Treating fungal infections, Part 1: Overview and candidiasis.

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Journal of Critical Illness

June, 2001

Treating fungal infections, Part 1: Overview and candidiasis.

Author/s:

With the increased incidence of superficial and deep fungal infections over

the past 10 years, new oral and parenteral antifungal agents have

proliferated and practical antifungal susceptibility tests have emerged.

Clinical advances have been so numerous that the 1990s were dubbed " the

decade of the antimycotics. " [1]

New guidelines developed by the Infectious Diseases Society of America

(IDSA) have been developed to help clinicians keep pace with advances in the

management of fungal diseases. [2-10] These practice guidelines, compiled by

more than 40 specialists and based on more than 1000 literature references,

provide evidence-based recommendations for selecting antifungal therapy in

numerous clinical situations.

This Clinical Update series will summarize the IDSA's practice guidelines.

Part 1 offers a general overview of antifungal medications and summarizes

recommendations for the treatment of patients with candidiasis. [3,4]

Subsequent installments, to be published in future issues of this journal,

will cover antifungal therapy for aspergillosis, histoplasmosis,

cryptococcosis, blastomycosis, coccidioidomycosis, and sporotrichosis.

OVERVIEW

Antifungal drugs approved in this country for systemic use include

amphotericin B and its derivatives, oral azoles, and pyrimidines. Additional

agents, including other azoles and the polyene nystatin, can be used for

mucocutaneous infection.

Amphotericin B

Conventional amphotericin B is the standard therapy for many invasive or

life-threatening fungal infections. New lipid formulations of amphotericin

B--amphotericin B lipid complex, amphotericin B choleseryl sulfate, and

liposomal amphotericin B--offer the possibility of greater efficacy and less

toxicity than the parent compound. The lipid agents, however, are

significantly more expensive.

For the most part, the clinical advantages of the lipid formulations have

not been demonstrated in comparative trials. [11] In addition, parameters

for optimal use of these agents, such as dosage and dosing intervals, remain

to be defined. In general, all 3 lipid agents are indicated for patients who

have a systemic fungal infection and are unable to take conventional

amphotericin B.

Liposomal amphotericin B has been approved as empiric therapy for the

patient with neutropenia and persistent fever despite treatment with

broad-spectrum antibiotics. Lipid formulations are not recommended initially

for most patients with blastomycosis, candidiasis, coccidioldomycosis,

cryptococcosis, histoplasmosis, and paracoccidioidomycosis.

For the most serious or life-threatening fungal infections, the target

dosage is 1 to 1.5 mg/kg of conventional amphotericin B (in the standard

deoxycholate preparation) or 3 to 6 mg/kg of a lipid formulation. Patients

who are less ill may receive half of the maximum dosage on the first day of

therapy and the maximum dosage on the second day.

Rapid infusion of conventional amphotericin B is as safe and well-tolerated

as prolonged infusion but should be avoided in patients who are azotemic or

hyperkalemic, are receiving the infusion through a central catheter that

extends into the right side of the heart, or are being treated with more

than 1 mg/kg. Liposomal amphotericin B can be safely infused more rapidly

than amphotericin B lipid complex or amphotericin cholesteryl sulfate.

Nephrotoxicity of all forms of amphotericin B can be minimized by

maintaining intravascular volume and by preventing concurrent exposure to

other nephrotoxic agents (including radiocontrast dyes).

Pretreatment is often given to prevent or minimize adverse effects, but it

is not recommended because data do not demonstrate the efficacy of this

practice. Pretreatment regimens include diphenhydramine, acetaminophen,

corticosteroids, and heparin, alone or in various combinations. Most

patients become able to tolerate amphotericin B over time without

pretreatment.

Oral azole agents

Ketoconazole (an imidazole), itraconazole (a triazole), and fluconazole (a

triazole) are broad-spectrum anti-fungal agents that often can be used in

place of amphotericin B. All 3 are useful in the treatment of blastomycosis,

candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis,

paracoccidioidomycosis, and sporotrichosis. Itraconazole is also effective

against aspergillosis. Fluconazole and itraconazole are generally more

effective and better tolerated than ketoconazole; fluconazole possesses the

most desirable pharmacologic profile. [12]

Success with oral azoles is limited by their tendency to interact with other

drugs and by the emergence of resistance to fluconazole. Such resistance is

particularly problematic when treating patients with candidiasis.

Pyrimidines

The only approved member of this class is flucytosine, also known as

5-fluorocytosine. Its use is limited to candidiasis, cryptococcosis, and

some mold infections. It has a high propensity for causing toxic adverse

effects, including liver dysfunction, bone marrow suppression, rash, and GI

discomfort. Significant resistance to flucytosine among Candida species has

emerged.

Flucytosine is used primarily in combination with amphotericin B to treat

patients with cryptococcal meningitis and life-threatening candidal

syndromes. These include endocarditis, meningitis, and hepatosplenic

disease. When treating immunocompromised patients who have cryptococcal

meningitis and renal insufficiency, a dosage of 100 mg/kg/d is recommended.

[13]

Susceptibility testing

Antifungal susceptibility testing of Candida isolates may be appropriate in

several clinical settings. When patients have persistent candidemia or

progressive disseminated candidiasis despite fluconazole therapy, Candida

isolates from the bloodstream and other normally sterile sites should be

tested for susceptibility to that drug. In patients with candidemia or

invasive candidal disease, Candida isolates other than Candida albicans

should be tested for susceptibility to fluconazole.

Testing of sterile site isolates may allow construction of a local biogram

that can guide empiric therapy. In addition, testing of mucosal Candida

isolates may help determine the cause when a patient's condition falls to

improve with treatment that should be effective.

CANDIDIASIS

Candidal infections are the most common fungal infections. [4] Treatment

recommendations for acute hematogenous candidiasis are founded on randomized

trial data, while recommendations for other forms of systemic candidal

infection are based on case series and anecdotal reports.

General considerations

In vitro susceptibility testing has an important role in guiding therapy,

especially when infection is caused by species other than C albicans. C

albicans is the most frequently isolated pathogen in oropharyngeal and

cutaneous candidiasis, but non-albicans species of Candida are becoming

increasingly prevalent. Amphotericin B is usually effective in candidiasis

therapy, but susceptibility testing for azole resistance is now important.

First-line therapy in systemic candidal infections is conventional

amphotericin B in the standard deoxycholate preparation. Amphotericin B

lipid complex and liposomal amphotericin B have been approved for use as

second-line therapy when patients with proven candidiasis cannot tolerate

conventional amphotericin B or their infection is refractory to first-line

treatment. The oral azoles are used preferentially in mucocutaneous

candidiasis.

In general, the pharmacokinetics of amphotericin B appears to be similar in

adults and children (including neonates). The pharmacokinetics of

fluconazole depends on the age of the patient; fluconazole is cleared more

rapidly in children than in adults. Clearance of flucytosine is directly

proportional to glomerular filtration rate, so it may be slow in infants of

very low birth weight.

Disseminated candidiasis

In candidemia and acute hematogenously disseminated candidiasis, therapy is

necessary to resolve signs and symptoms of sepsis, sterilize the bloodstream

and sites of hematogenous dissemination, and treat occult sites of

infection. intravenous amphotericin B or intravenous or oral fluconazole is

recommended (Table 1). Flucytosine in combination with amphotericin B or

fluconazole may be considered.

For empiric therapy for suspected disseminated candidiasis in the febrile,

nonneutropenic patient, intravenous amphotericin B or intravenous or oral

fluconazole may be considered. Such medication is usually restricted to

patients who have candidal colonization, multiple risk factors, and no other

correctable causes of fever.

Empiric antifungal therapy for neutropenic patients with prolonged fever

despite antibacterial therapy should address occult yeast and mold

infections. Intravenous amphotericin B at a dosage of 0.5 to 0.7 mg/kg/d is

the preferred agent, but intravenous itraconazole may be an alternative.

Liposomal amphotericin B appears to be equally effective, with better safety

and tolerability. Fluconazole is not recommended.

To eradicate the foci of chronic disseminated candidiasis (hepatosplenic

candidiasis), the use of intravenous amphotericin B or intravenous or oral

fluconazole is recommended. Fluconazole, 6 mg/kg/d, is preferred for stable

patients. Amphotericin B, 0.6 to 0.7 mg/kg/d, is appropriate when patients

are acutely ill or have refractory disease. Some authorities recommend a 1-

to 2-week course of amphotericin B for all patients. Flucytosine may be

given with amphotericin B or fluconazole.

Infants with congenital candidiasis who are at risk for acute bloodstream or

visceral dissemination may be treated with intravenous amphotericin B, 0.5

to 1 mg/kg/d to a total dose of 10 to 25 mg/kg, or fluconazole, 6 mg/kg q

12h. Amphotericin B is well tolerated in neonates. Term infants with normal

birth weight and who are otherwise healthy may be treated with topical

antifungal agents.

Invasive candidiasis

For most forms of invasive candidiasis other than mucocutaneous disease,

there are 2 choices of therapy. Either oral or intravenous fluconazole or

intravenous amphotericin B, possibly with oral flucytosine, may be used.

Therapy for nongenital mucocutaneous candidiasis includes topical azoles

(such as clotrimazole or miconazole) and nystatin, as well as the oral

azoles and amphotericin B. Genital candidiasis (vaginitis) is managed with a

more extensive range of topical azoles (including over-the-counter

preparations), nystatin, oral azoles, and boric acid (Table 2).

Asymptomatic candiduria usually does not require therapy. Candiduria should

be managed in symptomatic patients, neutropenic patients, low-birth-weight

infants, patients who have renal allografts, and patients who are expected

to undergo urologic procedures. Therapy should be given for 7 to 14 days;

removal or replacement of stents and Foley catheters often is helpful.

Amphotericin B alone is appropriate for treating primary candidal pneumonia.

When pneumonia is secondary to disseminated infection, therapy is given for

hematogenously disseminated candidiasis. Laryngeal candidiasis responds to

intravenous amphotericin B (0.7 to 1 mg/kg/d), but switching to fluconazole

once symptoms have improved may be appropriate also.

Patients with osteomyelitis (including mediastinitis) or arthritis require

arthroscopic or open debridement or drainage before initiation of systemic

antifungal therapy. Effective therapies include intravenous amphotericin B,

0.5 to 1 mg/kg/d for 6 to 10 weeks, and fluconazole, 6 mg/kg/d for 6 to 12

months. Another option is to give amphotericin B for 2 to 3 weeks and then

fluconazole for up to 12 months. Infected prosthetic joints require

resection arthroplasty followed by similar antifungal medication.

Intravenous amphotericin B or fluconazole is indicated for candidal disease

of the biliary tree. Intravenous (but not intraperitoneal) amphotericin B is

appropriate for catheterassociated candidal peritonitis. Peritonitis with

fecal contamination should be treated with amphotericin B or fluconazole

intravenously after surgical repair and drainage.

Initial therapy for patients who have candidal meningitis is intravenous

amphotericin B, 0.7 to 1 mg/kg/d, plus oral flucytosine, 25 mg/kg qid.

Therapy is given for at least 4 weeks beyond clinical resolution of all

signs and symptoms.

Patients with candidal endophthalmitis are usually treated with intravenous

amphotericin B, but oral or intravenous fluconazole has been used also, and

oral flucytosine is sometimes given with the amphotericin B. Initial therapy

consisting of amphotericin B and flucytosine should be followed by

fluconazole such that the total course is 6 to 12 weeks. Vitrectomy may save

sight, but the role of intravitreal antifungal therapy has not been

determined.

Esophageal candidiasis must be treated systemically. Fluconazole (100 mg/d

orally) or itraconazole (200 mg/d orally) solution is used for 14 to 21

days. Intravenous amphotericin B, 0.3 to 0.7 mg/kg/d, is given for

azole-refractory infections.

Prophylaxis

Strategies to prevent invasive candidiasis are appropriate for patients with

prolonged neutropenia and patients who are undergoing solid-organ

transplantation. Patients at significant risk for invasive candidiasis may

be given fluconazole, 400 mg/d, during the neutropenic period; high-risk

liver transplant recipients can be given fluconazole, 400 mg/d, early in the

postoperative period.

(1.) Sobel JD, for the Mycoses Study Group. Practice guidelines for the

treatment of fungal infections. Clin Infect Dis. 2000;30:652.

(2.) McGowan JE Jr. Chesney PJ, Crossley KB, Laforea FM. Guidelines for the

use of systemic glucocortico-steroids in the management of selected

infections. J Infect Dis. 1992;165:1-13.

(3.) Dismukes WE. Introduction to antifungal drugs. Clin Infect Dis.

2000;30:653-657.

(4.) Rex JH, Walsh TJ, Sobel JD et al. Practice guidelines for the treatment

of candidiasis. Clin Infect Dis. 2000;30:662-678.

(5.) s DA, Kan VL, Judson MA, at al. Practice guidelines for diseases

caused by Aspergillus. Clin Infect Dis. 2000;30:669-709.

(6.) Wheat J, Sarosi G, McKinsey D, at al. Practice guidelines for the

management of patients with histoplasmosis. Clin Infect Dis.

2000;30:688-695.

(7.) Saag MS. Graybill RJ, Larsen RA, et al. Practice guidelines for the

management of cryptococcal disease. Clin Infect Dis. 2000,30:710-718.

(9.) Galgiani JN, Ampel NM, Catanzaro A, at al. Practice guidelines for the

treatment of coccidioidomycosis. Clin Infect Dis. 2000;30:658-661.

(8.) Chapman SW, Bradsher RW Jr, GD, et al. Practice guidelines for

the management of patients with blastomycosis. Clin Infect Dis.

2000;30:679-683.

(10.) Kauffman CA, Hajjeh R, Chapman SW, for the Mycoses Study Group.

Practice guidelines for the management of patients with sporotrichosis. Clin

Infect Dis. 2000;30:684-687.

(11.) Wong-Beringer A, s RA, Guglialmo BJ. Lipid formulations of

amphotericin B: clinical efficacy and toxicities. Clin Infect Dis.

1998;27:603-618.

(12.) HoesleyC, Dismukes WE. Overview of oral azola drugs as systemic

antifungal therapy. Semin Respir Crit Care Med. 1997;18 301-309.

(13.) Van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptccoccal

meningitis associated with the acquired immunodeficiency syndrome. N Engl J

Med. 1997;337:15-21.

Table 1 -- Treatment options for disseminated candidiasis

Clinical setting Antifungal options

Candidemia; acute hematogenously Intravenous amphotericin B, oral or

disseminated candidiasis intravenous fluconazole, flucytosine

with amphotericin B or fluconazole

Empiric therapy, suspected Intravenous amphotericin B, oral or

disseminated candidiasis, febrile intravenous fluconazole

nonneutropenic patients

Chronic disseminated candidiasis Intravenous amphotericin B, oral or

(hepatosplenic candidiasis) intravenous fluconazole, flucytosine

with amphotericin B or fluconazole

Disseminated cutaneous neonatal Intravenous amphotericin B, oral or

candidiasis intravenous fluconazole

Table 2 -- Treatment options for invasive candidiasis

Clinical setting Antifungal options

Urinary candidiasis Intravenous amphotericin B

(possibly with

oral flucytosine), oral or

intravenous

fluconazole

Candidal pneumonia Intravenous amphotericin B,

intravenous fluconazole

Laryngeal candidiasis Intravenous amphotericin B, oral

or intravenous fluconazole

Candidal osteomyelitis Intravenous amphotericin B, oral

or

intravenous fluconazole

Candidal mediastinitis Intravenous amphotericin B, oral

or

intravenous fluconazole

Candidal arthritis Intravenous amphotericin B, oral

or

intravenous fluconazole

Candidal infections of Intravenous amphotericin B, oral

gallbladder, or

pancreas, peritoneum intravenous fluconazole

Candidal endocarditis, Intravenous amphotericin B

pericarditis, (possibly with

suppurative phlebitis oral flucytosine), oral or

intravenous

fluconazole

Candidal meningitis Intravenous amphotericin B

(possibly with

oral flucytosine), intravenous

fluconazole

Candidal endophthalmitis Intravenous amphotericin B

(possibly with

oral flucytosine), oral or

intravenous

fluconazole

Oropharyngeal candidiasis Topical azoles, oral azoles,

nystatin,

intravenous amphotericin B, *

amphotericin B suspension

Esophageal candidiasis Fluconazole solution, [+]

itraconazole

solution, [+] intravenous

amphotericin B

Candidal onychomycosis Oral itraconazole

Candidal paronychia and skin Topical azoles, nystatin

infections

Chronic mucocutaneous candidiasis Oral azoles

Genital candidiasis (vaginitis) Topical azoles, nystatin, oral

azoles,

boric acid (600-mg gelatin

capsule)

(*)Only for patients with azole-refractory infections.

(+)For patients unable to swallow, parenteral therapy should be given.