lippincott's illustrated reviews:...

Antifungal Drugs 35I. OVERVIEW

Infectious diseases caused by fungi are called mycoses, and they are often chronic in nature.1 Some mycotic infections are superficial and some involve the skin (cutaneous mycoses extending into the epidermis), but fungi may also penetrate the skin, causing subcutaneous infections. The fungal infections that are most difficult to treat are the systemic myco-ses, which are often life threatening. Unlike bacteria, fungi are eukary-otic. They have rigid cell walls composed largely of chitin (a polymer of N-acetylglucosamine) rather than peptidoglycan (a characteristic com-ponent of most bacterial cell walls). The fungal cell membrane contains ergosterol rather than the cholesterol found in mammalian membranes. These chemical characteristics are useful in targeting chemotherapeutic agents against fungal infections. Fungal infections are generally resistant to antibiotics used in the treatment of bacterial infections, and, conversely, bacteria are resistant to the antifungal agents. The last two decades have seen a rise in the incidence of fungal infections such that candidemia is a significant cause of septicemia. This increased incidence of fungal infec-tions is associated with greater numbers of patients with chronic immune suppression following organ transplant, from undergoing chemotherapy for myelogenous and solid tumors, or from the human immunodeficiency virus (HIV). During this same period, there have been significant changes in the therapeutic options available to the clinician, including new azoles and echinocandins. Figure 35.1 lists clinically useful agents for subcutane-ous and systemic mycoses as well as cutaneous mycoses.

II. DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOTIC INFECTIONS

A. Amphotericin B

Amphotericin [am-foe-TER-i-sin] B is a naturally occurring polyene macrolide antibiotic produced by Streptomyces nodosus. In spite of its toxic potential, amphotericin B is the drug of choice for the treat-ment of life-threatening systemic mycoses. [Note: Conventional amphotericin (amphotericin B deoxycholate, the nonlipid formula-tion) has undergone several formulation improvements to reduce the incidence of side effects, particularly nephrotoxicity.] The drug is also sometimes used in combination with flucytosine to achieve more rapid sterilization of the cerebrospinal fluid (CSF).

INFOLINK

1See Chapter 20 in Lippincott’s Illustrated Reviews: Microbiology for a discussion of fungal infections.

DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOSESAmphotericin B AMBISOMEAnidulafungin ERAXISCaspofungin CANCIDASFluconazole DIFLUCANFlucytosine ANCOBONItraconazole SPORANOXKetoconazole NIZORALMicafungin MYCAMINEPosaconazole NOXAFILVoriconazole VFEND

DRUGS FOR CUTANEOUS MYCOSESButenafine LOTRIMIN ULTRAClotrimazole, LOTRIMIN AFCiclopirox PENLACEconazole ECONAZOLE NITRATEGriseofulvin GRIFULVIN V, GRIS-PEGMiconazole FUNGOID, MICATIN, MONISTATNaftifine NAFTINNystatin MYCOSTATINOxiconazole OXISTATSertaconazole ERTACZOSulconazole EXELDERMTerbinafine LAMISILTerconazole TERAZOLTioconazole VAGISTAT-1Tolnaftate TINACTIN

Figure 35.1Summary of antifungal drugs.

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430 35. Antifungal Drugs

1. Mechanism of action: Several amphotericin B molecules bind to ergosterol in the plasma membranes of sensitive fungal cells. There, they form pores (channels) that require hydrophobic interactions between the lipophilic segment of the polyene antibiotic and the sterol (Figure 35.2). The pores disrupt membrane function, allow-ing electrolytes (particularly potassium) and small molecules to leak from the cell, resulting in cell death. [Note: Because the polyene antibiotics bind preferentially to ergosterol rather than to choles-terol (the sterol found in mammalian membranes) a relative (but not absolute) specifi city is conferred.]

2. Antifungal spectrum: Amphotericin B is either fungicidal or fungi-static, depending on the organism and the concentration of the drug. It is eff ective against a wide range of fungi, including Candidaalbicans, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, and many strains of Aspergillus. [Note: Amphotericin B is also used in the treatment of the protozoal infection leishmaniasis.]

3. Resistance: Fungal resistance, although infrequent, is associated with decreased ergosterol content of the fungal membrane.

4. Pharmacokinetics: Amphotericin B is administered by slow, intra-venous (IV) infusion (Figure 35.3). Amphotericin B is insoluble in water, and injectable preparations require the addition of sodium deoxycholate, which produces a soluble colloidal dispersion. The more dangerous intrathecal route is sometimes chosen for the treat-ment of meningitis caused by fungi that are sensitive to the drug. Amphotericin B has also been formulated with a variety of artifi cial lipids that form liposomes. The three amphotericin B lipid formula-tions marketed in the United States are AMPHOTEC, ABELCET, and AMBISOME. For example, the simplest and smallest of the lipo-some preparations, AMBISOME, is produced by the incorporation of amphotericin B into a single liposomal bilayer composed of phos-pholipids and cholesterol (Figure 35.4). These liposomal prepara-tions have the primary advantage of reduced renal and infusion toxicity. However, because of their high cost, liposomal prepara-tions are reserved mainly as salvage therapy for those individuals who cannot tolerate conventional amphotericin B. Amphotericin B is extensively bound to plasma proteins and is distributed through-out the body, becoming highly tissue bound. Infl ammation favors penetration into various body fl uids, but little of the drug is found in the cerebrospinal fl uid (CSF), vitreous humor, or amniotic fl uid. However, amphotericin B does cross the placenta. Low levels of the drug and its metabolites appear in the urine over a long period of time, and some are also eliminated via the bile. Dosage adjustment is not required in patients with compromised hepatic function, but when conventional amphotericin B causes renal dysfunction, the total daily dose is decreased by 50 percent. To minimize nephro-toxicity, alternatives including sodium loading with infusions of nor-mal saline and the lipid-based amphotericin B products are used.

5. Adverse eff ects: Amphotericin B has a low therapeutic index. The total adult daily dose should not exceed 1.5 mg/kg. Small test doses may be administered to assess the degree of negative responses, such as anaphylaxis or convulsions. Other toxic manifestations include the following (Figure 35.5).

FUNGAL CELL

Amphotericin B

K+ and othersmall molecules

Figure 35.2Model of a pore formed by amphotericin B in the lipid bilayer membrane.

K+

Amphotericin B

K+

FUNGAL CELL

K+ and othersmall molecules

Amphotericin B interactshydrophobically with ergosterol in the fungal cell membrane, forming a pore.

Potassium and other smallmolecules are lost throughthe pore, causing cell death.

1

2

pore

IV

Topical

Amphotericin B

Figure 35.3Administration and fate ofamphotericin B. CNS = central nervous system.

Minimal penetrationinto the CNS, vitreous humor, amniotic �uid

Some eliminationvia the bile

Part of doseappears inurine over a long period of time

Some eliminationvia the bile

Part of doseappears inurine over a long period of time

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II. Drugs For Subcutaneous And Systemic Mycotic Infections 431

a. Fever and chills: These occur most commonly 1 to 3 hours after starting the IV administration, but they usually subside with repeated administration of the drug. Premedication with a corticosteroid or an antipyretic helps to prevent this problem.

b. Renal impairment: Despite the low levels of the drug excreted in the urine, patients may exhibit a decrease in glomerular fi ltration rate and renal tubular function. Creatinine clearance can drop, and potassium and magnesium are lost. [Note: Nephrotoxicity may be potentiated by sodium depletion. A bolus infusion of normal saline before and after amphotericin B infusion may reduce the incidence of drug-induced nephrotoxicity.] Normal renal function usually returns with suspension of the drug, but residual damage is likely at high doses. Azotemia (elevated blood urea) is exacerbated by other nephrotoxic drugs, such as aminoglycosides, cyclosporine, and pentamidine, although adequate hydration can decrease its severity.

c. Hypotension: A shock-like fall in blood pressure accompanied by hypokalemia may occur, requiring potassium supplementation. Care must be exercised in patients taking digoxin.

d. Anemia: Normochromic, normocytic anemia caused by a reversible suppression of erythrocyte production may occur. This may be exacerbated in patients infected with HIV who are taking zidovudine.

e. Neurologic eff ects: Intrathecal administration can cause a variety of serious neurologic problems.

f. Thrombophlebitis: Adding heparin to the infusion can alleviate this problem.

Figure 35.4A. Amphotericin B intercalated between the phospholipids of a spherical liposome (AmBisome®). B. Outcomes of antifungal therapy in febrile, neutropenic cancer patients treated with conventional amphotericin B andliposomal amphotericin B.

Phospholipidbilayer

Coventional amphotericin B

Liposomal amphotericin B

Survival at 7 days

Key:

Nephrotoxicity(elevated serum creatinine levels)

Hypokalemia

Percentage of patients0 50 100 Amphotericin B

molecules

A B

Patient survival is similar with conventional and liposomal preparations, but liposomal amphotericin Bshows lower toxicity.

Figure 35.5Adverse effects of amphotericin B.

98.6Fever

Chills

BPHypotension

Anemia

Kidneyfailure

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B. Flucytosine

Flucytosine [fl oo-SYE-toe-seen] (5-FC) is a synthetic pyrimidine antime-tabolite that is oft en used in combination with amphotericin B. This combination of drugs is administered for the treatment of systemic mycoses and for meningitis caused by Cryptococcus neoformans and Candida albicans.

1. Mechanism of action: 5-FC enters fungal cells via a cytosine- specifi c permease, which is an enzyme not found in mammalian cells. 5-FC is then converted by a series of steps to 5-fl uorodeoxyu-ridine 5’-monophosphate. This false nucleotide inhibits thymidy-late synthase, thereby depriving the organism of thymidylic acid, an essential DNA component (Figure 35.6). The unnatural mononu-cleotide is further metabolized to a trinucleotide (5-fl uorodeoxyu-ridine 5’-triphosphate) and is incorporated into fungal RNA, where it disrupts nucleic acid and protein synthesis. [Note: Amphotericin B increases cell permeability, allowing more 5-FC to penetrate the cell. Thus, 5-FC and amphotericin B are synergistic (Figure 35.7).]

2. Antifungal spectrum: 5-FC is fungistatic. It is eff ective in combi-nation with itraconazole for treating chromoblastomycosis and in combination with amphotericin B for treating candidiasis and cryptococcosis.

3. Resistance: Resistance due to decreased levels of any of the enzymes in the conversion of 5-FC to 5-fl uorouracil (5-FU) and beyond or from increased synthesis of cytosine can develop during therapy. This is the primary reason that 5-FC is not used as a single antimycotic drug. The rate of emergence of resistant fungal cells is lower with a com-bination of 5-FC plus a second antifungal agent than it is with 5-FC alone.

4. Pharmacokinetics: 5-FC is well absorbed by the oral route. It distrib-utes throughout the body water and penetrates well into the CSF. 5-FU is detectable in patients and is probably the result of metabo-lism of 5-FC by intestinal bacteria. Excretion of both the parent drug and its metabolites is by glomerular fi ltration, and the dose must be adjusted in patients with compromised renal function.

5. Adverse eff ects: 5-FC causes reversible neutropenia, thrombocy-topenia, and dose-related bone marrow depression. Caution must be exercised in patients undergoing radiation or chemotherapy with drugs that depress bone marrow. Reversible hepatic dysfunction with elevation of serum transaminases and alkaline phosphatase may occur. Gastrointestinal disturbances, such as nausea, vomiting, and diarrhea, are common, and severe enterocolitis may also occur. [Note: Some of these adverse eff ects may be related to 5-FU formed by intestinal organisms from 5-FC.]

C. Ketoconazole

Ketoconazole [kee-toe-KON-a-zole] was the fi rst orally active azole avail-able for the treatment of systemic mycoses.

1. Mechanism of action: Azoles are predominantly fungistatic. They inhibit C-14 α-demethylase (a cytochrome P450 [CYP450] enzyme), thereby blocking the demethylation of lanosterol to ergosterol, the

dUMP dTMP

DNA

5-Flurouracil

Thymidylate synthase

5-FdUMP

FlucytosineAmphotericin B

FUNGAL CELL

NH2F

HN

N

O

H2O

NH3

Cytosinedeaminase

Figure 35.6Mode of action of �ucytosine. 5-FdUMP = 5-�uorodeoxyuridine 5'-monophosphate; dTMP = deoxy-thymidine 5'-monophosphate.

Permease

NH2F

HN

N

O

dUMP dTMP

DNA

Thymidylate synthase

Decreased dTMP leads toinhibition of DNA synthesisand cell division.

+

Figure 35.7Synergism between �ucytosineand amphotericin B.

Flucytosine

Amphotericin B

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principal sterol of fungal membranes (Figure 35.8). This inhibition disrupts membrane structure and function, which, in turn, inhibits fungal cell growth. [Note: Unfortunately, as is often the case for the initial member of a class of drugs, the selectivity of ketoconazole toward its target is not as precise as those of later azoles. For exam-ple, in addition to blocking fungal ergosterol synthesis, the drug also inhibits human gonadal and adrenal steroid synthesis, lead-ing to decreased testosterone and cortisol production. In addition, ketoconazole inhibits CYP450-dependent hepatic drug-metaboliz-ing enzymes.]

2. Antifungal spectrum: Oral ketoconazole is active against many fungi, including Histoplasma, Blastomyces, Candida, and Coccidioides, but not aspergillus species. Itraconazole has largely replaced ketocon-azole in the treatment of most mycoses because of its broader spec-trum, greater potency, and fewer adverse eff ects. As a second-line drug, oral ketoconazole is a less-expensive alternative for the treat-ment of mucocutaneous candidiasis. However, strains of several fun-gal species that are resistant to ketoconazole have been identifi ed. Topical ketoconazole is used to treat tinea corporis, tinea cruris, and tinea pedis caused by Trichophyton rubrum, Trichophyton menta-grophytes, and Epidermophyton fl occosum. Also, topical ketocon-azole is used to treat tinea versicolor caused by Malassezia furfur, cutaneous candidiasis caused by Candida species. It is also used top-ically in the treatment of seborrheic dermatitis and dandruff .

3. Resistance: This is becoming a signifi cant clinical problem, particu-larly in the protracted therapy required for those with advanced HIV infection. Identifi ed mechanisms of resistance include mutations in the C-14 α-demethylase gene, which cause decreased azole bind-ing. Additionally, some strains of fungi have developed the ability to pump the azole out of the cell.

4. Pharmacokinetics: When ketoconazole is administered orally (Figure 35.9), it requires gastric acid for dissolution and is absorbed through the intestinal mucosa. Drugs that raise gastric pH, such as antacids, or that interfere with gastric acid secretion, such as H2-histamine–receptor blockers and proton-pump inhibitors, impair absorption. Administering acidifying agents, such as cola drinks, before tak-ing the drug can improve absorption in patients with achlorhydria. Ketoconazole is extensively bound to plasma proteins. Although penetration into tissues is limited, it is eff ective in the treatment of histoplasmosis in lung, bone, skin, and soft tissues. The drug does not enter the CSF. Extensive metabolism occurs in the liver, and excretion is primarily through the bile. Levels of parent drug in the urine are too low to be eff ective against mycotic infections of the urinary tract.

5. Adverse eff ects: In addition to allergies, dose-dependent gastro-intestinal disturbances, including nausea, anorexia, and vomiting, are the most common adverse eff ects of ketoconazole treatment. Endocrine eff ects, such as gynecomastia, decreased libido, impo-tence, and menstrual irregularities, result from the blocking of androgen and adrenal steroid synthesis by ketoconazole. Transient increases in serum transaminases occur in 2 to 10 percent of patients receiving ketoconazole. Frank hepatitis occurs rarely, but requires

Lanosterol

H3

Figure 35.8Mode of action of ketoconazole.

P450C

Ketoconazole

ErgosterolErgosterol

Ergosterol

Inhibition of ergosterol synthesisdisrupts membrane function and increases permeability

Ketoconazole

Eliminationvia bile

Figure 35.9Administration and fate of ketoconazole.

Eliminationvia bile

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immediate cessation of ketoconazole treatment. [Note: Ketoconazole may accumulate in patients with hepatic dysfunction. Plasma con-centrations of the drug should be monitored in these individuals.]

6. Drug interactions and contraindications: By inhibiting CYP450, ketoconazole can potentiate the toxicities of drugs such as cyclosporine, phenytoin, triazolam, and warfarin, among others (Figure 35.10). Rifampin, an inducer of the CYP450 system, can shorten the duration of action of ketoconazole and the other azoles. Drugs that decrease gastric acidity, such as H2-receptor blockers, ant-acids, proton-pump inhibitors, and sucralfate, can decrease absorp-tion of ketoconazole. Ketoconazole and amphotericin B should not be used together, because the decrease in ergosterol in the fungal membrane reduces the fungicidal action of amphotericin B (Figure 35.11). Finally, ketoconazole is teratogenic in animals, and it should not be given during pregnancy.

D. Fluconazole

Fluconazole [floo-KON-a-zole] is a member of the triazole class of anti-fungal products. It is clinically important because of its lack of the endo-crine side effects of ketoconazole and its excellent penetrability into the CSF of both normal and inflamed meninges. Fluconazole is employed prophylactically, with some success, for reducing fungal infections in recipients of bone marrow transplants. It inhibits the synthesis of fungal membrane ergosterol in the same manner as ketoconazole and is the drug of choice for Cryptococcus neoformans after therapy with ampho-tericin B, for most candidemias, and for coccidioidomycosis. Fluconazole is effective against most forms of mucocutaneous candidiasis. [Note: Treatment failures due to resistance have been reported in some HIV-infected patients.] Fluconazole is administered orally or intravenously. For the treatment of vaginal candidiasis, the dose is 150 mg as a single oral dose. Its absorption is excellent and, unlike that of ketoconazole, is not dependent on gastric acidity. Binding to plasma proteins is mini-mal. Unlike ketoconazole, fluconazole is poorly metabolized. The drug is excreted via the kidney, and doses must be reduced in patients with compromised renal function. The adverse effects caused by flucon-azole treatment are less of a problem than those with ketoconazole. Fluconazole has no endocrinologic effects because it does not inhibit the CYP450 system responsible for the synthesis of androgens. However, it can inhibit the P450 cytochromes that metabolize other drugs listed in Figure 35.10. Nausea, vomiting, and rashes are a problem. There is a caution for patients with liver dysfunction. Fluconazole is teratogenic, as are other azoles, and should not be used in pregnancy.

E. Itraconazole

Itraconazole [it-ra-KON-a-zole] is an antifungal agent with a broad anti-fungal spectrum. Like fluconazole, it is a synthetic triazole and also lacks the endocrinologic side effects of ketoconazole. Its mechanism of action is the same as that of the other triazoles. Itraconazole is the drug of choice for the treatment of blastomycosis, sporotrichosis, paracoc-cidioidomycosis, and histoplasmosis. Unlike ketoconazole, it is effective in acquired immunodeficiency syndrome–associated histoplasmosis. Itraconazole is well absorbed orally, but it requires acid for dissolution. Food increases the bioavailability of some preparations. The drug is extensively bound to plasma proteins and distributes well throughout

Figure 35.11Ketoconazole and amphotericin B should not be used together.

Ketoconazole

Amphotericin B

Contraindicated

P450

CyclosporinePhenytoinTriazolamWarfarin

Metabolites

Ketoconazole

Serum concentrationincreases

Figure 35.10By inhibiting cytochrome P450, ketoconazole can potentiate the toxicities of other drugs.

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most tissues, including bone and adipose tissues. However, therapeu-tic concentrations are not attained in the CSF. Like ketoconazole, itra-conazole is extensively metabolized by the liver, but it does not inhibit androgen synthesis. Its major metabolite, hydroxyitraconazole, is bio-logically active, with a similar antifungal spectrum. Little of the parent drug appears in the urine, eliminating the need for dose reduction with renal failure. Adverse effects include nausea and vomiting, rash (espe-cially in immunocompromised patients), hypokalemia, hypertension, edema, and headache. Itraconazole should be avoided in pregnancy. Itraconazole inhibits the metabolism of many drugs, including oral anticoagulants, statins, and quinidine. Inducers of the CYP450 system increase the metabolism of itraconazole. The capsules should not be taken by patients with evidence of ventricular dysfunction, such as con-gestive heart failure (CHF) or a history of CHF.

F. Voriconazole

Voriconazole [vor-i-KON-a-zole], a triazole, has the advantage of being a broad-spectrum antifungal agent. It is available for both IV and oral administration and is approximately 96 percent bioavailable. Voriconazole is approved for the treatment of invasive aspergillosis and has replaced amphotericin B as the treatment of choice for this indication. Voriconazole is also approved for treatment of serious infections caused by Scedosporium apiospermum and Fusarium species. Voriconazole pen-etrates tissues well, including the CNS. Elimination is primarily by metab-olism through the CYP450 2C19, 2C9, and 3A4 enzymes. The significant number of drug interactions due to its metabolism through the various hepatic enzymes may limit its use. Side effects are similar to those of the other azoles. High trough concentrations are associated with visual and auditory hallucinations.

G. Posaconazole

Posaconazole [poe-sa-KONE-a-zole], a triazole, is a new oral, broad-spectrum antifungal agent with a chemical structure similar to that of itraconazole. It was approved in 2006 to prevent Candida and Aspergillus infections in severely immunocompromised patients and for the treatment of oropharyngeal candidiasis. Due to its spectrum of activity, posaconazole could possibly be used in the treatment of fungal infections caused by Mucor species and other zygomycetes. To date, amphotericin B formulations are the only other antifungal agents available for treatment of zygomycete infections. Overall, posaconazole is relatively well tolerated. The most common side effects observed were gastrointestinal issues (nausea, vomiting, diarrhea, and abdom-inal pain) and headaches. Like other azoles, posaconazole can cause an elevation of the liver function tests, causing elevated serum levels of hepatic transaminases. Additionally, in patients who are receiving concomitant cyclosporine or tacrolimus for management of transplant rejection, rare cases of hemolytic uremic syndrome, thrombotic throm-bocytopenic purpura, and pulmonary embolus have been report-ed. Due to its inhibition of CYP450 3A4 enzymes, posaconazole may increase the effect and toxicity of many drugs, including cyclosporine, tacrolimus, and sirolumus. Concomitant use of posaconazole with ergot alkaloids, pimozide, and quinidine is contraindicated. To be effective, posaconazole must be administered with a high fat meal. Posaconazole may be given two or four times daily for a total daily dose of 800 mg.

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Figures 35.12 and 35.13 summarize the azole antifungal agents.

H. Echinocandins

Echinocandins interfere with the synthesis of the fungal cell wall by inhibiting the synthesis of β(1,3)-D-glucan, leading to lysis and cell death. Caspofungin, micafungin, and anidulafungin are available for IV adminstration once daily. Micafungin does not require a loading dose.

1. Caspofungin: Caspofungin [kas-poh-FUN-jin] is the first approved member of the echinocandins class of antifungal drugs. Caspofungin has activity against Aspergillus and most Candida species, includ-ing those species resistant to azoles. Adverse effects include fever, rash, nausea, and phlebitis. Flushing occurs, which is probably due to the release of histamine from mast cells. The dose of caspofungin does not need to be adjusted in renal impairment but is warranted with moderate hepatic dysfunction. Concomitant administra-tion of caspofungin with CYP450 enzyme inducers may require an increase in the daily dose administered. Caspofungin should not be co administered with cyclosporine due to the high incidence of ele-vation of hepatic transaminases with concurrent use. Caspofungin is a second-line antifungal for those who have failed or cannot tolerate amphotericin B or an azole.

2. Micafungin and anidulafungin: Micafungin (mi-ka-FUN-gin) and anidulafungin (ay-nid-yoo-la-FUN-jin) are the newer members of the echinocandins class of antifungal drugs. Micafungin and anidu-lafungin have similar efficacy against Candida species, but the effi-cacy for treatment of other fungal infections has not been estab-lished. The dose of micafungin and anidulafungin does not need to be adjusted in renal impairment or mild-to-moderate hepatic dys-function. No studies have been done with the use of micafungin in severe hepatic dysfunction, but andulafungin can be administered in this condition. Also, they are not substrates for CYP450 enzymes and do not have any associated drug interactions.

III. DRUGS FOR CUTANEOUS MYCOTIC INFECTIONS

Mold-like fungi that cause cutaneous skin infections are called dermato-phytes or tinea. These tinea infections are classified by the site of their infec-

Figure 35.12Summary of some azole fungistatic drugs. CSF = cerebrospinal �uid.

Narrow

Oral

6–9

No

No

Frequent

Dose-dependent inhibitory e�ect

Expanded

Oral, IV

30

Yes

Yes

Occasional

No inhibition

Expanded

Oral

20–66

Yes

No

Frequent

No inhibition

SPECTRUM

ROUTE(S) OF ADMINISTRATION

t1/2 (HOURS)

CSF PENETRATION

RENAL EXCRETION

INTERACTION WITH OTHER DRUGS

INHIBITION OF MAMMALIAN STEROL SYNTHESIS

KETOCONAZOLE FLUCONAZOLE POSACONAZOLE

Expanded

Oral, IV

6–24

Yes

No

Frequent

No inhibition

VORICONAZOLE

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III. Drugs For Cutaneous Mycotic Infections 437

tion, such as tinea pedis, which refers to an infection of the feet. Common dermatomycoses, such as tinea infections that appear as rings or round red patches with clear centers, are often referred to as “ringworm.” This is a mis-nomer, because fungi rather than worms cause the disease. The three differ-ent fungi that cause the majority of cutaneous infections are Trichophyton, Microsporum, and Epidermophyton. These pathogens have a high affinity for keratinized tissue such as skin, hair, and nails. The drugs used in the treat-ment of cutaneous mycoses are listed in Figure 35.1.

A. Squalene epoxidase inhibitors

These agents act by inhibiting squalene epoxidase, resulting in the blocking of the biosynthesis of ergosterol, an essential component of fungal cell membrane.

1. Terbinafine: Oral terbinafine [TER-bin-a-feen] is the drug of choice for treating dermatophytoses and, especially, onychomycoses (fun-gal infections of nails). It is better tolerated, requires shorter dura-tion of therapy, and is more effective than either itraconazole or griseofulvin.

Figure 35.13Major or life-threatening drug interactions of azole fungistatic drugs. indicates increased; indicates decreased.* Where an interaction has been reported for one triazole, the contraindication has been extended to all others.

INTERACTING DRUG DRUGMAIN CLINICALCONSEQUENCE OFINTERACTION

EFFECT ON DRUGEXPOSURE

Astemizole, bepridil, cisapride, halofantrine,pimozide, quinidine, sertindole, terfenadine

exposure to voriconazole

QT interval prolongation with risk of torsade depointes

exposure to interacting drugs

exposure to ergot alkaloid

Ergot alkaloids

Treatment failure of voriconazole




Neurotoxicity

Risk of sirolimus toxicity


Uveitis

Risk of efavirenz toxicity

exposure to HMG-CoA reductase inhibitor

Ergotism

Risk of rhabdomyolysis

Sleepiness

exposure to sirolimus

exposure to vinca alkaloids

Itraconazole

Itraconazole

Itraconazole

Carbamazepine Voriconazole

Voriconazole

Voriconazole

Voriconazole

Voriconazole

Voriconazole

Efavirenz

Itraconazole, �uconazole, voriconazole, posaconazole*

Lovastatin, simvastatin

Midazolam, triazolam

Rifabutin

Rifampicin (rifampin)

Vincristine-vinblastine

Sirolimus

High-dose ritonavir (400 mg twice daily)

Itraconazole, �uconazole, voriconazole, posaconazole*

exposure to benzodiazepine




exposure to efavirenz


exposure to rifabutin

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a. Mechanism of action: Terbinafi ne inhibits fungal squalene epoxidase, thereby decreasing the synthesis of ergosterol (Figure 35.14). This plus the accumulation of toxic amounts of squalene result in the death of the fungal cell. [Note: Signifi cantly higher concentrations of terbinafi ne are needed to inhibit human squalene epoxidase, an enzyme required for the cholesterol synthetic pathway.]

b. Antifungal spectrum: The drug is primarily fungicidal. Topical terbinafi ne is active against Trichophyton rubrum and Trichophyton mentagrophytes . It may also be eff ective against Candida albicans, Epidermophyton fl occosum, and Scopulariopsis brevicaulis, but the safety and effi cacy in treating clinical infections due to these pathogens has not been established. Topical terbinafi ne 1% cream and solution are used to treat tinea pedis, tinea corporis, and tinea cruris. Therapy is prolonged (usually about 3 months) but considerably shorter than that with griseofulvin.

c. Pharmacokinetics: Terbinafi ne is available for oral and topical administration, although its bioavailability is only 40 percent due to fi rst-pass metabolism. Absorption is not signifi cantly enhanced by food. Terbinafi ne is greater than 99 percent bound to plasma proteins. It is deposited in the skin, nails, and fat. Terbinafi ne accumulates in breast milk and should not be given to nursing mothers. A prolonged terminal half-life of 200 to 400 hours may refl ect the slow release from these tissues. Oral terbinafi ne is extensively metabolized prior to urinary excretion (Figure 35.15). Patients with either moderate renal impairment or hepatic cirrhosis have reduced clearance.

d. Adverse eff ects: The most common adverse eff ects from terbinafi ne are gastrointestinal disturbances (diarrhea, dyspepsia, and nausea), headache, and rash. Taste and visual disturbances have been reported as well as transient elevations in serum liver enzyme levels. All adverse eff ects resolve upon drug discontinuation. Rarely, terbinafi ne may cause hepatotoxicity and neutropenia. Although terbinafi ne is extensively metabolized, there does not seem to be a signifi cant risk of reduced clearance of other drugs. Rifampin decreases blood levels of terbinafi ne, whereas cimetidine increases blood levels.

2. Naftifi ne: Naftifi ne [NAF-ti-feen] is active against Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, and Epidermophyton fl occosum. Naftifi ne 1% cream and gel is used for topical treatment of tinea corporis, tinea cruris, and tinea pedis.

3. Butenafi ne: Butenafi ne [byoo-TEN-a-feen] is active against Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, Epidermophyton fl occosum, and Malassezia furfur. Butenafi ne 1% cream is used for topical treatment of tinea corporis, tinea cruris, interdigital tinea pedis, and tinea versicolor.

B. Griseofulvin

Griseofulvin [gris-e-oh-FUL-vin] has been largely replaced by oral ter-binafi ne for the treatment of dermatophytic infections of the nails, although it is still used for ringworm and dermatophytosis of the skin

Squalene

Squaleneepoxidase

Fungal cell death

Fungal cell death

Figure 35.14 Mode of action of squalene epoxidase inhibitors.

Terbina�neNafti�neButena�ne

ErgosterolErgosterol

Ergosterol

Toxic products

Toxic products

Terbina�ne

Metabolitesexcretedin urine

Figure 35.15Administration and fate ofterbina�ne.

Pharm 5th 3-21-11.indb 438 3/21/11 2:28:46 PM

III. Drugs For Cutaneous Mycotic Infections 439

and hair. Griseofulvin requires treatment of 6 to 12 months in duration. It is only fungistatic. Griseofulvin accumulates in newly synthesized, ker-atin-containing tissue, where it causes disruption of the mitotic spindle and inhibition of fungal mitosis (Figure 35.16). Duration of therapy is dependent on the rate of replacement of healthy skin and nails. Ultrafine crystalline preparations are absorbed adequately from the gastrointes-tinal tract, and absorption is enhanced by high-fat meals. Griseofulvin induces hepatic CYP450 activity (Figure 35.17). It also increases the rate of metabolism of a number of drugs, including anticoagulants. It may exacerbate intermittent porphyria.

C. Nystatin

Nystatin [nye-STAT-in] is a polyene antibiotic, and its structure, chemistry, mechanism of action, and resistance profile resemble those of ampho-tericin B. Its use is restricted to topical treatment of Candida infections because of its systemic toxicity. The drug is negligibly absorbed from the gastrointestinal tract, and it is never used parenterally. It is admin-istered as an oral agent (“swish and swallow” or “swish and spit”) for the topical treatment of oral candidiasis. Excretion in the feces is nearly quantitative. Adverse effects are rare because of its lack of absorption orally, but nausea and vomiting occasionally occur.

D. Imidazoles

Imidazoles are azole derivatives, which currently include butocon-azole [byoo-toe-KON-a-zole], clotrimazole [kloe-TRIM-a-zole], econazole [e-KONE-a-zole], ketoconazole, miconazole [my-KON-a-zole], oxicon-azole [oks-i-KON-a-zole], sertaconazole [ser-ta-KOE-na-zole], sulconazole [sul-KON-a-zole], terconazole [ter-KON-a-zole], and tioconazole [tye-oh-KONE-a-zole]. As a class of topical agents, they have a wide range of activity against Epidermophyton, Microsporum, Trichophyton, Candida albicans, and Malassezia furfur, depending on the agent. Topical use is associated with contact dermatitis, vulvar irritation, and edema. Miconazole is a potent inhibitor of warfarin metabolism and has pro-duced bleeding in warfarin-treated patients even when applied locally to the vaginal area. No significant difference in clinical outcomes is asso-ciated with any azole or nystatin in the treatment of vulvar candidiasis.

E. Ciclopirox

Ciclopirox [sye-kloe-PEER-oks] inhibits the transport of essential ele-ments in the fungal cell, disrupting the synthesis of DNA, RNA, and protein. Ciclopirox is active against Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis, Candida albicans, and Malassezia furfur. Ciclopirox 1% shampoo is used for treatment of seborrheic dermatitis. Ciclopirox 0.77% gel is used for treatment of interdigital tinea pedis, tinea corporis, and seborrheic der-matitis. Ciclopirox 8% solution is used for treatment of onychomycosis of nails without lanula involvement. Ciclopirox 0.77% cream and sus-pension is used for treatment of dermatomycosis, candidiasis, and tinea versicolor.

F. Tolnaftate

Tolnaftate [tole-NAF-tate] distorts the hyphae and stunts mycelial growth in susceptible fungi. Tolnaftate is active against Epidermophyton, Microsporum, and Malassezia furfur. [Note: Tolnaftate is not effective against Candida.] Tolnaftate is used to treat tinea pedis, tinea cruris, and tinea corporis. It is available as a 1% solution, cream, and powder.

Magni�er1-art

Figure 35.16Inhibition of mitosis by griseofulvin.

Griseofulvin

Griseofulvin

Metabolite

P450P450

P450

Figure 35.17Induction of hepatic cytochrome P450 activity by griseofulvin.

Pharm 5th 3-21-11.indb 439 3/21/11 2:28:47 PM


Study questions

Choose the ONE best answer.

35.1 A 60-year-old female referred to a dermatologist by her primary care physician because of a pain-less, inflamed, erupting ulcer that has been on her right hand for two months. This patient works in her vegetable and herb garden daily and states that the lesion began as a small red papule. Despite 10 days of treatment with cephalexin, the papule has con-tinued to enlarge. The dermatologist cultured the ulcer and the results demonstrated the patient has sporotrichosis, an infection caused by Sporothrix schenckii. What is the most appropriate therapy that should be recommended to treat the infection?

A. Flucytosine.B. Amphotericin B.C. Itraconazole.D. Micafungin.

35.2 A 47-year-old female is admitted to the hospital for treatment of a Candida infection. Upon obtaining a medical history from the patient, the practitioner learns that the patient has had a liver transplant and is taking cyclosporine, to avoid organ rejection. What intravenous antifungal agent would avoid any potential drug interactions or potential toxicities of concomitant administration with cyclosporine, yet provide an efficacious treatment for the Candida infection?

A. Caspofungin.B. Voriconazole.C. Micafungin.D. Posoconazole.

35.3 A 22-year-old male has been treating his “athlete’s foot” with an over-the-counter drug without much success. Upon examination, it is found that the nail bed of both great toes is infected. Which one of the following antifungal agents would be most appro-priate for this patient?

A. Caspofungin.B. Fluconazole.C. Griseofulvin.D. Nystatin.E. Terbinafine.

Correct answer = C. Itraconazole is the drug of choice for treatment of sporotrichosis. Itraconazole is well absorbed orally, but requires an acid envi-ronment for dissolution. Flucytosine is a synthetic pyrimidine antimetabolite that is often used in combination with Amphotericin B for the treatment of systemic mycoses. Micafungin is an echinocandin antifungal agent that has efficacy against Candida species, yet effectiveness against other fungal infec-tions has not been established.

Correct answer = C. Micafungin is efficacious against Candida species and does not have any drug interaction with cyclosporine. Caspofungin should not be administered with cyclosporine, due to the possible increase of serum concentration of caspo-fungin caused by cyclosporine. Azole antifungal agents, such as Voriconazole and Posoconazole, may decrease the metabolism of cyclosporine, therefore, concomitant administration is not recommended.

Correct answer = E. Terbinafine is the drug of choice for the treatment of dermatophytic infections. Because it is fungicidal, it requires a shorter course of therapy than does griseofulvin. Drug interactions are also not a problem with terbinafine. Dermato-phytes may respond to fluconazole, but this drug is reserved for more serious systemic infections. Nysta-tin and caspofungin are not useful in the treatment of dermatophytic infections.

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