`artist shows a happy outcome, in which the ill child receives
`a visitor, perhaps an older sister, who brings flowers. The
`image has an engaging, if studied, informality, with. the
`visitor's hat tossed on the floor and sunlight filling the room.
`On the chest by the window, the artist has painted "treat(cid:173)
`ments," including a glass dispenser and lemons. The paint(cid:173)
`ing belongs to the Sutcliffe Gallery, Harrogate, North York(cid:173)
`shire. (Ann Arvin, Cover Art Editor)
`
`1 March News
`
`MAJOR ARTIClES
`
`541 A Randomized, Double-Blind, Placebo-Controlled,
`Dose-Ranging Trial of Tafenoquine for Weekly Prophylaxis
`against Plasmodium falciparum
`Braden R. Hale, Seth Owusu-Agyei, David J. Fryauff. Kwadwo A. Karam, Martiil Adjuik,
`Abraham R. Oduro, W. Roy Prescott, J. Kevin Baird, Francis Nkrumah, Thomas L. Ritchie,
`Eileen D. Franke, Fred N. Binka, John Horton, and Stephen L. Hoffman
`
`550 Adenovirus Type 21-Associated Acute Flaccid Paralysis during
`an Outbreak of Hand-Foot-and-Mouth Disease in Sarawak, Malaysia
`Mof').g How Ooi, See Chang Wong, Daniela Clear, David Perera, Shekhar Krishnan, Teresa Preston,
`Phaik Hooi Tio, Hugh J. Willison, Brian Tedman, Rachel Kneen, Mary Jane Cardosa,
`and Tom Solomon
`
`560 Two Doses of a Lipid Formulation of Amphotericin B
`for the Treatment of Mediterranean Visceral Leishmaniasis
`Vassiliki Syriopoulou, George L. Daikos, Maria Theodoridou, Joanna Pavlopoulou,
`Archondia G. Manolaki, Evagelia Sereti, Aikaterini Karamboula, Dimitra Papathanasiou,
`Xenophon Krikos. and George Saroglou
`
`567 Acute Encephalopathy Associated with Influenza A Virus Infection
`Christoph Steininger, Theresia Popow-Kraupp, Hermann Laferl, Andreas Seiser, Irene Gtidl,
`Schiva Djamshidian, and Elisabeth Puchhammer-Sttickl
`
`575 Klebsiella Infection in Patients with Thalassemia
`B. H. Y. Chung, S. Y. Ha, G. C. F. Chan, A. Chiang, T. L. Lee, H. K. Ho, C. Y. Lee, C. W. Luk,
`and Y. L. Lau
`
`580 Recurrent Clostridium difficile Colitis: Case Series Involving
`18 Patients Treated with Donor Stool Administered
`via a N asogastric Tube
`Johannes Aas, Charles E. Gessert, and Johan S. Bakken
`
`586 Chlamydia Antibody Response in Healthy Volunteers Immunized
`with Nonchlamydial Antigens: A Randomized, Double-Blind,
`Placebo-Controlled Study
`Stine Johnsen, Paul L. Andersen, Gerold Stanek, Gunna Christiansen, Svend Birkelund,
`Lene M. Berthelsen, and Lars 0stergaard
`
`592 Adverse Clinical and Economic Outcomes Attributable
`to Methicillin Resistance among Patients with Staphylococcus aureus
`Surgical Site Infection
`John J. Engemann, Yehuda Carmeli, Sara E. Cosgrove, Vance G. Fowler, Melissa Z. Bronstein,
`Sharon L. Trivette, Jane P. Briggs, Daniel J. Sexton, and Keith S. Kaye
`
`599 Risk Factors Associated with Tuberculin Skin Test Positivity
`among University Students and the Use of Such Factors
`in the Development of a Targeted Screening Program
`Venkatarama Rao Koppaka, Eric Harvey, Beth Mertz, and Betty Anne Johnson
`
`lllllllllllllllllllllllllllllllllllllllllllllllll
`
`1 058-4838(20030301 )36:5;1-E
`
`PHOTO QUIZ
`
`608 A Man with a Prosthetic Aortic Valve and Subacute Calf Pain
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2097 - 2/13
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`

`
`AGING AND INFECTIOUS DISEASES
`
`ANSWER TO PHOTO QUIZ
`
`609 Sexually Transmitted Diseases Other
`than Human Immtmodeficiency Virus
`Infection in Older Adults
`Helene M. Calvet
`
`CliNICAl PRACTICE
`
`615 Combination Antibiotic Therapy for Infective
`Endocarditis
`Thuan Le and Arnold S. Bayer
`
`CONFRONTING BIOLOGICAl WEAPONS
`
`622 Can Postexposure Vaccination against Smallpox
`Succeed?
`Philip P. Mortimer
`
`REVIEWS OF ANTI-INFECTIVE AGENTS
`
`630 Voriconazole: A New Triazole Antifungal Agent
`Leonard B. Johnson and Carol A. Kauffman
`
`VACCINES
`
`638 Key Issues for a Potential Human
`Immunodeficiency Virus Vaccine
`Dale J. Hu, Charles R. Vitek, Bradford Bartholow,
`and Timothy D. Mastro
`
`HIV/AIDS
`
`645 Discontinuation of Secondary Prophylaxis
`for Pneumocystis carinii Pneumonia in Human
`Immunodeficiency Virus-Infected Patients:
`A Randomized Trial by the ClOP Study Group
`Cristina Mussini, Patrizio Pezzotti, Andrea Antinori. Vanni Borghi,
`Antonella d'Arminio Monforte, Alessandra Govoni, Andrea De Luca,
`Adriana Ammassari, Nicola Mongiardo, Maria Chiara Cerri,
`Andrea Bedini, Cristina Beltrami, Maria Alessandra Ursitti, Teresa Bini,
`Andrea Cossarizza, and Roberto Esposito, for the Changes in
`Opportunistic Prophylaxis (ClOP) Study Group
`
`652 Review of Human Immunodeficiency Virus
`Type 1-Related Opportunistic Infections
`in Sub-Saharan Africa
`Charles B. Holmes, Elena Losina, Rochelle P. Walensky,
`Yazdan Yazdanpanah, and Kenneth A. Freedberg
`
`663 Bacterial Vaginosis Is a Strong Predictor
`of Neisseria gonorrhoeae and Chlamydia
`trachomatis Infection
`Harold C. Wiesenfeld, Sharon L. Hillier, Marijane A. Krohn,
`Daniel V. Landers, and Richard L. Sweet
`
`669 A Man with a Prosthetic Aortic Valve
`and Subacute Calf Pain
`
`CORRESPONDENCE
`
`671 Diverse Etiologies for Chronic Fatigue Syndrome
`John K. S. Chia and Andrew Chia
`
`672 Reply
`David M. Koelle, Serge Barcy, Meei-li Huang, Rhoda L. Ashley,
`Lawrence Corey, Judy Zeh, Suzanne Ashton, and Dedra Buchwald
`
`673 Removing Hospitalization as a Barrier
`to Immunization
`Mark Woods and Jill T. Robke
`
`674 Reply
`Gregory A. Poland
`
`674 Diagnosis of Rabies by Use of Brain Tissue Dried
`on Filter Paper
`Supaporn Wacharapluesadee, Patta Phumesin, Boonlert Lumlertdaecha,
`and Thiravat Hemachudha
`
`675 Persistent MRSA Bacteremia in a Patient
`with Low Linezolid Levels
`Steven J. Sperber, Jerome F. Levine, and Peter A. Gross
`
`BOOK REVIEW
`
`677 Principles and Practice of Clinical Research
`Edited by John I. Gallin
`Reviewed by Eugene D. Shapiro
`
`677 New Books Received
`
`678 ElECTRONIC ARTICLES
`First Case of Mycobacterium ulcerans Disease
`(Buruli Ulcer) Following a Human Bite
`Martine Debacker, Claude Zinsou, Julia Aguiar, Wayne M. Meyers,
`and Frangoise Portaels
`
`Tsukamurella tyrosinosolvens Intravascular
`Catheter Infection Identified Using 16S
`Ribosomal DNA Sequencing
`Elizabeth A. S. Sheridan~ Simon Warwick, Anthony Chan,
`Martino Dall' Antonia, Maria Koliou, and Armine Sefton
`
`Diabetes Mellitus, Insulin, and Melioidosis
`in Thailand
`Andrew J. H. Simpson, Paul N. Newton, Wirongrong Chierakul,
`Wipada Chaowagul, and Nicholas J. White
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2097 - 3/13
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`Online Submissions to Clinical Infectious Diseases
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`Clinical Infedious Diseases
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`An Official Publication of the Infectious Diseases Society of America
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`Sherwood L. Gorbach
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2097 - 5/13
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`

`
`Louis D. Saravolatz, Section Editor
`
`INVITED ARTICLE
`
`Voriconazole: A New Triazole Antifungal Agent
`
`Leonard B. Johnson 1 and Carol A. Kauffman2
`1Division of Infectious Diseases, St. John Hospital & Medical Center, Wayne State University, Detroit, and 2Division of Infectious Diseases, Veterans Affairs
`Ann Arbor Healthcare System, University of Michigan Medical School, Ann Arbor, Michigan
`
`Voriconazole is a second-generation azole antifungal agent that shows excellent in vitro activity against a wide variety of
`yeasts and molds. It can be given by either the intravenous or the oral route; the oral formulation has excellent bioavailability.
`The side effect profile· of voriconazole is unique in that non-sight-threatening, transient visual disturbances occur in ~30%
`of patients given the drug. Rash (which can manifest as photosensitivity) and hepatitis also occur. The potential for drug(cid:173)
`drug interactions is high and requires that careful attention be given to dosage regimens and monitoring of serum levels
`and effects of interacting drugs. Voriconazole has been 'approved for the treatment of invasive aspergillosis and refractory
`infections with Pseudallescheria/Scedosporium and Fusarium species, and it will likely become the drug of choice for treatment
`of serious infections with those filamentous fungi.
`
`The 1990s witnessed an expansion of the antifungal armamen(cid:173)
`tarium to include 2 new azole agents, fluconazole and itracon(cid:173)
`azole. These agents changed our approach to treating many
`fungal infections. However, neither was an ideal agent. Itra(cid:173)
`conazole was plagued by absorption problems; fluconazole had
`a limited spectrum of antifungal activity, and resistance was
`soon noted in immunosuppressed hosts who received long(cid:173)
`term treatment. Second-generation triazole agents have been
`in development for the past decade. The first of these new
`agents to receive approval from the US Food and Drug Ad(cid:173)
`ministration (FDA) is voriconazole, a synthetic derivative of
`fluconazole. Replacement of one of the triazole rings with a
`fluorinated pyrimidine and the addition of an a-methyl group
`resulted in expanded activity, compared with that of flucona(cid:173)
`zole. The development of voriconazole proceeded primarily
`because of this broadened antifungal spectrum.
`
`IN VITRO ACTIVITY
`
`The mechanism of action of voriconazole, similar to that of all
`azole agents, is inhibition of cytochrome P450 (CYP 450)(cid:173)
`dependent 14a-lanosterol demethylation, which is a vital step
`
`Received 16 July 2002; accepted 2 December 2002; electronically published 10 February
`2003.
`
`Reprints or correspondence: Dr. Leonard B. Johnson, St. John Hospital & Medical Center,
`22101 Morass Rd., Detroit, Ml 48236 (Leonard.Johnson@stjohn.org).
`
`2003;36:630-7
`Clinical Infectious Diseases
`© 2003 by the Infectious Diseases Society of America. All rights reserved.
`1058-4838/2003/3605-0014$15.00
`
`in cell membrane ergosterol synthesis by fungi [ 1]. For yeasts,
`voriconazole appears to be fungistatic, as are other azoles. How(cid:173)
`ever, for some filamentous organisms, voriconazole and other
`second -generation azoles are fungicidal [ 2]. This effect may
`relate to the stronger avidity of the new azoles for the lanosterol
`14a-demethylase found in molds, compared with that found
`in yeasts, which may allow more-complete interruption of er(cid:173)
`gosterol synthesis and lead to cell death.
`Voriconazole is active against all Candida species, including
`Candida krusei, strains of Candida glabrata that are inherently
`fluconazole-resistant, and strains of Candida albicans that have
`acquired resistance to fluconazole (table 1) [ 2-6]. In general,
`the MICs of voriconazole for C. albicans are 1-2 log lower than
`the MICs of fluconazole. For some, but not all, fluconazole(cid:173)
`resistant strains of C. albicans, MICs of voriconazole are higher
`than those noted for fluconazole-susceptible strains [6]. The
`MICs for C. glabrata and C. krusei are higher than those for
`other species, but they are still in the presumed susceptible
`range. Voriconazole shows good in vitro activity against other
`yeasts, including Cryptococcus neoformans, Trichosporon beigelii,
`and Saccharomyces cerevisi(Je [ 7-9].
`Voriconazole appears to be broadly active against many spe(cid:173)
`cies of Aspergillus, including Aspergillus terreus, which is often
`resistant to amphotericin B (table 2) [2, 10-14]. Time-kill
`curves demonstrate that dose-dependent killing of Aspergillus
`species is not as efficient as that noted for amphotericin B but
`is much more efficient than that noted for itraconazole [2].
`Voriconazole appears to have reasonable activity against Bias-
`
`630 • CID 2003:36 (1 March) • REVIEWS OF ANTI-INFECTIVE AGENTS
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`
`In vitro susceptibilities of voriconazole compared with those· of
`Table 1.
`other antifungal agents that are active against common yeast-like species.
`
`Species,
`antimicrobial agent
`
`Candida albicans
`Fluconazole
`ltraconazole
`Voriconazole
`
`Candida tropica/is
`Fluconazole
`ltraconazole
`Voriconazole
`
`Candida parapsilosis
`Fluconazole
`ltraconazole
`Voriconazole
`Candida glabrata
`Fluconazole
`ltraconazole
`Voriconazole
`Candida krusei
`Fluconazole
`ltraconazole
`Voriconazole
`C. albicans,
`fluconazole-resistant
`Fluconazole
`ltraconazole
`Voriconazole
`Cryptococcus neoformans
`Fluconazole
`ltraconazole
`Voriconazole
`
`NOTE. Data are from [3-9].
`
`MIC50 range
`or value,
`p.,g/ml
`
`MIC90 range
`or value,
`p.,g/ml
`
`MIC range,
`p.,g/ml
`
`0.25-0.5
`0.03-0.125
`0.002-0.06
`
`0.25-8
`0.12-0.25
`0.015-0.5
`
`0.06 to >128
`0.01 to >8
`~0.002 to> 16
`
`0.06-0.5
`0.06-0.25
`0.007-0.06
`
`0.5-1.0
`0.06-0.25
`0.007-0.06
`
`4-16
`0.5-1
`0.06-1
`
`16-64
`0.25-2
`0.12-0.5
`
`32
`0.25
`0.25
`
`2
`0.12-0.5
`0.06-0.25
`
`1.0-8
`0.12-0.5
`0.03-0.25
`
`8-64
`1-4
`0.25-2
`
`0.12 to >128
`0. 015 to >8
`~0.002 to> 16
`
`0.12-16
`
`~0.015-2
`
`~0.0002-1
`
`0.25 to >128
`0.06 to >8
`0.004-8
`
`64 to >128
`0.25-4
`0.5-2
`
`2 to ~128
`0.12to>4
`0.015-2
`
`~128
`
`16 to ~128
`0.03-1
`0.015-8
`
`2-4
`0.125-0.25
`0.06-0.25
`
`8-16
`0.5-1
`0.12-0.25
`
`0.125-16
`
`~0.007-1
`
`~0.007-2
`
`tomyces dermatitidis, Coccidioides immitis, and Histoplasma cap(cid:173)
`sulatum but is less active against Sporothrix schenckii [9, 15].
`A variety of dematiaceous and hyaline molds, many of which
`are resistant to amphotericin B, are susceptible to voriconazole
`in vitro. This includes some, but not all, strains of Pseudalles(cid:173)
`cheria boydii and its asexual form, Scedosporium apiospermum;
`Fusarium species; Paecilomyces species; Bipolaris species; Alter(cid:173)
`naria species; and others [12, 14, 16, 17]. The zygomycetes are
`not susceptible to voriconazole [ 18].
`
`PHARMACOLOGY
`
`Voriconazole is available in both intravenous and oral for(cid:173)
`mulations. The intravenous formulation is solubilized in sul(cid:173)
`fobutyl ether ,6-cyclodextrin sodium (SBECD) and is infused
`
`over 1-2 h. In adults, steady-state plasma levels after intrave(cid:173)
`nous infusion of 3-6 mg/kg twice daily range from 3 to 6 p,g/
`mL [ 19]. Steady-state concentrations are achieved only after
`5-6 days, but, if a loading dose is given, steady-state concen(cid:173)
`trations are achieved within 1 day [20]. The recommended
`regimen is a loading dose of 6 mg/kg every 12 h for 2 doses,
`followed by a maintenanc.e dose of 4 mg/kg every 12 h.
`The oral formulation of voriconazole is available as 50-mg
`and 200-mg tablets. When administered either 1 h before or 1
`h after a meal, the bioavailability of the oral formulation is
`>90o/o. Gastric acid is not needed for absorption; fatty foods
`decrease bioavailability to "'80o/o. In adults, after oral admin(cid:173)
`istration of 200 mg twice daily, steady-state plasma concentra(cid:173)
`tions generally range from 2 to 3 p,g/mL [21]. Patients who
`weigh >40 kg should receive 200 mg every 12 h, and those who
`
`REVIEWS OF ANTI-INFECTIVE AGENTS • CID 2003:36 (I March) • 631
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`in vitro susceptibilities of voriconazole compared with those
`Table 2.
`of other antifungal agents that are active against common Aspergillus
`species .and other molds.
`
`Species,
`antimicrobial agent
`
`Aspergillus fumigatus
`Amphotericin B
`ltraconazole
`Voriconazole
`Aspergillus flavus
`Amphotericin B
`ltraconazole
`Voriconazole
`Aspergillus niger
`Amphotericin B
`ltraconazole
`Voriconazole
`Aspergillus terreus
`Amphotericin B
`ltraconazole
`Voriconazole
`Scedosporium apiospermum
`Amphotericin B
`ltraconazole
`Voriconazole
`Scedosporium prolificans
`Amphotericin B
`ltraconazole
`Voriconazole
`Fusarium so/ani
`Amphotericin B
`ltraconazole
`Voriconazole
`
`MIC 50 range MIC90 range
`or value,
`or value,
`fLg/mL
`fLg/mL
`
`MIC range,
`fLg/mL
`
`0.25-1
`0.06-0.5
`0.03-0.5
`
`0.125-2
`0.25-0.5
`0.25-1
`
`0.125-0.5
`0.25-1
`0.25-1
`
`8
`0.06
`0.5
`
`0.5-4
`0.5-1.0
`0.25-2
`
`0.5-8
`0.25-1
`0.5-2
`
`0.125-4
`0.5-4
`0.5-4
`
`4 to >16
`0.125-0.25
`
`0.125-8
`<0.03-32
`<0.03-4
`
`0.125-8
`0.125-16
`0.125-2
`
`0.125-4
`0.06-8
`0.25-4
`
`0.5-32
`0.03-0.5
`0.25-2
`
`2-4
`8 to >16
`0.25-1
`
`8 to >16
`4 to >16
`0.25-2
`
`1 to >16
`.03 to >16
`0.01-2
`
`8 to> 16
`
`~16
`
`~16
`
`2-16
`
`>16
`4-16
`
`0.125 to >16
`8 to >16
`0.06-32
`
`>16
`2
`
`2-4
`
`>16
`4 to >8
`
`0.5-4
`
`>16
`1 to >8
`
`NOTE. Data are from [9-14, 16, 17].
`
`weigh <40 kg should receive 100 mg every 12 h. Steady-state
`concentrations are achieved within 24 h if a loading dose twice
`the amount of the daily dosage is given on day 1.
`In adults, voriconazole exhibits nonlinear pharmacokinetics,
`which is thought to be related to saturation of metabolism [20].
`There is substantial intersubject variability in the serum con(cid:173)
`centrations achieved. In children, elimination is linear, and
`higher dosages are required to attain the serum concentrations
`noted in adults [22]. Voriconazole is 58o/o protein bound and
`has a large volume of distribution. In animals and humans,
`concentrations in the CSF are -SOo/o of plasma concentrations;
`concentrations in brain tissue are higher than those in the CSF.
`Less than So/o of the drug is excreted unchanged in the urine.
`Metabolism of voriconazole occurs in the liver via the
`CYP450 enzyme family, including the CYP2C9, CYP3A4, and
`
`CYP2C19 isoenzymes. The metabolites do not have antifungal
`activity. The activity of the CYP2C19 pathway, which is the
`major metabolic pathway for voriconazole, is highly dependent
`on genetic characteristics; as many as 20o/o of non-Indian Asians
`have low CYP2C19 activity and can achieve voriconazole levels
`as much as 4 times higher than those noted in homozygous
`subjects who metabolize the drug more extensively. This "poor
`metabolizer" trait is uncommon in white and black populations
`worldwide. There are no dosage adjustments recommended
`with regard to this observation at this point in time. However,
`the observation that hepatic toxicity might be dose related
`should prompt careful attention to the monitoring of liver
`enzyme levels in this population. As might be predicted, drug(cid:173)
`drug interactions (see the next section, below) are of major
`importance in the safe use of voriconazole.
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`Dosage adjustments are necessary for patients with liver dys(cid:173)
`function. The standard loading dose should be used but the
`maintenance dosage should be halved in patients with mild(cid:173)
`to-moderate liver disease. No studies have evaluated the safety
`of voriconazole in patients with severe liver disease. No ad(cid:173)
`justment in the dosage of the oral formulation of voriconazole
`is necessary in patients with renal insufficiency. However, mod(cid:173)
`erate renal insufficiency (creatinine clearance of30-50 mL/min)
`results in accumulation of the intravenous vehicle SBECD, and,
`therefore, intravenous administration should be avoided for
`patients who have a creatinine clearance <50 mL/min.
`
`DRUG-DRUG INTERACTIONS
`
`The potential for drug interactions 'with voriconazole is high
`because of its metabolism by CYP450 isoenzymes (table 3) [ 19].
`Inducers of CYP450, such as rifampin, long-acting barbiturates,
`and carbamazepine, decrease voriconazole concentrations, and
`use of these drugs in combination with voriconazole should
`be avoided. Rifabutin and voriconazole coadministration hot
`only leads to decreased voriconazole levels but also increases
`rifabutin serum concentrations to toxic levels; concomitant use
`of these 2 agents is contraindicated. A similar 2-way interac(cid:173)
`tion occurs between voriconazole and phenytoin, which is a
`
`CYP2C9 substrate and potent CYP450 inducer. Phenytoin de(cid:173)
`creases voriconazole levels; when the 2 drugs are given con(cid:173)
`comitantly, the dosage of voriconazole given orally should be
`doubled. However, voriconazole increases phenytoin levels by
`competing for the CYP2C9 enzyme by which phenytoin is me(cid:173)
`tabolized. Thus, phenytoin levels must be monitored carefully
`when the 2 agents are used concomitantly.
`Voriconazole also interferes with the metabolism of several
`other drugs through inhibition of either the CYP3A4 or the
`CYP2C9 pathway, and coadministration can lead to toxic levels
`of those other drugs. Sirolimus, ergot alkaloids, terfenidine,
`astemizole, quinidine, and cisapride are contraindicated when
`voriconazole is used because of the potential for life-threatening
`reactions. The effects of voriconazole on tacrolimus, cyclo~
`sporine, and warfarin have been studied [23, 24]; decreasing
`the dosages of these medications is necessary, along with very
`careful evaluation of serum levels of the drug or markers for
`the drug's activity (e.g., prothrombin time). Care should be
`taken with concomitant administration of voriconazole and
`statins, benzodiazepines, calcium channel blockers, sulfonylu(cid:173)
`reas, proton pump inhibitors, or vinca alkaloids. In most cases,
`the dosage of the other drug should be decreased anq/or mark(cid:173)
`ers for its activity carefully monitored, because inhibition of
`metabolism and increased serum levels are likely. Correspond-
`
`Table 3.
`
`Drug interactions with voriconazole.
`
`Type of interaction, drug
`
`Decreases voriconazole levels
`Carbamazepine
`Long-acting barbiturates
`Rifampin
`Levels increased by voriconazole
`Astemizole
`Cisapride
`Cyclosporine
`Ergot alkaloids
`Omeprazole
`Quinidine
`Sirolimus
`Tacrolimus
`
`Terfenadine
`Warfarin
`Decreases voriconazole levels and
`increases other drug levels
`Rifabutin
`Phenytoin
`
`Levels likely increased by voriconazole:
`sulfonylureas, statins, vinca alka(cid:173)
`loids, calcium channel blockers,
`benzodiazepines
`
`Recommendation
`
`Contraindicated
`Contraindicated
`Contraindicated
`
`Contraindicated
`Contraindicated
`Reduce dosage by one-half and monitor levels
`Contraindicated
`Reduce dosage by one-half
`Contraindicated
`Contraindicated
`Reduce dosage to one-third of its original level
`and monitor levels
`Contraindicated
`Monitor prothrombin time
`
`Contraindicated
`Double voriconazole dosage and monitor for
`increased phenytoin levels
`Monitor effects of drug and consider decreasing
`dosage when voriconazole is added
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`ingly, when voriconazole treatment is stopped, the dosages of
`these drugs will need to be increased. Drugs that do not require
`dosage adjustment include cimetidine, digoxin, indinavir, mac(cid:173)
`rolides, mycophenolate, prednisolone, and ranitidine.
`
`SIDE EFFECTS
`
`Voriconazole is generally well tolerated. The most common side
`effect-one not previously noted with other azoles-is a re(cid:173)
`versible disturbance of vision (photopsia). This occurs in,...., 30%
`of patients but rarely leads to discontinuation of the drug
`[20-22, 25-27]. Visual disturbances include altered color dis(cid:173)
`crimination, blurred vision, the appearance of bright spots and
`wavy lines, and photophobia. Symptoms tend to occur during
`the first week of therapy and decrease or disappear in spite of
`continued therapy in most patients. Patients whose therapy is
`initiated in an outpatient setting should be cautioned that driv(cid:173)
`ing may be hazardous because of the risk of visual disturbances.
`The visual effects are associated with changes in electroretin(cid:173)
`ogram tracings, which revert to normal when treatment with
`the drug is stopped; no permanent damage to the retina has
`been noted.
`Skin rashes are the second most common adverse effect
`noted with voriconazole therapy. Most of these are mild and
`constitute no major problem. However, severe reactions, in(cid:173)
`cluding Stevens-Johnson syndrome and toxic epidermal nec(cid:173)
`rolysis, have been reported in a very small number of patients.
`Patients should be warned to avoid direct sunlight, because
`photosensitivity reactions can occur. Five patients who devel(cid:173)
`oped facial erythema and cheilitis have been described; 1 of
`these patients also developed lesions similar to those charac(cid:173)
`teristic of discoid lupus erythematosus [ 28]. All of these effects
`disappeared after voriconazole treatment was stopped, but a
`direct causal relationship was not clear for all 5 patients.
`Elevations in hepatic enzyme levels occur with voriconazole
`therapy, as they do with other azole therapy. The usual pattern
`described has been elevations in the serum levels of alanine
`aminotransferase and aspartate aminotransferase, but eleva(cid:173)
`tions in alkaline phosphatase levels have also been noted. Al(cid:173)
`though most patients have asymptomatic elevation of hepatic
`enzyme levels, several patients with severe life-threatening hep(cid:173)
`atitis have been described. The risk of developing hepatitis ap(cid:173)
`pears to increase with increased serum voriconazole levels [29]
`and resolves with discontinuation of treatment with the drug.
`Patients receiving voric:onazole should have liver function tests
`performed prior to therapy, within the first 2 weeks after the
`initiation of therapy, and then every 2-4 weeks throughout
`therapy.
`Other less commonly noted side effects include headache,
`nausea and vomiting, diarrhea, abdominal pain, and visual hal-
`
`lucinations. Visual hallucinations occurred at a rate of 5% in
`one clinical trial and clearly differed from photopsia [27].
`
`CLINICAL USE
`
`Aspergillosis. Voriconazole is approved for the treatment of
`invasive aspergillosis on the basis of the results of a large, mul(cid:173)
`tinational, randomized treatment trial that compared vori