The role of azole antifungal agents for systemic antifungal therapy

CURRENT DRUG THERAPY Y U - P I N G LEE, PHARMD Dr. Lee is a p h a r m a c y res iden t a t t h e C leve land Clinic, spec ia l i z ing in in fec t ious disease.

M O R T O N G O L D M A N , PHARMD Dr. G o l d m a n is t h e pha rmaceu t i ca l care c l in ical m a n a g e r in t h e D e p a r t m e n t o f Pharmacy a t t h e C leve land Clinic.

D O N A L D G. VIDT, M D , EDITOR

• KEY POINTS:

Amphotericin B remains the first-line agent for serious fungal infections in most patients, including immunocom-promised patients (eg, those w i th AIDS) and in central nervous system infections.

The overall prevalence of resistance to azole agents is low. The only exception is in AIDS patients, in whom resistance is much higher than in other popula-tions, and is increasing.

Azole agents can increase the concen-trat ion of phenytoin, cisapride, oral glucose-lowering agents, warfarin, digoxin, terfenadine, astemizole, and cydosporine, potentially leading to toxicity.

The role of azole antifungal agents for systemic antifungal therapy • Al though amphotericin B remains the corner-stone of antifungal drug therapy, fluconazole and itraconazole have been found useful for long-term maintenance or prophy-lactic regimens. This article reviews characteristics of f lucona-zole and itraconazole and compares them wi th ketoconazole and amphotericin B.

Ketoconazole, fluconazole, and itraconazole have not supplanted amphotericin B for managing most serious fungal infections, hut they offer alternatives in a variety of unique situations. These drugs (the "azoles") are becoming standard as antifungal prophylactic agents in transplant recipients and as long-term

suppressive agents for cryptococcal meningitis in patients with acquired immunodeficiency syndrome (AIDS). Fluconazole may also be useful in treating AIDS-related candidemia. Itraconazole and keto-conazole are both effective for blastomycosis, histoplasmosis, and coc-cidiomycosis. The azoles are significantly less nephrotoxic than amphotericin B, but are not without side effects. They also demon-strate a number of significant drug interactions.

• HISTORY OF THE AZOLES

Miconazole, the first systemic azole agent, was introduced in 1969. However, its toxicity, side effects (especially arrhythmia), and poor effi-cacy limit its use.

Ketoconazole, introduced in 1977, was the first oral azole agent. It is not active against Aspergillus, but otherwise shares a similar spectrum of action with amphotericin B.

Fluconazole was introduced in 1990 and quickly became popular

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 2 FEBRUARY 1997 99 on January 23, 2022. For personal use only. All other uses require permission.www.ccjm.orgDownloaded from

http://www.ccjm.org/

ANTIFUNGAL THERAPY W LEE AND GOLDMAN

owing to its attractive pharmacokinetic and side-effect profiles and its availability in intra-venous and oral formulations.

Itraconazole was introduced in 1992. It is active against Aspergillus and has fewer side effects than ketoconazole.

HOW THE AZOLES WORK

The azoles alter fungal membrane permeabili-ty by inhibiting fungal cytochrome P450 and C-14 alpha-demethylase1'2—enzymes shared by humans. Fluconazole and itraconazole act more specifically on the fungal enzymes than ketoconazole does, and therefore cause less blockage of human steroid synthesis and fewer side effects.1-3

PHARMACOKINETICS

Giving terfenadine or astemizole with itraconazole or ketoconazole is contraindicated because of the potential for serious cardio-vascular events

Fluconazole is highly bioavailable; others less so Over 9 0 % of an oral dose of fluconazole reach-es the blood stream, perhaps owing to its relatively high water solubility and low molec-ular weight. Neither food nor gastric pH affects fluconazole's absorption.

In contrast, oral doses of ketoconazole and itraconazole are less bioavailable, with 3 7 % to 9 7 % of ketoconazole and 70% of itraconazole reaching the blood stream. Giving these drugs with food enhances their systemic absorption, especially itraconazole. Gastric pH affects the absorption of both agents, with a lower pH allowing improved absorption.

Ketoconazole and itraconazole are highly protein-bound; fluconazole less so Ketoconazole and itraconazole are highly bound to plasma proteins (98% and 99.8%, respectively), and therefore are not signifi-cantly dialyzable and achieve relatively low levels in the cerebrospinal fluid. Nevertheless, itraconazole has been reported effective in treating cryptococcal and coccidioidal menin-gitis, a paradox similar to that seen with amphotericin B.

Fluconazole is more hydrophilic and has a low degree of protein binding. It is therefore dialyzable, and patients need dosage adjust-

ment after dialysis. Fluconazole enters the cerebrospinal fluid easily, where concentra-tions reach 50% to 9 0 % of the plasma con-centration.

Ketoconazole, itraconazole are metabolized in the liver; fluconazole is excreted by the kidneys Ketoconazole and itraconazole undergo exten-sive metabolism by the cytochrome P450 sys-tem in the liver (more than 30 metabolites of itraconazole have been reported).

Fluconazole, in contrast, is primarily excreted unchanged by the kidneys. Patients with renal insufficiency require dosage adjust-ments with fluconazole but not with itracona-zole or ketoconazole.

• SPECTRUM OF ACTIVITY

Ketoconazole, fluconazole, and itraconazole are all active in vitro against Cryptococcus neoformans, Candida albicans, Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis, and Paracoccidioides brasiliensis. Both fluconazole and itraconazole—but not ketoconazole—are active against Sporothrix schenckii. Itraconazole is the only currently available azole agent that covers Aspergillus. Fluconazole is less active against Candida glabrata and inactive against Candida krusei.4

THERAPEUTIC ROLES

Amphotericin B still the drug of choice Amphotericin B remains the drug of choice for serious systemic fungal infections (TABLE 1). It is also the first-line agent for serious fungal infec-tions in immunocompromised patients (eg, those with AIDS) and central nervous system infections.5-7 In coccidioidomycosis meningi-tis, amphotericin B is often given intravenous-ly and intrathecally.6

In studies in non-AIDS-related crypto-coccal meningitis, adding flucytosine to amphotericin B boosted the cure rate and reduced the rates of treatment failure and relapse.8-9 However, for AIDS-related crypto-coccal meningitis, amphotericin B is suggested by itself, since adding flucytosine has not been

1 06 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 6 4 • NUMBER 2 FEBRUARY 1997

on January 23, 2022. For personal use only. All other uses require permission.www.ccjm.orgDownloaded from


Type of i n f e c t i o n

shown to increase the survival rate or to decrease the relapse rate of infection.10

Ketoconazole Ketoconazole is the drug of choice for Mahssezia furfur infec-tions.6 Other uses:

• In blastomycosis and coc-cidioidomycosis (high doses rec-ommended).11 '12

• In histoplasmosis and paracoc-cidioidomycosis (in which its effi-cacy is comparable to that of itra-c o n a z o l e ) . ^ ^

• As prophylaxis in neu-tropenic patients17-20 (although its role is not well defined, because its absorption is erratic).

• In severe recalcitrant cuta-neous dermatophyte infections not responding to topical therapy or oral griseofulvin or in patients unable to take griseofulvin.2

Fluconazole Fluconazole has no effect against Aspergillus or C krusei, and is not very potent against blastomyco-sis,21-22 chromoblastomycosis,23 or Pénicillium rmrneffei.24 It has vari-able efficacy against C glabrata.

Candidal infections. Flu-conazole is useful in several situations:

• As prophylaxis against can-didal infections in bone-marrow transplant recipients, who receive cytotoxic chemotherapy or radia-tion therapy. 25-28

• In oropharyngeal and esophageal candidiasis (in which it is the drug of choice, and several studies evaluated it in patients with AIDS) . 2 9 - 3 2

• In urinary candidiasis (drug of choice).33-34

• In vaginal candidiasis (drug of choice).^33,35-38

• In systemic candidal infections (although fluconazole was as effective as amphotericin B for candidemia, the studies were limited to catheter-related infections or included patients treated with amphotericin B for prolonged periods before starting flucona-z o l e ) . 3 ^ !

Cryptococcal infections. Fluconazole is an

T A B L E 1

ANTIMICROBIAL EFFECTIVENESS OF AZOLE AGENTS AND AMPHOTERICIN B

A m p h o t e r i c i n B K e t o c o n a z o l e F luconazole I t r a c o n a z o l e

A s p e r g i l l o s i s +++ 0 0 ++

Blastomycosis I m m u n o c o m p e t e n t p a t i e n t s ++++ +++ 0 to + +++ I m m u n o s u p p r e s s e d pat ients ++++ ++ to + 1 + 0 to + +++

C a n d i d i a s i s B l o o d ++++ + +++ 7

O r o p h a r y n g e a l , e s o p h a g e a l ? ++ +++ +++ Urinary 7 7 +++ 7

V a g i n a l 7 +44 +++ + + to + + + Prophy lax i s ? 7 +++ 7

C h r o m o b l a s t o m y c o s i s ++ ++ 0 to + +++

Cocc id iomycos i s N o n m e n i n g i t i s +++ +++ ++ +++ M e n i n g i t i s +++ + + t o + + + + + to + + + + + t o + + +

Cryptococca l N o n - A I D S pat ients ++++ 0 +++ 7 A I D S pat ients ++++ 0 + + to + + + ++ M a i n t e n a n c e t h e r a p y ++ 7 + + to + + + +++

Histop lasmos is ++++ +++ ++ +++

Le i shmanias i s +++ TI- 7 ++

Malassezia furfur In fect ion 7 l t to + + + 7 + + t o + + +

N e u t r o p e n i c p r o p h y l a x i s +++ + + to + + + +++ + + t o + + +

O n y c h o m y c o s i s 7 +++ +++ +++

P a r a c o c c i d i o i d o m y c o s i s +++ +++ 7 +++

Pénicillium marneffei i n f e c t i o n + to H 7 0 to + + t o + +

Sporotr ichos is ++ 0 + to + + ++

Scale: 0

+++ HH 7

Not effective Less effective Moderately effective Effective Very effective Not yet established

alternative to amphotericin B in clinically sta-ble patients without AIDS who have crypto-coccal infections. In one study, fluconazole was as effective as amphotericin B in treating cryp-tococcal meningitis, but it was associated with a higher mortality rate during the first 2 weeks of therapy.42 Cerebrospinal fluid cultures remained positive for Cryptococcus significant-ly longer with fluconazole than with ampho-tericin (40.6 days vs 15.6 days).43

Prophylactic use. Prudent use in bone marrow transplant recipients is warranted,44-51

even though excessive use of fluconazole can lead to drug resistance: an increased emergence of C krusei and C glabrata infections

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 2 FEBRUARY 1997 1 0 1



ANTIFUNGAL THERAPY W LEE AND GOLDMAN mm k J

ADVERSE REACTIONS TO AZOLE AGENTS

F r e q u e n c y

Very c o m m o n (> 1 0 % )

C o m m o n ( 1 - 1 0 % )

Less c o m m o n ( < 1 % )

Rare

Reac t ions

K e t o c o n a z o l e F luconazo le I t r a c o n a z o l e

- - N a u s e a

A b d o m i n a l pa in A b d o m i n a l pa in A b d o m i n a l pa in A s y m p t o m a t i c A s y m p t o m a t i c A s y m p t o m a t i c

l iver d y s f u n c t i o n l iver d y s f u n c t i o n l iver d y s f u n c t i o n ( 2 - 1 2 % ) (< 5 % ) ( 0 . 3 - 2 . 7 % )

Nausea D i a r r h e a H e a d a c h e Prur itus H e a d a c h e Rash V o m i t i n g Nausea V o m i t i n g

Skin rash V o m i t i n g

B u l g i n g f o n t a n e l l e s D izz iness A n o r e x i a Chi l ls H y p o k a l e m i a D e c r e a s e d l ib ido D iarrhea Pal lor D i a r r h e a D izz iness D i z z i n e s s Fever E d e m a G y n e c o m a s t i a F a t i g u e H e a d a c h e Fever H e m o l y t i c a n e m i a H y p e r t e n s i o n Impotence H y p o k a l e m i a L e u k o p e n i a I m p o t e n c e P h o t o p h o b i a M a l a i s e S o m n o l e n c e Prur i tus T h r o m b o c y t o p e n i a S o m n o l e n c e

- Severe h e p a t o t o x l c i t y -

• • • B B M H I H l

has been reported.44.45 Nevertheless, drug resistance has not been a major problem.

Itraconazole is also effective in treat-ing superficial dermatomycoses,55 as it persists in the skin, nails, and hair folli-cles at therapeutic levels for weeks after

discontinuation. However, whether it offers any significant advantage over ketoconazole, fluconazole, or clotrima-zole for treating superficial infections remains unclear.

• MICROBIAL RESISTANCE

The overall prevalence of resistance to azole agents is low.46'47-51 T h e only exception is in AIDS patients, in whom resistance is much higher than in other populations ( 3 3 % vs 11%)—and increasing.56 A.s mentioned above, resis-tant strains of C krusei and C glabrata have emerged with incremental use of fluconazole.45'57 Resistant strains of C neoformans have been reported in AIDS populations.58

Amphotericin R remains very active against many species, with no resistance by candidal species being reported.59

The only organisms reported resistant to amphotericin R are Pseudallescheria boy-dii and Trichosporon beigelii,59-6i

Tests of antifungal susceptibility corre-late poorly with clinical outcome; an

exception may be in HIV patients with Candida infections.62,65

• a t )

Itraconazole Itraconazole can be used to treat pulmonary and extrapulmonary aspergillosis in patients who cannot tolerate amphotericin R, or for whom amphotericin R fails.52 Other uses are shown in T A B L E 1 . Some clinicians prefer itra-conazole to ketoconazole because it has fewer side effects, even though it is more expensive.

Itraconazole has also been used for neu-tropenic prophylaxis. Failures, however, have been reported in bone marrow transplant and AIDS patients when serum concentrations were less than 250 ng/mL.55-54 This may be because of decreased itraconazole absorption due to changes in gastric pH.

• ADVERSE DRUG REACTIONS

TABLE 2 summarizes adverse drug reactions asso-ciated with ketoconazole, fluconazole, and itraconazole. Endocrine effects such as gyneco-mastia, decreased libido, and impotence are more frequent with ketoconazole than with itraconazole or fluconazole, because of keto-conazole's less-specific binding to human steroids.4

Use in pregnancy. The Food and Drug Administration places ketoconazole, itracona-zole, and fluconazole in category C (studies in animals have shown adverse effects on the fetus, but no adequate studies have been

1 06 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 2 FEBRUARY 1997



performed in humans). Ampho-tericin B, in contrast, is in category B (no adverse effects on the fetus in animal studies; no adequate studies in humans).

In studies in rats and mice, itra-conazole caused dose-related mater-nal toxicity, embryotoxicity, and ter-atogenicity at doses of 40 to 160 mg/kg/day. Therefore, it should be used in pregnancy only when its ben-efits outweigh its potential risks.55

• DRUG INTERACTIONS

Fluconazole and itraconazole have fewer drug interactions than does ketoconazole, because they are more selective for fungal than for human cytochrome P450 (TABLE 3).

Azole agents can increase the concentration of phenytoin, cis-apride, oral glucose-lowering agents, warfarin, digoxin, terfenadine, astem-izole, and cyclosporine, potentially leading to toxicity.64 Giving terfena-dine or astemizole with itraconazole or ketoconazole is contraindicated because of the potential for serious cardiovascular adverse events, including ventricular tachycardia, torsade de pointes, and sudden death.2

Rifampin, isoniazid, phénobarbi-tal, carbamazepine, and phenytoin a s m s induce hepatic enzymes and can lower fluconazole or itraconazole concentra-tions, potentially resulting in treatment failure.65

Classic Coca-Cola has been reported to increase the serum concentration of ketocona-zole, and is used to counteract ketoconazole's compromised absorption in persons with high gastric pH,66 and to boost its effect in AIDS patients and bone-marrow transplant recipients.

• DOSAGE AND FORMULATION

The dosage and duration of antifungal therapy depend on the type of infection, the severity of disease, and the patient's immune status (TABLE 4). Ketoconazole and itraconazole are available only in oral form; fluconazole comes in both intravenous and oral forms.

Because fluconazole is mainly excreted by the kidneys, dosage adjustment in patients

T A B L E 3

DRUG INTERACTIONS OF AZOLE AGENTS

I n t e r a c t i o n K e t o c o n a z o l e F luconazo le I t r a c o n a z o l e

A z o l e a g e n t increases t h e leve l or e f fec t of these drugs:

A z o l e a g e n t decreases t h e level or e f fec t o f these drugs:

These drugs increase t h e leve l or e f f e c t of the azo le a g e n t :

These drugs decrease t h e leve l or e f fec t of the azo le a g e n t :

A s t e m i z o l e (+++) C i s a p r i d e (++) Cor t i costero ids (++) C y c l o s p o r i n e (++) Ora l s u l f o n y l u r e a s (++) P h e n y t o i n (++) T e r f e n a d i n e (+++) T h e o p h y l l i n e (++)

T h e o p h y l l i n e * (++)

C i m e t i d i n e (++) Classic C o c a - C o l a t (++)

A n t a c i d s (++) HZ a n t a g o n i s t s (++) I s o n i a z i d (++) O m e p r a z o l e (++) R i f a b u t i n (++) R i f a m p i n (++)

A s t e m i z o l e (++) C a f f e i n e (+) C y c l o s p o r i n e (+) Ora l s u l f o n y l u r e a s (+) P h e n y t o i n (++) T e r f e n a d i n e (++) T h e o p h y l l i n e (++) W a r f a r i n (++) Z i d o v u d i n e (+)

C i m e t i d i n e (+)

C a r b a m a z e p i n e (+) I s o n i a z i d (+) P h é n o b a r b i t a l (+) P h e n y t o i n (+) R i f a b u t i n (+) R i f a m p i n (+)

A s t e m i z o l e ( + + + ) C i s a p r i d e ( + + ) C y c l o s p o r i n e (++) D i g o x i n (+) Ora l s u l f o n y l u r e a s (+) P h e n y t o i n ( + + ) T e r f e n a d i n e ( + + + ) T h e o p h y l l i n e (++)

C i m e t i d i n e (++)

A n t a c i d s ( + + ) C a r b a m a z e p i n e (++) HZ a n t a g o n i s t s (++) I s o n i a z i d ( + + ) O m e p r a z o l e (++) P h é n o b a r b i t a l (++) P h e n y t o i n ( + + ) R i f a b u t i n ( + + ) R i f a m p i n ( + + )

•Ketoconazole was reported to possibly alter the absorption of sustained-release theophyll ine dosage forms without a l ter ing the phar-macokinetic profi le of theophyll ine; until additional information is available, patients receiving sustained-release theophyl l ine should be observed for reduced theophyll ine response during ketoconazole admin i s t rat ion^

tClassic Coca-Cola has been used to increase the systemic concentration of ketoconazole, especially In patients with high gastric pH (eg, with long-term use of omeprazole) '®

Scale: + minor interaction; ++ moderate interaction; +++ major Interaction

with renal insufficiency is necessary. Patients with a creatinine clearance less than 50 mb/minute should receive 5 0 % of the normal maintenance dose.

Giving itraconazole via nasogastric tube without clogging the tube is a challenge. Ong and Fobes67 recommend dissolving itracona-zole beads in cranberry juice to avoid this problem.

• COST CONSIDERATIONS

Ketoconazole 400 mg costs $2 to $4; an equiv-alent oral dose of fluconazole costs approxi-mately four times as much, itraconazole costs five times as much, and intravenous flucona-zole costs 25 times as much—approximately $100 for a 400-mg bag, wholesale, not count-ing administration fees.

Since fluconazole has high bioavailability, the same dose can be given orally instead of

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 2 FEBRUARY 1997 1 01




DOSAGE GUIDELINES FOR AZOLE AGENTS

Since fluconazole has high bio-availability, the same dose can be given orally instead of intravenously

A g e n t and i n f e c t i o n Dosage D u r a t i o n

Ke toconazo le

Systemic in fect ions ( i n c l u d i n g b lastomycos is , h i s top lasmos is )

2 0 0 - 4 0 0 mg da i ly Cand id ias i s : at least 1 - 2 w e e k s Other systemic mycoses: 6 m o n t h s Chron ic m u c o c u t a n e o u s c a n d i d i a s i s usual ly r e q u i r e s m a i n t e n a n c e t h e r a p y

Reca lc i t rant d e r m a t o p h y t e in fect ions

2 0 0 - 4 0 0 mg da l ly 4 w e e k s

Fluconazole

O r o p h a r y n g e a l cand id ias i s L o a d i n g : M a i n t e n a n c e :

200 m g 100 m g dai ly

14 days

E s o p h a g e a l cand id ias i s L o a d i n g : M a i n t e n a n c e :

200 m g 100 m g da l ly

21 days

Systemic candid ias i s L o a d i n g : M a i n t e n a n c e :

400 m g 200 m g da l ly

28 days

A c u t e cryptococca l m e n i n g i t i s

L o a d i n g : M a i n t e n a n c e :

400 m g 200 m g da l ly

10-12 w e e k s a f ter c e r e b r o s p i n a l f l u i d c u l t u r e b e c o m e s n e g a t i v e

Chron ic c ryptococca l m e n i n g i t i s

200 mg da i ly For l ife, in p a t i e n t w i t h HIV i n f e c t i o n

V a g i n a l yeast In fect ion 150 m g O n e dose

P r e v e n t i o n of cand id ias i s in b o n e m a r r o w t r a n s p l a n t pat ients

400 m g da i ly Start severa l days b e f o r e t h e a n t i c i p a t e d onset o f n e u t r o p e n i a , c o n t i n u e f o r 1 days a f ter t h e n e u t r o p h i l c o u n t rises a b o v e 1000 ce l l s /mm 3

I t r aconazo le

Blastomycosis 2 0 0 - 4 0 0 mg da l ly V a r i a b l e

H is top lasmos is 2 0 0 - 4 0 0 mg da l ly V a r i a b l e

A s p e r g i l l o s i s 2 0 0 - 4 0 0 mg da i ly V a r i a b l e

L i f e - t h r e a t e n i n g in fect ions L o a d i n g :

M a i n t e n a n c e :

200 m g three t imes a day for 3 days 2 0 0 - 4 0 0 m g dai ly

A t least 3 m o n t h s and unt i l act ive f u n g a l I n f e c t i o n has reso lved

intravenously without compromising serum concentrations—at one fifth the cost. At 400 mg/day, switching to oral fluconazole would save $78 per day or $546 per week. A t 200 mg/day, the oral form would save $56 per day or $392 per week.

For these reasons, we encourage using oral

fluconazole whenever possible. However, while intravenous fluconazole is rarely indicat-ed, it may be appropriate in patients who are sedated or unconscious, cannot tolerate the oral form, have significant nausea and vomit-ing, or have ileus. •

1 06 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 2 FEBRUARY 1997



• REFERENCES

1. Sud IJ, Feingold DS. Mechanisms of action of the antimycotic imidazoles. J Invest Dermatol 1981; 7 6 : 4 3 8 - 4 4 1

2. Sewester C S , Olin BR, Hebel SK, et al. Drug facts and comparisons. St Louis: Wolters Kluwer, 1995 :355C-359F.

3. Bailey EM, Hrakovsky DJ, Pyhak MJ. T h e triazole antifungal agents: a review of itraconazole and fluconazole. Pharmacotherapy 1990; 1 0 : 1 4 6 - 1 5 3 .

4- Como J A , Dismukes WE. Oral azole drugs as systemic antifungal ther-apy. N Eng J Mud 1994; 3 3 0 : 2 6 3 - 2 7 2 .

5. Drugs for AIDS and associated infections. Med Lett Drugs Ther 1992; 3 4 : 1 4 - 1 6 .

6. Mandell GL, Bennett JE, Dolin R. Principles and practice of infec-tious diseases 4th ed. New York: Churchill Livingstone, 1995.

7. Prata A . Treatment of kala-azar with amphotericin B. Trans R Soc Trop Med Hyg 1963; 5 7 : 2 6 6 - 2 6 8 .

8. Bennett JE, Dismukes W E , Duma RJ, et al. A comparison of ampho-tericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Eng J Med 1979; 3 0 1 : 1 2 6 - 1 3 1 .

9. Dismukes WE, Cloud G, Gallis HA, et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. N Eng J Med 1987; 3 1 7 : 3 3 4 - 3 4 1 .

10. Chuck SI, Sande M A . Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome. N Eng J Med 1989; 3 2 1 : 7 9 4 - 7 9 9 .

11. Bradsher RW, Rice DC, Abernathy R S . Ketoconazole therapy for endemic blastomycosis. A n n Intern Med 1985; 1 0 3 : 8 7 2 - 8 7 9 .

12. Graybill FR, Stevens DA, Galgiani JN, et al. Ketoconazole treatment of coccidioidal meningitis. A n n NY Acad Sei 1988; 5 4 4 : 4 8 8 - 4 9 6 .

13. Negroni R, Rohles A M , Arechavala A, Tucule MA, Galimberti R. Ketoconazole in the treatment of paracoccidioidomycosis and histo-plasmosis. Rev Infect Dis 1980; 2 : 6 4 3 - 6 4 9 .

14. Drugs for AIDS and associated infections. Med Lett Drugs Ther 1991; 3 3 : 9 5 - 1 0 2 .

15. Dismukes WE, Bradsher RW Jr, Cloud G C , et al. Itraconazole therapy for blastomycosis and histoplasmosis: N I A I D Mycoses Study Group. Am J Med 1992; 9 3 : 4 8 9 - 4 9 7 .

16. Drugs for AIDS and associated infections. Med Lett Drugs Ther 1991; 3 3 : 9 5 - 1 0 2 .

17. Shepp DH, Klosterman A , Siegel MS, Meyers JD. Comparative trial of ketoconazole and nystatin for prevention of fungal infection in neutropenic patients treated in a protective environment. J Infect Dis 1985; 152 :1257-1263 .

18. Bodey GP. Azole antifungal agents. Cl in Infect Dis 1992; 14(Suppl 1 ):S 161—Si 69.

19. Hann IM, Prentice HG, Corringham R, et al. Ketoconazole versus nystatin plus amphotericin B for fungal prophylaxis in severely immunocompromised patients. Lancet 1982; 1 :826-829 .

20. Benhamou E, Hartmann O, Nogues C , Maraninchi D, Valteau D, Lemer le J . Does ketoconazole prevent fungal infection in children treated with high-dose chemotherapy and bone marrow transplanta-tion? Results of a randomized placebo-controlled trial. Bone Marrow Transplant 1991; 7 : 1 2 7 - 1 3 1 .

21. Pappas PG, Bradsher RW, Chapman SW, et al. Fluconazole in the treatment of blastomycosis [abstract]. In: Program and abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago. Sep 29 to O c t 2, 1991. Washington, DC: American Society for Microbiology 1991:292.

22. Pappas PG, Bradsher RW, Chapman SW, et al. Treatment of blasto-mycosis with fluconazole: a pilot study. T h e National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1995; 20 :267-271 .

23. Diaz M, Negroni R, Montero-Gei F, et al. A pan-American 5-year study of fluconazole therapy for deep mycosis in the immunocompe-tent host. Clin Infect Dis. 1992; 14(suppl) :568-576.

24- Supparatpinyo K, Nelson KE, Merz W G , et al. Response to antifungal therapy by human immunodeficiency virus-infected patients with dis-seminated Penicillium marneffei infections and in vitro susceptibilities of isolates from clinical specimens. Antimicrob Agents Chemotherapy 1993; 2407-2411 .

25. Alangaden G, Chandrasekar PH, Bailey E, et al. Antifungal prophy-laxis with low-dose fluconazole during bone marrow transplantation. Bone Marrow Transplant 1994; 14 :919 -924 .

26. Wingard J R , Merz W G , Rinaldi M G , et al. Association of Torulopsis

glabrata infections with fluconazole prophylaxis in neutropenic hone marrow transplant patients. Antimicrob Agents Chemother 1993; 3 7 : 1 8 4 7 - 1 8 4 9 .

27. Akiyama H, Sakamaki H, Onozawa Y. Fluconazole prophylaxis in patients with leukemia [letter]. A n n Intern Med 1993; 119:951.

28. Goldman M, Pottage J C , Weaver DC. Candida krusei fungemia: report of four cases and review of the literature. Medicine 1993; 7 2 : 1 4 3 - 1 5 0 .

29. Marchisio P, Principi N. Treatment of oropharyngeal candidiasis in HIV-infected children with oral fluconazole. Eur J C l i n Microbiol Infect Dis 1994; 13 :338 -340 .

30. Pletenberg A, Stoehr A, Hoffken G, et al. Fluconazole therapy of oral candidiasis in HIV-infected patients: results of a multicentre study. Infection 1994; 22 :58 -63 .

31. Akova M, Akahn HE, Uzun O, et al. Efficacy of fluconazole in the treatment of upper gastrointestinal candidiasis in neutropenic patients with cancer: factors influencing the outcome. Clin Infect Dis 1994; 18 :298-304 .

32. Hernandez-Sampelayo T. Fluconazole versus ketoconazole in the treatment of oropharyngeal candidiasis in HIV-infected children. Multicentre Study Group. Eur J Clin Microbiol Infect Dis 1994 13 :340-344 .

33. Product information: Diflucon, fluconazole, Roerig Division, New York, 1994.

34. Bozzette S A , Gordon RL, Yen A, et al. Biliary concentrations of flu-conazole in a patient with candidal cholecystitis: case report. Clin Infect Dis 1992; 15 :701-703 .

35. Bramer KW, Feczko JM. Single-dose oral fluconazole in the treatment of vaginal candidiasis. Ann NY Acad Sci 1988; 5 4 4 : 5 6 1 - 5 6 3 .

36. Multicentre Study Group. Treatment of vaginal candidiasis with a sin-gle oral dose ol fluconazole. Eur J Clin Microbiol Infect Ois 1988; 7 : 3 6 4 - 3 6 7 .

37. Osinusi BO, Rotowa NA. Fluconazole as single-dose treatment of vulvo-vaginal candidiasis. Curr T h e r Res 1988; 4 3 : 1 0 1 4 - 1 0 1 8 .

38. Phillips RJM, Watson S A , McKay FF An open multicentre study of the efficacy and safety ol a single dose ol fluconazole 150 mg in the treatment of vaginal candidiasis in general practice. Br J Clin Pract 1990; 4 4 : 2 1 9 - 2 2 2 .

39. Edwards JE Jr, Filler S G . (Current strategies lor treating invasive can-didiasis: emphasis on infections in non-neutropenic patients. Clin Infect Dis 1992; 14(Suppl 1 ) : S 1 0 6 - S 1 1 3 .

40. Rex JH, Bennett JE, Sugar A M , et al. Fluconazole vs amphotericin B for treatment of candidemia: results ol a randomized multicenter trial [abstract]. In: program and abstracts ol the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, October 17-20, 1993. Washington DC: American Society for Microbiology, 1993:267.

41. Kauffman C A , Bradley SF, Ross SG, Weber DR. I lepatosplenic can-didiasis: successful treatment with fluconazole. Am J Med 1991; 91:137 141.

42. Saag MS, Powderly W G , Cloud G A , et al. Comparison o f ampho-tericin B with fluconazole in the treatment ol acute AIDS-associated cryptococcal meningitis. N Eng J Med 1992; 3 2 6 : 8 3 - 8 9 .

43. Larsen RA, Leal MAE, Chan LS. Fluconazole compared with ampho-tericin B plus flucytosine for cryptococcal meningitis in A I D S : a ran-domized trial. Ann Intern Med 1990; 113 :183-187 .

44. Karyotakis N C , Dignani MG, Anaissie EJ. S C H 51048 , a new anti-fungal triazole active against hematogenous Candida krusei infections in neutropenic mice. Antimicrob Agents Chemother 1995; 39:775-777.

45. Nguyen MH, Peacock JE, Morris AJ, et al. T h e changing face of can-didemia: emergence of non-candida albicans species and antifungal resistance. Am J Med 1996; 100 :617-623 .

46. Dudley MN. Clinical pharmacology of fluconazole. Pharmacotherapy 1990; 10(Suppl) :141-145 .

47. Johnson L, Chryssanthou E, Petrini B, et al. Fluconazole failure in two cases of disseminated candidiasis. Scand J Infect Dis 1995; 2 7 : 4 2 1 - 4 2 4 .

48. Laguna F, Rodriguez-Tudela JL, Enriquez A. Fungemia due to flucona-zole-resistant Candida albicans in a patient with A I D S . Cl in Infect Dis 1994; 19 :542 -543 .

49. Newman SL, Flanigan TP, Fisher A, et al. Clinically significant mucosal candidiasis resistant to fluconazole treatment in patients with A I D S . Clin Infect Dis 1994; 19 :684-686 .

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 2 FEBRUARY 1997 1 01



Let us hear your opinions about the Cleveland Clinic Journal of Medicine. Do you like current articles and sections? What topics would you like to see covered and how can we make the Journal more useful to you?

E-mail: [email protected]

WWW: http://www.ccf.org/ed/ccjhome.htm Cleveland Clinic Journal of Medicine The Cleveland Clinic Foundation, EE37 9500 Euclid Avenue Cleveland, Ohio 44195

Phone: 216.444.2661 Fax: 216.444.9385


50. Whi te A , Goetz M B . Azole-resistant Candida albicans: report of two cases of resistance to fluconazole and review. Cl in Infect Dis 1994; 19 :687 -692 .

51. Fulton P, Phillips P. Fluconazole resistance during suppressive thera-py of AIDS-related thrush and esophagitis caused by Candida albi-cans [abstract]. International Conference on A I D S 1990; 6 :239 .

52. Product information: Sporanox, itraconazole, Janssen Pharmaceutical, Titusville, NI, 1994.

53. Denning DW, Donnelly JP, Hellreigel KP, Ito J , Martino P, Van's Wout JW. Antifungal prophylactics during neutropenia or allogene-ic bone marrow transplantation: W h a t is the state of the art? Chemotherapy 1992; 38(Suppl l ) : 4 3 - 4 9 .

54- Boogaerts MA, Verhoef GE, Zachee P, Demuynck H, Verbist L , De Beule K. Antifungal prophylactics with itraconazole in prolonged neutropenia: Correlation with plasma levels. Mycoses 1989; 32(Suppl 1): 1 0 3 - 1 0 8 .

55. Gupta AK, Sauder DN, Shear NH. Antifungal agents: A n overview. Part 1 & II. J A m Acad Dermatol 1994; 3 0 : 6 7 7 - 9 3 3 .

56. Law D, Moore B, Wardle HM et al. High prevalence of antifungal resistance in Candida spp from patients with A I D S . J Antimicrob Chemother 1994; 34 :659-668 .

57. Powderly W G . Resistant candidiasis. A I D S Research & Human Retroviruses 1994; 10:9 2 5-929.

58. Paugam A, Dupouy-Camet J, Blanche P, Gangneux JP, Troute-Schaefer C, Sicard D. Increased fluconazole resistance of Cryptococcus neoformans isola:edfrom a patient with A I D S and recurrent meningitis. Cl in Infect Dis 1994; 1 9 : 9 7 5 - 9 7 6 .

59. Still J M Jr, Lae EJ, Belcher KE, Spencer SA. A comparison of sus-ceptibility to five antifungal sgents of yeast cultures from burn patients. Burns 1995; 21:167-170.

60 . Walsh M, W h i t e L, Atkinson K, Enno A. Fungal Pseudalkscheria boydii lung infiltrates unresponsive to amphotericin B in leukaemic patients. Royal Newcastle Hospital, NSW. Aust NZ J Med 1992 2 2 : 2 6 5 - 2 6 8 .

61. Walsh TJ , Melcher GP, Rinaldi MG, et al. Trichosporon beigelii, an emerging pathogen resistant to amphotericin Br. J Cl in Microbiol 1990; 2 8 : 1 6 1 6 - 1 6 2 2 .

62 . Baily G G , Perry FM, Denning DW, Mandat BK. Management of candidiasis after failure of fluconazole in an HIV cohort. A I D S 1994; 8 : 7 8 7 - 9 2 .

63. Moore CB, Law D, Ganguli LA, Keaney M G L , Denning DW. High prevalence of antifungal resis:ance in Candida in patients with AIDS. J Antimicrob Chemother 1994; 4 5 : 6 5 9 - 6 6 8 .

64. Itraconazole. Med Lett Drugs Ther 1993; 3 5 : 7 - 9 . 65. Murphy E. Ketoconazole-theophyllin interaction. Irish Med J 1987;

80 :123 . 66 . Chin TWF, Loeb M, Fong IW. Effects of an acidic beverage (Coca-

Cola) on absorption of ketoconazole. Antimicrob Agents Chemother 1995; 39 :1671-1675 .

67 . Ong DL, Fobes LM. Administering itraconazole via nasogastric tube [letter]. Am J Health-Syst Pharm 1996; 53 :1962 .

ADDRESS REPRINT REQUESTS t o Morton Goldman, PharmD, The Cleveland Clinic Foundation, S107, 9500 Euclid Avenue, Cleveland, OH 44107 .

1 0 6 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 2 FEBRUARY 1997


mailto:[email protected]

http://www.ccf.org/ed/ccjhome.htm


Documents

The role of azole antifungal agents for systemic antifungal therapy