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University of Arkansas for Medical Sciences Myeloma and Transplantation Research Center oduction in whole or in part without permission is pr
University of Arkansas for Medical Sciences Fungi are common pathogens among critically ill or immunosuppressed patients. In the past 15 years safer and/or more bioavailable formulations of older antifungal agents (eg, itraconazole oral solution, lipid amphotericin B formulation) oup unless otherwise noted.
have been marketed. A new class of antifungal agents—the echinocandins—has been developed and now contains 3 agents. In addition, 2 compounds—voriconazole and posaconazole—have been added to the triazole class of agents in this decade.
Today, with increased choices, clinicians are better fungal cell membrane, and inhibition of its synthesis equipped to develop targeted antifungal regimens to compromises cell membrane integrity.
treat invasive fungal infections and tailor therapy to Echinocandins—The echinocandins are lipopeptides meet the needs of a specific patient. This article will derived from natural fungal fermentation products. The summarize the pharmacology, pharmacokinetics, safety, fungal cell wall is composed mostly of polysaccharides, and potential for drug-drug interactions of the currently of which glucans are the most abundant. This class works on a novel target, β-(1,3)-glucan synthase.15 Inhi- ohibited.
bition of this enzyme prevents the synthesis of β-(1,3)- Pharmacology
glucan, compromising cell wall integrity.
Polyenes—Amphotericin B, the primary systemically acting polyene, disrupts eukaryotic cellular membranes Azoles—The systemically acting azoles include flu- by binding nonspecifically to ergosterol and cholesterol conazole, itraconazole, ketoconazole, posaconazole, in fungal and mammalian cells, respectively. In addi- and voriconazole. This class inhibits the cytochrome tion to its effects on sterols, amphotericin B stimulates P-450 (CYP)–dependent enzyme C-14α-demethylase, cytokine release.16 These actions, which are most pro- which is necessary for the conversion of lanosterol to nounced with the deoxycholate formulation, produce ergosterol.14 Ergosterol is critical to the stability of the untoward effects on the renal tubules and vasculature I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
I N F E C T I O U S D I S E A S E S P E C I A L E D I T I O N • 2 0 0 9
that ultimately reduce renal function and complicate than 1% of a dose is eliminated renally as unchanged drug, with approximately 71% of a dose eliminated as Pyrimidine—Flucytosine (Ancobon, Valeant; 5-FC) is parent drug and metabolite(s) in feces.15,30 Unlike other the sole member of the pyrimidine class of antifungals. echinocandins, anidulafungin is excreted primarily Fungi must convert 5-FC intracellularly to its active moi- extrahepatically by slow chemical degradation at phys- ety, which inhibits protein synthesis.
Polyenes—Amphotericin B deoxycholate is rapidly Pharmacokinetics
cleared from the circulation, widely distributed into tis-sue throughout the body, and then eliminated over a ABSORPTION/DISTRIBUTION/METABOLISM/ELIMINATION prolonged period. During a 7-day period, approximately All rights r
Azoles—Chemically, azoles are lipophilic weak bases. 70% of a single dose is recovered from the urine and With the exception of the capsule form of itraconazole, feces, while the remaining 30% of the administered all azoles have good relative or absolute bioavailability Copyright 2009 McMahon Publishing Gr
after oral administration. When ketoconazole and itra- Lipid amphotericin B formulations differ in physico- conazole are administered as solid oral dosage forms, chemical properties and composition, resulting in sub- eserved. Repr
their dissolution in the stomach is significantly influ- tle pharmacokinetic differences. With the exception of liposomal amphotericin B, the lipid formulations are With the exception of posaconazole, all of these also rapidly cleared from the circulation. In general, the agents require extensive oxidative (CYP) metabolism clearance of these compounds from the bloodstream is to be eliminated from the body.19,20 Unlike the other strongly influenced by several important physicochem- triazoles, posaconazole undergoes minimal (2%) CYP ical properties, particularly molecular size.32,33 Larger metab olism; most of its metabolites are glucuronide molecules (ie, diameter ≥100 nm) are cleared more effi- oduction in whole or in part without permission is pr
con jugates formed by uridine diphosphate glucurono- ciently from the circulation by the macrophage–phago- syltransferase (UGT) pathways, mainly UGT1A4.21,22 Flu- cyte system than are smaller molecules (ie, <100 nm). conazole is less lipophilic, and therefore it requires less In terms of toxicity, formulation of amphotericin B with oxidative (CYP) metabolism. The azoles are inhibitors a lipid product alters its distribution to renal tissues of CYP3A4, the primary oxidative drug-metabolizing and perhaps plasma lipoproteins and reduces its toxic enzyme in humans.19,23,24 However, the azoles all differ effects.34 However, whether the subtle pharmacoki- in their affinity for this enzyme. Fluconazole and vori- netic differences translate into clinically significant dif- conazole also inhibit CYP2C9/19, and fluconazole inhib- ferences in efficacy remains to be determined.
its a UGT pathway (UGT2B7).23,25 The significance of the Pyrimidine—The absorption of 5-FC is rapid and com- plete, and in the fasting state it exhibits excellent bio- A variety of transport proteins are expressed in tis- availability.35 Renal clearance is highly correlated with oup unless otherwise noted.
sues throughout the body and facilitate the uptake or creatinine clearance.35 Approximately 90% of a dose is efflux processes involved in drug disposition in humans. Growing evidence indicates that the azoles and echi-nocandins vary in their interactions with transport proteins.26-28 Among the azoles, itraconazole, ketocon- Azoles—The primary toxicities associated with the azole, and posaconazole interact with P-glycoprotein, azoles involve the liver. These toxicities range from the the best-known efflux transport protein.4,28 Ketocon- common transient elevations in serum transaminases to azole and itraconazole interact with another transporter, the less common fulminant hepatoxicity and liver fail- known as breast cancer resistance protein (BCRP).29 ure. Liver failure is rare but it may occur with any azole.
The significance of these interactions with BCRP have Voriconazole produces clinically significant transami- not been fully elucidated, but they may, in part, explain nase abnormalities in approximately 13% of patients.36 certain interactions that previously could not be ade- Whether voriconazole is more hepatotoxic than other quately described by interactions with CYP.
azoles is debatable. The frequency of transaminase Echinocandins—The large molecular size of the echi- abnormalities increases with increases in dose, but most nocandins precludes their oral absorption; thus, all reported cases in voriconazole clinical trials were mild agents are available only as IV formulations. Caspo- to moderate and rarely (approximately 3% of cases) ohibited.
fungin is converted via hydrolysis and N-acetylation resulted in drug discontinuation.37-39 Serum voricon- to inactive metabolites, which are excreted in the bile azole concentrations are weakly associated with the and feces.15 Like all echinocandins, caspofungin does incidence of transaminase abnormalities and do not not interact with CYP at clinically achievable concen- appear to be useful in predicting their occurrence.36 trations.15 However, caspofungin does interact with a Itraconazole has been associated with the develop- transport protein known as organic anion-transporting ment of congestive heart failure.2 The likelihood and polypeptide (OATP 1B1).27 This transporter may facili- severity of this effect are such that the risk and benefits tate the slow metabolism of caspofungin. Micafungin is of using itraconazole for non–life-threatening infections hepatically metabolized by several enzymes (eg, aryl- (eg, onchyomycosis) must be seriously considered.
sulfatase, catechol-O-methyltransferase [COMT]); more Certain azoles have unique toxicities. For example, I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
because of its lack of selectivity for fungal CYP, keto- liposomal amphotericin B was associated with signifi- conazole can produce endocrine abnormalities that lead cantly less nephrotoxicity than was amphotericin B lipid to gynecomastia and adrenocortical insufficiency. Vori- conazole produces visual disturbances in approximately Pyrimidine—The use of 5-FC is primarily associated 20% to 30% of subjects in clinical trials.36 These reac- with myelosuppression. This toxicity is observed with tions are generally mild and transient and rarely lead to elevated concentrations resulting from excessive dos- premature discontinuation of therapy.36 The underlying ing in the presence of diminished renal function. 5-FC is mechanism of this side effect has not been elucidated, used almost exclusively in combination with amphoteri- but it is believed to be concentration- or dose-related.
cin B. Therefore, clinicians should always be cognizant Echinocandins—The echinocandin class has demon- of the additive toxicity of this combination (ie, ampho- All rights r
strated a notable lack of significant toxicity. To date, tericin B–induced reduction in renal function and sub- transient elevations in serum liver enzymes and gastro- intestinal effects (eg, nausea, vomiting, and diarrhea) Copyright 2009 McMahon Publishing Gr
are the most common toxicities associated with the use Potential Drug–Drug Interactions
of caspofungin acetate.15 Micafungin and anidulafungin These agents can interact with a wide array of agents eserved. Repr
are similarly well tolerated. In clinical trials, micafungin through a variety of mechanisms (eg, pharmaco- has demonstrated safety comparable to that of flucon- dynamic, pH, complexation and electrostatic interac- azole. The most commonly reported adverse events tions, CYP and P-glycoprotein). In general, interactions associated with micafungin have been fever, nausea involving amphotericin B are pharmacodynamic and and diarrhea, headache, and transaminase abnormali- occur as a result of its renal toxicity.51,52 By contrast ties.15 Clinical experience with anidulafungin is still rel- with amphotericin B, the azoles are relatively safe, but atively limited; however, in clinical studies of patients they can interact with a wide array of other drugs. Inter- oduction in whole or in part without permission is pr
during its development, treatment-related adverse actions involving the azoles are pharmacokinetic and events including diarrhea, transaminase abnormalities, result as a consequence of their physicochemical prop- and hypokalemia occurred in at least 3% of patients.15 erties.51-53 Ketoconazole and itraconazole are subject to Polyenes—Amphotericin B deoxycholate is primar- ily associated with infusion-related adverse effects (eg, Drugs that will likely interact with these azoles fever, shaking chills, nausea, vomiting, and rash), and include agents that are cationic or increase gastric pH renal dysfunction (eg, nephrotoxicity). The most com- or are lipophilic CYP3A4 substrates with poor oral avail- mon infusion-related adverse events, fever, shaking, and ability. In addition, because of the complex pharmacoki- chills, appear to diminish with subsequent dosing.40 netic properties of itraconazole, predicting the extent Several regimens of diphenhydramine and acetamino- or duration of an interaction is difficult. Fluconazole is phen are used as pretreatment to prevent these adverse not affected by cationic agents or those that increase oup unless otherwise noted.
effects, but their efficacy has not been established.40 gastric pH.54 However, because of its significant renal Infusion-related adverse events may be attenuated elimination, its potential to interact with CYP sub- by using liposomal amphotericin B.41 Although the inci- strates is often overlooked. In addition, its potential to dence of infusion-related adverse effects with the other cause CYP-mediated interactions is greater than is sug- lipid amphotericin B formulations is probably similar gested by in vitro studies.55,56 CYP-mediated interac- to that with amphotericin B deoxycholate, the studies tions involving fluconazole are often dose-dependent. comparing these formulations with the deoxycholate Because of its linear and predictable pharmacoki- formulation were not designed to address this issue.
netic properties, these interactions may sometimes be Although noxious to the patient, infusion-related avoided or managed by using the lowest effective dose adverse events rarely cause early discontinuation of therapy. By contrast, amphotericin B–associated neph- Like fluconazole, voriconazole interacts with multi- rotoxicity often limits the use of amphotericin B deoxy- ple CYP enzymes.23 Therefore, although many interac- cholate and interferes with the use of other medications. tions have yet to be studied, the potential interactions The incidence of amphotericin B–associated nephrotox- may encompass a wide array of medications. There are icity ranges from 12% to 80% and varies with definition few published data from properly controlled studies and patient population studied.16 Risk factors for this investigating drug interactions involving posaconazole. ohibited.
toxicity also vary depending on the population studied, Although posaconazole is minimally metabolized by but the concomitant use of cyclosporine is a risk factor CYP3A4, it is an inhibitor of this enzyme. Moreover, the that has been consistently shown in several studies.42-46 UGT pathways are subject to inhibition and induction by Hydration with 500 mL of normal saline before dos- other medicines. Therefore, as this agent becomes more ing has been shown to reduce the incidence of neph- widely used, it is likely that its drug interaction potential rotoxicity with amphotericin B deoxycholate.16 All lipid will manifest. To date, significant interactions between amphotericin B formulations have significantly lower posaconazole and rifabutin (Mycobutin, Pfizer) and with incidences of nephrotoxicity than that of amphoteri- phenytoin have been reported.57,58 Given its chemical cin B deoxycholate.41,44,47-49 In a head-to-head com- similarity to itraconazole, it is reasonable to assume that parison between lipid amphotericin B formulations, posaconazole will interact with agents that interact with I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
itraconazole, including cyclosporine, tacrolimus (Prograf, P450 enzymes involved in the N-oxidation of voriconazole. Drug Astellas), and certain statins and benzodiazepines; how- Metab Dispos. 2003;31(5):540-547.
ever, the extent of the interactions may differ. 21. Krieter P, Flannery B, Musick T, Gohdes M, Martinho M, Courtney R. Interactions involving 5-FC are pharmacodynamic Disposition of posaconazole following single-dose oral administration in healthy subjects. Antimicrob Agents Chemother. and involve drugs that reduce its renal elimination or share its myelosuppressive properties. Drug interac- uan Y, et al. Identification of human UDP- tions with caspofungin and micafungin are rare, likely glucuronosyltransferase enzyme(s) responsible for the do not involve CYP reactions, and often are not clini- glucuronidation of posaconazole (Noxafil). Drug Metab Dispos. 2004;32(2):267-271.
cally significant.2 Clinical experience with anidulafungin is still limited, but to date its use has been relatively a T, Shiraga T, Takagi A. Effect of antifungal drugs on cyto- All rights r
chrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities devoid of any associated drug interaction.6 in human liver microsomes. Biol Pharm Bull. 2005;28(9):1805-1808.
Conclusion
exler D, Courtney R, Richards W, Banfield C, Lim J, Laughlin M. Copyright 2009 McMahon Publishing Gr
Effect of posaconazole on cytochrome P450 enzymes: a The choice of systemic antifungal agents is growing. randomized, open-label, two-way crossover study. Eur J Pharm Sci. Clinicians must recognize the differences in toxicity and eserved. Repr
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18. Lange D, Pavao JH, Wu J, Klausner M. Effect of a cola beverage on ood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleiner- the bioavailability of itraconazole in the presence of H2 blockers. J mans D. Pharmacokinetics and safety of voriconazole Clin Pharmacol. 1997;37(6):535-540.
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of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. 41. Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for L Amph/ABLC Collaborative Study Group. Clin Infect Dis. empirical therapy in patients with persistent fever and neutrope- nia. National Institute of Allergy and Infectious Diseases Mycoses 51. Gubbins PO, Amsden JR. Drug-drug interactions of antifungal Study Group. N Engl J Med. 1999;340(10):764-771.
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43. ennedy MS, Deeg HJ, Siegel M, Crowley JJ, Storb R, Thomas All rights r
ED. Acute renal toxicity with combined use of amphotericin B 3. enkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of and cyclosporine after marrow transplantation. Transplantation. the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet. 2000;38():111-180.
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e MH, Bowden RA, Sandler ES, et al. Randomized, Andrea DT, Florentino BM, et al. Increased gastric pH and the bioavailability of fluconazole and ketoconazole. Ann Intern double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clin Infect Dis. 1998;2 eserved. Repr 7():296-302.
MD. Ketoconazole and fluconazole inhibition of the metabo- elli L, Gurwith M, Bowden R. Treatment of inva- lism of cyclosporin A by human liver in vitro. Ther Drug Monit. sive fungal infections with amphotericin B colloidal dispersion in bone marrow transplant recipients. Bone Marrow Transplant. ola KT, Ahonen J, Neuvonen PJ. The effects of the systemic antimycotics, itraconazole and fluconazole, on the , Kelsey S, Chu P, et al. Amphotericin B lipid complex pharmacokinetics and pharmacodynamics of intravenous and (ABLC) for the treatment of confirmed or presumed fungal oral midazolam. Anesth Analg. 1996;82(3):511-516.
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oup unless otherwise noted.
Notes to Tables
Polyenes—Destabilize the fungal cell membrane. Bind to the ste- rol ergosterol incorporated in the fungal cell membrane, creating pores in the membrane and leading to depolarization of the mem- brane with subsequent cell leakage. In mammalian cells, polyenes conventional amphotericin B (deoxycholate) CNS/CSF central nervous system/cerebrospinal fluid penetration
Pyrimidine—Transported intracellularly by cytosine permease. Converted to fluorouracil via cytosine deaminase, then to 5-fluo- rouridine triphosphate, which is incorporated into fungal RNA and interferes with protein synthesis. The flucytosine intermediate also inhibits thymidylate synthase and interferes with DNA synthesis.
Echinocandins—Inhibition of β-(1,3) glucan synthesis via inhibition of β-(1,3) glucan synthase. Fungal cell wall is mostly polysaccharides, and glucans are the most abundant polymers in fungal cell walls. Glucan synthase catalyzes polymerization of these polysaccarides. Inhibition of this enzyme leads to increased cell wall permeability Azoles—Interfere with sterol synthesis via inhibition of CYP- ohibited.
demethylase, a fungal CYP enzyme important in converting lanosterol to ergosterol.
uridine diphosphate glucuronosyltransferase b The incidence, clinical significance, and causality of the adverse event in relation to the drug are not fully established.
c Differences in the incidence of these adverse effects exist among d Pharmacokinetic values for IV and PO fluconazole are similar.
e Rare and can occur with any azole; however, itraconazole has been f Also occurs with oral voriconazole.
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
Table 1. Overview of Drugs Approved in the United States
For the Treatment of Systemic Mycoses

Indications
Absorption/Distribution
Amphotericin
Potentially life-threatening fungal infections, including aspergillosis, blastomycosis, Absorption: NA; Protein Binding: Significant; Vd: B deoxycholate
coccidioidomycosis, cryptococcosis, histoplasmosis, systemic candidiasis, and zygo- 2.3-4 L/kg; CNS/CSF: Minimal; Tissue Concentrations: (various)
mycosis; infections caused by susceptible species of Conidiobolus and Basidiobolus; sporotrichosis; leishmaniasis. Unlabeled uses: prophylaxis of fungal infection in patients with BMT; primary amoebic meningoencephalitis caused by Naegleria fowleri; ocular aspergillosis; candidal cystitis; chemoprophylaxis in immunocompromised patients at risk for aspergillosis; severe meningitis unresponsive to I.V. therapy; coccidioidal arthritis.
All rights r
Amphotericin B
Invasive aspergillosis in patients in whom renal impairment or unacceptable toxicity Absorption: NA; Protein Binding: Unknown; colloidal dispersion
precludes the use of amphotericin B deoxycholate in effective doses; patients with inva- Vd: 1.1-4.1 L/kg; CNS/CSF: <L-AMB, ≈CAB, ABLC; (Amphotec, Three
sive aspergillosis in whom prior amphotericin B deoxycholate therapy has failed.
Copyright 2009 McMahon Publishing Gr
Amphotericin B lipid
Invasive fungal infections in patients who are refractory to or intolerant of amphoteri- Absorption: NA; Protein Binding: Unknown; Vd: complex (Abelcet,
Very large; CNS/CSF: <L-AMB, ≈CAB, ABCD; eserved. Repr
Liposomal
Empiric therapy for presumed fungal infection in febrile neutropenic patients; treat- Absorption: NA; Protein Binding: Significant, but amphotericin B
ment of cryptococcal meningitis in HIV-infected patients; treatment of Aspergillus spp, <CAB; Vd: Small (≈plasma volume); CNS/CSF: >CAB, (AmBisome, Astellas)
Candida spp, and/or Cryptococcus spp infections refractory to amphotericin B deoxy- ABLC, ABCD; Tissue Concentrations: Unknown cholate, or in patients in whom renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate; treatment of visceral leishmaniasis.
Flucytosine
Serious infections caused by susceptible strains of Candida and/or Cryptococcus spp.
Absorption: Fasting: Rapid; Fed: Slow; Bioavailability: (Ancobon, Valeant)
≈90%; pH-dependent: No; Protein Binding: Minimal oduction in whole or in part without permission is pr
(4%); Vd: Approximates total body water; CNS/CSF: Significant (75% serum); Tissue Concentrations: Good yrimidine
P

Anidulafungin
Candidemia and other forms of Candida infections (intra-abdominal abscess and Absorption: NA; Protein Binding: Significant (84%); (Eraxis, Pfizer)
peritonitis); esophageal candidiasis.
Vd: 0.6 L/kg; CNS/CSF: Unknown Caspofungin
Candidemia and the following Candida infections: intra-abdominal abscesses, Absorption: NA; Protein Binding: Significant; (Cancidas, Merck)
peritonitis, and pleural space infections; esophageal candidiasis; invasive aspergillosis in Vd: 0.15 L/kg; CNS/CSF: Likely minimal; Tissue patients refractory to or intolerant of other therapies (amphotericin B, lipid formulations of amphotericin B, and/or itraconazole); empiric therapy for presumed fungal infections in febrile neutropenic patients.
chinocandins
E

Micafungin
Candidemia, acute disseminated candidiasis, Candida peritonitis, and abscesses; esoph- Absorption: NA; Protein Binding: Significant; Vd: 0.4 (Mycamine, Astellas)
ageal candidiasis; Candida infection prophylaxis in patients undergoing HSCT.
L/kg; CNS/CSF: Undetectable; Tissue Concentrations: oup unless otherwise noted.
Fluconazoled
Vaginal, oropharyngeal, and esophageal candidiasis; cryptococcal meningitis; prophy- Absorption: Fasting: Rapid (1-3 h); Fed: Rapid (1-3 h); (Diflucan, Pfizer;
laxis to decrease the incidence of candidiasis in patients undergoing BMT who receive Bioavailability: >93%; pH-dependent: No; Protein various)
cytotoxic chemotherapy and/or radiation.
Binding: Minimal (<10%); Vd: Small (0.7-0.8 L/kg); CNS/CSF: Significant (60%-80%); Tissue Concentrations: High—Brain, eye, liver, prostate, skin, vagina Itraconazole
IV, oral capsule: Pulmonary and extrapulmonary blastomycosis; histoplasmosis,
Oral capsulesAbsorption: Fasting: Slow (4-6 h);
(Sporanox, Janssen/
including chronic cavitary pulmonary disease and disseminated, nonmeningeal Fed: Slow (4-6 h); Bioavailability: ≈30%; pH-depen- Ortho-McNeil;
histoplasmosis; aspergillosis in patients who are refractory to or intolerant of various)
Oral solutionAbsorption: Fasting: Rapid (1-2 h);
Oral capsules only: Nonimmunocompromised patients: treatment of onychomycosis
Fed: Rapid (1-2 h); Bioavailability: 55%; pH-depen- of the toenail, with or without fingernail involvement, or of the fingernail alone, due to dent: No; Food: ↓ Absorption All dosage formsProtein Binding: Significant
Oral solution only: Oropharyngeal and esophageal candidiasis.
(99.8%); Vd: Very large (≈11 L/kg); CNS/CSF: Minimal (<1%); Tissue Concentrations: High—Fat, skin, prostate; Moderate—Bone, liver, lung; Low—Kidney, muscle, spleen Ketoconazole
Candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, Absorption: Fasting: Rapid (1-2 h); Fed: Slow (3-4 h); (Nizoral, Janssen/
coccidioidomycosis, histoplasmosis, chromoblastomycosis, and paracoccidioidomyco- Bioavailability: 80%; pH-dependent: Yes; Protein Ortho-McNeil;
sis; severe recalcitrant cutaneous dermatophyte infections that have not responded to Binding: Significant; Vd: Large; CNS/CSF: Minimal; ohibited.
various)
topical therapy or oral griseofulvin, or in patients unable to take griseofulvin.
Tissue Concentrations: High—Skin, tendon; Low—Bone, muscle Posaconazole
Prophylaxis of invasive Aspergillus and Candida infections in patients ≥13 years of age Absorption: Fasting: Slow (≈5h); Fed: Slow (≈5h); (Noxafil, Schering-
who are at high risk for these infections because of severe immunocompromise (HSCT Bioavailability: Unknown; pH-Dependent: Yes; Food: patients, GVHD, hematologic malignancies with prolonged neutropenia from chemo- ↑ Absorption; Protein Binding: Significant (>95%); therapy); oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to Vd: Very Large (1,774 L); CNS/CSF: Unknown Voriconazole
Invasive aspergillosis; candidemia in non-neutropenic patients and the following Absorption: Fasting: Rapid (1-2 h); Fed: Rapid (<1 h); (Vfend, Pfizer)
Candida infections: disseminated infections in skin and infections in abdomen, kidney, Bioavailability: ≈96%; pH-dependent: No; Food: bladder wall, and wounds; esophageal candidiasis; serious fungal infections caused by ↓ Absorption; Protein Binding: Notable (≈60%); Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium Vd: 2 L/kg; CNS/CSF: Probably significant; Tissue spp, including F. solani, in patients intolerant of, or refractory to, other therapy.
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
Table 1. Overview of Drugs Approved in the United States
For the Treatment of Systemic Mycoses (continued)

Metabolism/Elimination
Dosage Adjustments
Amphotericin
Metabolism: None; CYP/Pgp: None; Elimination: 40% in feces and bile after 1 wk; Renal: Switch to less nephrotoxic formulation if B deoxycholate
Urine Recovery: 32% after 1 wk; Excretion Into Breast Milk: Unknown SCr >2.5 mg/dL; Hemodialysis: Unknown; Hepatic: (various)
All rights r
Amphotericin B
Metabolism: None; CYP/Pgp: None; Elimination: Not fully elucidated; Urine Recovery: colloidal dispersion
Not fully elucidated; Excretion Into Breast Milk: Unknown (Amphotec, Three
Rivers) Copyright 2009 McMahon Publishing Gr
Amphotericin B lipid
Metabolism: None; CYP/Pgp: None; Elimination: Not fully elucidated; Urine Recovery: complex (Abelcet,
Not fully elucidated; Excretion Into Breast Milk: Unknown Enzon) eserved. Repr
Liposomal
Metabolism: None; CYP/Pgp: None; Elimination: 5% in feces and bile after 1 wk; amphotericin B
Urine Recovery: 5% after 1 wk; Excretion Into Breast Milk: Unknown (AmBisome, Astellas)
Flucytosine
Metabolism: None; CYP/Pgp: None; Elimination: Primarily excreted through urine; Renal: CrCl >40 mL/min: usual dose; CrCl = 20-40 (Ancobon, Valeant)
Urine Recovery: Very high; Excretion Into Breast Milk: Unknown mL/min: 12.5-37.5 mg/kg q12h; CrCl = 10-20 mL/ oduction in whole or in part without permission is pr
min: 12.5-37.5 mg/kg q24h; CrCl <10 mL/min: dose based on serum concentrations; Hemodialysis: yrimidine
20-50 mg/kg after dialysis; Hepatic: None Anidulafungin
Metabolism: Slow chemical degradation at physiologic temperature and pH to an Renal: None; Hemodialysis: None; Hepatic: None (Eraxis, Pfizer)
inactive open-ring peptide that is degraded and eliminated; CYP/Pgp: None; Other Transporters: Unknown; Elimination: Feces <10%; Urine Recovery: <1%; Excretion Into Breast Milk: Unknown; use caution during lactation Caspofungin
Metabolism: Hydrolysis, N-acetylation (liver); spontaneous degradation to an Renal: None; Hemodialysis: Unknown; Hepatic: (Cancidas, Merck)
open-ring peptide compound; CYP/Pgp: None/none; Other Transporters: OATP 1B1; Moderate impairment: 70-mg loading dose, then Elimination: Biliary and feces, 35%; Urine Recovery: 41%; Excretion Into Breast Milk: chinocandins
E

Micafungin
Metabolism: Hepatic via arylsulfatase, COMT, and hydroxylation; CYP/Pgp: Minimal/ Renal: None; Hemodialysis: None; Hepatic: (Mycamine, Astellas)
none; Other Transporters: Unknown; Elimination: Feces, 71%; Urine Recovery: <1% of Moderate impairment: None; Severe impairment: oup unless otherwise noted.
dose; Excretion Into Breast Milk: Unknown; use caution during lactation Fluconazoled
Metabolism: Minimal (10%) in liver; CYP/Pgp: S/I CYP 3A4, 2C9/19, no Pgp; Phase II Renal: 50- to 400-mg load, then CrCl >50 mL/ (Diflucan, Pfizer;
S/I: No/UGT2B7; Other Transporters: Unknown; Elimination: Primarily renally excreted; min: usual dose; CrCl ≤50 mL/min: half usual various)
Urine Recovery: 89%; Excretion Into Breast Milk: Yes dose; Hemodialysis: Usual dose after dialysis; Hepatic: None Itraconazole
Metabolism: Extensive in GI tract and liver; CYP/Pgp: S/I CYP3A4 and Pgp; Phase Capsules, solution: Renal: None; Hemodialysis/ (Sporanox, Janssen/
II S/I: No/no; Other Transporters: BCRP; Elimination: Excreted into bile and feces; Peritoneal Dialysis: None; Hepatic: Unknown Ortho-McNeil;
Urine Recovery: <1% of dose; Excretion Into Breast Milk: Yes various)
Ketoconazole
Metabolism: Extensive in GI tract and liver; CYP/Pgp: S/I CYP3A4 and Pgp; Renal: None; Hemodialysis: None; Hepatic: Unknown (Nizoral, Janssen/
Elimination: Excreted into bile and feces; Urine Recovery: <5% of dose; Ortho-McNeil;
Excretion Into Breast Milk: Likely ohibited.
various)
Posaconazole
Metabolism: Minimum of 67% eliminated as unchanged drug; 17% metabolized; CYP/ Renal: None; Hemodialysis: None; Hepatic: Unknown (Noxafil, Schering-
Pgp S/I: CYP3A4 substrate (2%), also I, likely Pgp S/I; Phase II S/I: UGT1A4 substrate; Other Transporters: Unknown; Elimination: feces 77%; Urine Recovery: <14%; Excretion Into Breast Milk: Unknown, use caution during lactation Voriconazole
Metabolism: Extensive in GI tract and liver; CYP/Pgp: S/I CYP 3A4, 2C9/19, and no Pgp; Oral: Renal: None
(Vfend, Pfizer)
Phase II S/I: No/no; Other Transporters: None; Elimination: Excreted into bile and feces; IV: Renal: Cl of excipient reduced 4-fold in moder-
Urine Recovery: <2% of dose; Excretion Into Breast Milk: Likely ate to severe renal impairment (CrCl 30-50 mL/min); avoid IV use if CrCl ≤50 mL/min unless benefit > risk; Hepatic: Mild to moderate hepatic cirrhosis; use stan-dard loading dose, then 50% of maintenance dose I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
Table 1. Overview of Drugs Approved in the United States
For the Treatment of Systemic Mycoses (continued)

Indications
Amphotericin
B deoxycholate
(various)

Amphotericin B
colloidal dispersion

(Amphotec, Three
Acute Infusion Reactions—Fever,c headache, nausea/vomiting, shaking chillsc; Cardiopulmonary—Arrhythmia, dyspnea, All rights r
hypotension, peripheral/pulmonary edema, tachypnea; Electrolyte Disturbances—Hypocalcemia, hypokalemia,c hypomagnesemiac; Gastrointestinal—Abdominal pain/dyspepsia, anorexia/weight loss (rare), diarrhea; Hematologic—Anemia; Hepatic—↑ LFT; CNS—Confusion (rare), malaise (rare), nervousness (rare), seizure (rare); Local Reactions—Erythema (rare), Amphotericin B lipid
pain/inflammation at injection site (rare); Nephrotoxicity—↑ BUN, SCrc; Miscellaneous—Joint/muscle pain (rare) complex (Abelcet,
Copyright 2009 McMahon Publishing Gr
Liposomal
eserved. Repr
amphotericin B
(AmBisome, Astellas)

Flucytosine
Cardiopulmonary—Arrhythmia (rare), dyspnea (rare); CNS—Headache, seizure (rare); Gastrointestinal—Abdominal (Ancobon, Valeant)
pain/dyspepsia, anorexia/weight loss (rare), diarrhea, hemorrhage/duodenal ulcer, nausea/vomiting; Hematologic—Myelosuppression; Hepatic—↑ LFT; Nephrotoxicity—Crystalluria (rare) yrimidine
P

oduction in whole or in part without permission is pr
Anidulafungin (Eraxis,
Acute Infusion Reactions—Peripheral edema, rigors; CNS—Headache; Electrolyte Disturbances—Hypokalemia; Gastrointestinal— Constipation, diarrhea, dyspepsia, nausea/vomiting, upper abdominal pain; General—Possible histamine-mediated symptoms including dyspnea, flushing, hypotension, pruritus, rash, and urticaria; rare when infusion rate ≤1.1 mg/min; Hepatic—↑ LFT; Caution: Must be reconstituted with the companion diluent (20% [w/w] dehydrated alcohol in water for injection) and subsequently diluted with only 5% dextrose injection, USP, or 0.9% sodium chloride injection, USP (normal saline); reconstituted solution must be further diluted into the appropriately sized IV bag; rate of infusion should not exceed 1.1 mg/min Caspofungin
Acute Infusion Reactions—Fever (rare), headache, nausea/vomiting, shaking chills (rare); Cardiovascular—Swelling and (Cancidas, Merck)
peripheral edema (rare); Electrolyte Disturbances—Hypercalcemia, hypokalemia; Gastrointestinal—Diarrhea; General—Possible histamine-mediated symptoms, including bronchospasm, facial swelling, pruritus, rash, and sensation of warmth; anaphylaxis; Hematologic—Anemia (rare); Hepatic—↑ LFT; clinically significant hepatic dysfunction (rare); Local Reactions—Pain/ chinocandins
E

inflammation at injection site (rare); Miscellaneous—Joint/muscle pain (rare) Micafungin
Acute Infusion Reactions—Fever, shaking chills; CNS—Dizziness, headache; Dermatologic/Hypersensitivity—Pruritus, rash; (Mycamine, Astellas)
Electrolyte Disturbances—Hypocalcemia, hypokalemia, hypomagnesemia; Gastrointestinal—Abdominal pain/dyspepsia, diarrhea, nausea/vomiting; Hematologic—Anemia, myelosuppression, thrombocytopenia; Hepatic—↑ LFT; Local Reactions—Erythema, pain/inflammation at injection site; Miscellaneous—Fever oup unless otherwise noted.
Fluconazoled
Cardiopulmonary—Hypotension (rare), peripheral/pulmonary edema (rare); CNS—Dizziness (rare), headache, seizure (Diflucan, Pfizer;
(rare); Dermatologic/Hypersensitivity—Anaphylaxis, eosinophilia, pruritus, rash; Electrolyte Disturbances—Hypokalemia various)
(rare); Gastrointestinal—Abdominal pain/dyspepsia, diarrhea, dysgeusia, nausea/vomiting; Hematologic—Anemia (rare), myelosuppression (rare), thrombocytopenia (rare); Hepatic—↑ LFT; hepatic necrosis/hepatitis/cholestasise; Miscellaneous—Alopecia, fever (rare) Itraconazole
Cardiopulmonary—Congestive heart failure, hypertension (rare), peripheral/pulmonary edema, tachycardia (rare), tachypnea (Sporanox, Janssen/
(rare); CNS—Dizziness (rare), headache; Dermatologic/Hypersensitivity—Anaphylaxis, eosinophilia, pruritus, rash; Electrolyte Ortho-McNeil;
Disturbances—Hypokalemia (rare); Endocrine—Altered hormone levels (rare), gynecomastia (rare); Gastrointestinalvarious)
Abdominal pain/dyspepsia, diarrhea, flatulence (rare), nausea/vomiting; Hepatic—↑ LFT, hepatic necrosis/hepatitis/cholestasise; Miscellaneous—Fever (rare), alopecia (rare) Ketoconazole
Cardiopulmonary—Hypertension (rare); CNS—Headache; Dermatologic/Hypersensitivity—Anaphylaxis, eosinophilia, pruritus, (Nizoral, Janssen/
rash; Endocrine—Adrenocortical insufficiency, altered hormone levels, gynecomastia, inhibition of cortisol synthesis; Ortho-McNeil;
Gastrointestinal—Abdominal pain/dyspepsia, diarrhea, flatulence (rare), nausea/vomiting; Hematologic—Anemia (rare), various)
myelosuppression (rare), thrombocytopenia (rare); Hepatic—↑ LFT, hepatic necrosis/hepatitis/cholestasise; Miscellaneous Posaconazole
Electrolyte Disturbance—Hypokalemia; Endocrine—Adrenal insufficiency (rare); Gastrointestinal—Abdominal pain, constipation, (Noxafil, Schering-
diarrhea, dyspepsia, nausea/vomiting; General—Allergic and/or hypersensitivity reactions (rare), anorexia, dizziness, edema, fatigue, fever, headache, lower extremity edema, rigors, weakness; Hepatic—↑ LFT, hepatic necrosis/hepatitis/cholestasise ohibited.
Voriconazole
Acute Infusion Reactions—Fever (rare), nausea/vomiting (rare), visual disturbancesf; Cardiopulmonary—Congestive heart (Vfend, Pfizer)
failure (rare), hypertension (rare), hypotension (rare), peripheral/pulmonary edema (rare), tachycardia (rare); CNS—Dizziness (rare), hallucinations (rare), headache, seizure (rare); Dermatologic/Hypersensitivity—Anaphylaxis, eosinophilia, pruritus, rash; Electrolyte Disturbances—Hypokalemia (rare); Endocrine—Adrenocortical insufficiency (rare), altered hormone levels (unknown), gynecomastia (unknown), inhibition of cortisol synthesis (unknown); Gastrointestinal—Abdominal pain/dyspepsia, diarrhea, dysgeusia (unknown), flatulence (rare), nausea/vomiting; Hematologic—Anemia (unknown), myelosuppression (unknown), thrombocytopenia (unknown); Hepatic—↑ LFT, hepatic necrosis/hepatitis/cholestasise; Miscellaneous—Alopecia (unknown), fever (unknown), joint/muscle pain (rare) I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
Table 2. Overview of Drugs Approved in the United States
For the Treatment of Systemic Mycoses

Interaction confirmed by controlled study; generally considered clinically significant;
avoid combination if possible, or monitor closely
Amphotericin B
deoxycholate (various)
mide, erythromycin, pentamidine, quinidine, sotalol Inotropes: cardiac glycosides All rights r
actions
er

Amphotericin B
colloidal dispersion
(Amphotec, Three
Copyright 2009 McMahon Publishing Gr
Amphotericin B
eserved. Repr
lipid complex
(Abelcet, Enzon)
ologic Drug–Drug Int
Liposomal
amphotericin B
(AmBisome, Astellas)
Flucytosine
(Ancobon, Valeant)
oduction in whole or in part without permission is pr
yrimidine
P

Anidulafungin
(Eraxis, Pfizer)

Caspofungin
(Cancidas, Merck)
Micafungin
chinocandins
(Mycamine, Astellas)
Fluconazoled
(Diflucan, Pfizer;
various)
oup unless otherwise noted.
Itraconazole
(Sporanox, Janssen/
Ortho-McNeil; various)
Others: ethinyl estradiol, fexofenadine, okinetic Drug–Drug Int
Ketoconazole
Antiretrovirals: amprenavir, didanosine, (Nizoral, Janssen/
Ortho-McNeil; various)
Posaconazole
(Noxafil, Schering-
ohibited.
Steroids/Immunosuppressants: cyclosporine, sirolimus, tacrolimus Voriconazole
(Vfend, Pfizer)
Antiepileptics: carbamazepine, phenobarbital I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
Table 2. Overview of Drugs Approved in the United States
For the Treatment of Systemic Mycoses (continued)

Interaction confirmed by controlled study; generally considered clinically significant;
use combination cautiously
Amphotericin B
deoxycholate (various)
All rights r
Amphotericin B
colloidal dispersion
(Amphotec, Three
Copyright 2009 McMahon Publishing Gr
Amphotericin B
lipid complex
(Abelcet, Enzon)
eserved. Repr
ologic Drug–Drug Int
Liposomal amphot-
ericin B (AmBisome,
Astellas)
Flucytosine
(Ancobon, Valeant)
Inotropes: cardiac glycosidesOthers: diuretics, oduction in whole or in part without permission is pr
yrimidine
Anidulafungin
(Eraxis, Pfizer)

Caspofungin
(Cancidas, Merck)
Micafungin
(Mycamine, Astellas)
chinocandins
E

Fluconazoled
(Diflucan, Pfizer;
various)
oup unless otherwise noted.
Itraconazole
(Sporanox, Janssen/
Ortho-McNeil; various)
pioglitazone, repaglinide, sulfonylureas okinetic Drug–Drug Int
Ketoconazole
(Nizoral, Janssen/
Ortho-McNeil; various)
ohibited.
Posaconazole
(Noxafil, Schering-
Plough)

Voriconazole
(Vfend, Pfizer)
dine, nelfinavir, nevirapine, ritonavir, Antineoplastics: vinblastine, vincristine with norethindrone 1 mg/ethinyl estradiol 35 mcg, oral hypoglycemics I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
Table 2. Overview of Drugs Approved in the United States
For the Treatment of Systemic Mycoses (continued)

Combination studied and no or minimal interaction observed; not clinically significant or
benefit of combination outweighs risk for interaction; combination can be used
Amphotericin B
deoxycholate (various)
All rights rAmphotericin B
colloidal dispersion
(Amphotec, Three
Rivers)

Copyright 2009 McMahon Publishing Gr
Amphotericin B
lipid complex
(Abelcet, Enzon)
eserved. Repr
mide, erythromycin, pentamidine, quinidine, sotalol Liposomal
amphotericin B
(AmBisome, Astellas)
ologic Drug–Drug Int
Others: diuretics, glucocorticoids, skel- oduction in whole or in part without permission is pr
Flucytosine
(Ancobon, Valeant)
yrimidine
P

Anidulafungin
(Eraxis, Pfizer)
Caspofungin
(Cancidas, Merck)
Micafungin
(Mycamine, Astellas)
oup unless otherwise noted.
chinocandins
E

Fluconazoled
(Diflucan, Pfizer;
various)
Antiretrovirals: delavirdine, didanosine, Itraconazole
(Sporanox, Janssen/
Ortho-McNeil; various)
okinetic Drug–Drug Int
Ketoconazole
(Nizoral, Janssen/
Ortho-McNeil; various)
ohibited.
Posaconazole
Antiretrovirals: indinavir, lamivudine, (Noxafil, Schering-
Voriconazole
(Vfend, Pfizer)
Antiretrovirals: indinavirGastric acid modifiers: cimetidine, ranitidine I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Source: http://infectiousdiseasese.com/download/Antifungal_Overview_WM.pdf

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