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## Complete Summary

#### GUIDELINE TITLE

Guidelines for treatment of candidiasis.

#### BIBLIOGRAPHIC SOURCE(S)

Pappas PG, Rex JH, Sobel JD, Filler SG, Dismukes WE, Walsh TJ, Edwards
JE. Guidelines for treatment of candidiasis. Clin Infect Dis 2004 Jan
15;38(2):161-89. \[344 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14699449)

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Rex JH, Walsh TJ, Sobel JD,
Filler SG, Pappas PG, Dismukes WE, Edwards JE. Practice guidelines for
the treatment of candidiasis. Infections Diseases Society of America.
Clin Infect Dis 2000 Apr;30(4):662-78.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [January 24, 2008, Leukine
    (sargramostim)](http://www.fda.gov/medwatch/safety/2008/safety08.htm#Leukine):
    Voluntary market suspension of the current liquid formulation of
    sargramostim, a granulocyte-macrophage colony-stimulating factor
    (GM-CSF), because of an upward trend in spontaneous reports of
    adverse reactions, including syncope (fainting). The lyophilized
    form of the drug is not affected. See the U.S. Food and Drug
    Administration (FDA) web site for more information.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Candidiasis, including invasive and mucocutaneous candidiasis

#### GUIDELINE CATEGORY

Diagnosis\
Management\
Treatment

#### CLINICAL SPECIALTY

Infectious Diseases\
Internal Medicine

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

-   To summarize current knowledge and provide recommendations for the
    treatment of multiple forms of candidiasis, including invasive and
    mucocutaneous candidiasis

-   To present prophylactic strategies for the prevention of invasive
    candidiasis in at-risk patients

#### TARGET POPULATION

Patients with candidiasis (infections due to *Candida*)

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Microbiology Laboratory Studies**

Susceptibility testing, such as the NCCLS M27-A method for testing the
susceptibility of *Candida* species to fluconazole, itraconazole, and
flucytosine.

**Other Studies**

1.  Ultrasonography or computed tomography for persistent candiduria

2.  Ophthalmological examination

**Pharmacotherapy**

1.  Amphotericin B deoxycholate

> **Note**: Lipid-based amphotericin B preparations are considered but
> not recommended as first-line therapy. They are considered second-line
> therapy for patients who are intolerant of or refractory to therapy
> with conventional amphotericin B.

2.  Azoles, such as caspofungin, fluconazole, itraconazole,
    ketoconazole, voriconazole

3.  Flucytosine

4.  Topical agents, including topical azoles such as clotrimazole,
    butoconazole, miconazole, tioconazole, terconazole

5.  Nystatin, oral or topical

**Nonpharmacologic Treatment Options**

1.  Removal of stents, catheters, and prosthetic devices when possible

2.  Surgery including open or arthroscopic debridement or drainage

3.  Vitrectomy

4.  Intravitreal antifungal therapy (discussed but not recommended)

5.  Parenteral therapy (for patients with esophageal candidiasis who are
    unable to swallow)

#### MAJOR OUTCOMES CONSIDERED

-   Reduction, prevention, or relief from signs and symptoms (e.g.,
    fever)

-   Prevention of development or progression of infection and associated
    complications

-   Eradication of infection (e.g., clearance of bloodstream, urine,
    and/or sites of infection)

-   Infection recurrence

-   Resolution of radiographic findings

-   Return of joint function in cases of candidal osteomyelitis and
    arthritis

-   Preservation of cardiac function in cases of candidal endocarditis,
    pericarditis, or suppurative phlebitis

-   Normalization of cerebrospinal fluid analysis, radiological
    findings, and stabilization of neurological function in cases of
    candidal meningitis

-   Preservation of sight in cases of candidal endophthalmitis

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Not stated

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Quality of Evidence**

1.  Evidence from at least one properly randomized, controlled trial

2.  Evidence from at least one well-designed clinical trial without
    randomization, from cohort or case-controlled analytic studies
    (preferably from more than one center), or from multiple time-series
    studies or dramatic results from uncontrolled experiments

3.  Evidence from opinions of respected authorities based on clinical
    experience, descriptive studies, or reports of expert committees

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Strength of Recommendation**

A.  Good evidence to support a recommendation for use

B.  Moderate evidence to support a recommendation for use

C.  Poor evidence to support a recommendation

D.  Moderate evidence to support a recommendation against use

E.  Good evidence to support a recommendation against use

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not stated

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

Each recommendation includes a ranking for the strength and the quality
of evidence supporting it. Definitions of the levels of evidence (I-III)
and grades of recommendation (A-E) are repeated at the end of the Major
Recommendations field.

**[Executive Summary]{.underline}**

*Candida* species are the most common cause of fungal infections.
*Candida* species produce infections that range from
non--life-threatening mucocutaneous illnesses to invasive processes that
may involve virtually any organ. Such a broad range of infections
requires an equally broad range of diagnostic and therapeutic
strategies. These guidelines summarize current knowledge about treatment
of multiple forms of candidiasis for the Infectious Diseases Society of
America (IDSA). This document covers the following 4 major topical
areas.

***The role of the microbiology laboratory***: To a greater extent than
for other fungi, treatment of candidiasis can now be guided by in vitro
susceptibility testing. However, susceptibility testing of fungi is not
considered a routine testing procedure in many laboratories, is not
always promptly available, and is not universally considered as the
standard of care. Knowledge of the infecting species, however, is highly
predictive of likely susceptibility and can be used as a guide to
therapy. The guidelines review the available information supporting
current testing procedures and interpretive breakpoints and place these
data into clinical context. Susceptibility testing is most helpful in
dealing with deep infection due to non--*albicans* species of *Candida*.
In this setting, especially if the patient has been treated previously
with an azole antifungal agent, the possibility of microbiological
resistance must be considered.

***Treatment of invasive candidiasis***: In addition to acute
hematogenous candidiasis, the guidelines review strategies for treatment
of 15 other forms of invasive candidiasis (See Table 2 in the original
guideline). Extensive data from randomized trials are available only for
therapy of acute hematogenous candidiasis in the nonneutropenic adult.
Choice of therapy for other forms of candidiasis is based on case series
and anecdotal reports. In general, amphotericin B--based preparations,
the azole antifungal agents, and the echinocandin antifungal agents play
a role in treatment. Choice of therapy is guided by weighing the greater
activity of amphotericin B--based preparations and the echinocandin
antifungal agents for some non--*albicans* species (e.g., *Candida
krusei*) against the ready availability of oral and parenteral
formulations for the azole antifungal agents. Flucytosine has activity
against many isolates of *Candida* but is infrequently used.

***Treatment of mucocutaneous candidiasis***: Therapy for mucosal
infections is dominated by the azole antifungal agents. These drugs may
be used topically or systemically and are safe and efficacious. A
significant problem with mucosal disease is the propensity for a small
proportion of patients to have repeated relapses. In some situations,
the explanation for such a relapse is obvious (e.g., recurrent
oropharyngeal candidiasis in an individual with advanced and
uncontrolled human immunodeficiency virus \[HIV\] infection), but in
other patients, the cause is cryptic (e.g., relapsing vaginitis in a
healthy woman). Rational strategies for these situations are discussed
in the guidelines and must consider the possibility of induction of
resistance with prolonged or repeated exposure.

***Prevention of invasive candidiasis***: Prophylactic strategies are
useful if the risk of a target disease is sharply elevated in a readily
identified patient group. Selected patient groups undergoing therapy
that produces prolonged neutropenia (e.g., some bone marrow transplant
recipients) or who receive a solid-organ transplant (e.g., some liver
transplant recipients) have a sufficient risk of invasive candidiasis to
warrant prophylaxis.

**[Key Recommendations by Diagnosis]{.underline}**

**Candidemia and Acute Hematogenously Disseminated Candidiasis**

If feasible, initial nonmedical management should include removal of all
existing central venous catheters **(B-II)**. The evidence for this
recommendation is strongest for the nonneutropenic patient population
and includes data in which catheter removal was associated with reduced
mortality in adults and neonates. In neutropenic patients, the role of
the gut as a source for disseminated candidiasis is evident from autopsy
studies, but, in an individual patient, it is difficult to determine the
relative contributions of the gut and a catheter as primary sources of
fungemia. An exception is made for fungemia due to *C. parapsilosis*,
which is very frequently associated with use of catheters **(A-II)**
(Anaissie et al, 1998). There are, however, no randomized studies of
this topic, and a recent exhaustive review clearly demonstrates the
limitations of the available data. However, the consensus opinion is
that existing central venous catheters should be removed, when feasible.
Anecdotal reports of successful in situ treatment of infected catheters
by instillation of antibiotic lock solutions containing as much as 2.5
mg/mL of amphotericin B deoxycholate suggest this as an option in
selected cases, but the required duration of therapy and the frequency
of relapse are not known.

Initial medical therapy should involve caspofungin, fluconazole, an
amphotericin B preparation, or combination therapy with fluconazole plus
amphotericin B. The choice between these treatments depends on the
clinical status of the patient, the physician\'s knowledge of the
species and/or antifungal susceptibility of the infecting isolate, the
relative drug toxicity, the presence of organ dysfunction that would
affect drug clearance, available knowledge of use of the drug in the
given patient population, and the patient\'s prior exposure to
antifungal agents. Experience with caspofungin (a 70-mg loading dose
followed by 50 mg daily) is, as yet, limited, but its excellent clinical
activity, its broad-spectrum activity against *Candida* species, and a
low rate of treatment-related adverse events make it a suitable choice
for initial therapy in adults **(A-I)**. For clinically stable patients
who have not recently received azole therapy, fluconazole
([\>]{.underline}6 mg/kg per day; i.e., [\>]{.underline}400 mg/day for a
70-kg patient) is another appropriate choice **(A-I)** (Edwards et al,
1997; Buchner et al, 2002). For clinically unstable patients infected
with an unspeciated isolate, fluconazole has been used successfully, but
many authorities prefer amphotericin B deoxycholate ([\>]{.underline}0.7
mg/kg per day) because of its broader spectrum. If a lipid associated
formulation of amphotericin B is selected, a dosage of at least 3
mg/kg/d appears suitable **(C-III)**. A combination of fluconazole (800
mg/day) plus amphotericin B deoxycholate (0.7 mg/kg per day for the
first 5 to 6 days) is also suitable **(A-I)**.

Neonates with disseminated candidiasis are usually treated with
amphotericin B deoxycholate because of its low toxicity and because of
the relative lack of experience with other agents in this population.
Fluconazole (6--12 mg/kg per day) has been used successfully in small
numbers of neonates. There are currently no data on the pharmacokinetics
of caspofungin in neonates.

Antifungal susceptibility can be broadly predicted once the isolate has
been identified to the species level (see the subsection Susceptibility
testing and drug dosing, in the Introduction). Infections with *C.
albicans*, *C. tropicalis*, and *C. parapsilosis* may be treated with
amphotericin B deoxycholate (0.6 mg/kg per day), fluconazole (6 mg/kg
per day), or caspofungin (70-mg loading dose followed by 50 mg/day)
**(A-I)**. Because *C. glabrata* often has reduced susceptibility to
both azoles and amphotericin B, opinions on the best therapy are
divided. Both *C. krusei* and *C. glabrata* appear susceptible to
caspofungin, and this agent appears to be a good alternative **(A-I)**.
Although fungemia due to *C. glabrata* has been treated successfully
with fluconazole (6 mg/kg per day), many authorities prefer amphotericin
B deoxycholate ([\>]{.underline}0.7 mg/kg per day) **(B-III)** (Buchner
et al, 2002). On the basis of pharmacokinetic predictions, fluconazole
(12 mg/kg per day; 800 mg/day for a 70-kg patient) may be a suitable
alternative, particularly in less-critically ill patients **(C-III)**.
If the infecting isolate is known or likely to be *C. krusei*, available
data suggest that amphotericin B deoxycholate (1.0 mg/kg per day) is
preferred **(C-III)**. On the basis of data on open-label salvage
therapy, voriconazole is licensed in Europe (but not the United States)
for \"treatment of fluconazole-resistant serious invasive *Candida*
infections (including *C. krusei*)\" and could be considered as an
alternative choice **(B-III)**. Many, but not all, isolates of *C.
lusitaniae* are resistant to amphotericin B. Therefore, fluconazole (6
mg/kg per day) is the preferred therapy for this species **(B-III)**.
Both voriconazole and caspofungin would be expected to be active against
this species **(C-III)**. Issues associated with selection and dosage of
the lipid amphotericin preparations are discussed in the Introduction.
As discussed above and elsewhere, susceptibility testing may be used to
identify isolates that are less likely to respond to fluconazole
**(A-II)** or amphotericin B **(B-II)** (see table 3 in original
guideline document) (Rex & Pfaller, 2002; Rex et al, 1997)\].

For candidemia, therapy should be continued for 2 weeks after the last
positive blood culture result and resolution of signs and symptoms of
infection **(A-III)**. Amphotericin B or caspofungin may be switched to
fluconazole (intravenous or oral) for completion of therapy **(B-III)**.
Patients who are neutropenic at the time of developing candidemia should
receive a recombinant cytokine that accelerates recovery from
neutropenia (granulocyte colony-stimulating factor or
granulocyte-monocyte colony-stimulating factor). Other forms of
immunosuppression should be modified, when possible (e.g., by reduction
of a corticosteroid dosage).

Breakthrough (or persistence of) candidemia in the face of ongoing
antifungal therapy suggests the possibility of an infected intravascular
device, significant immunosuppression, or microbiological resistance.
Therapy with an agent from a different class should be started, the
isolate should be promptly identified to the species level, and
susceptibility testing should be considered. Infected intravascular
devices should be removed, when feasible, and immunosuppression should
be ameliorated.

Finally, all patients with candidemia should undergo at least 1
ophthalmological examination to exclude the possibility of candidal
endophthalmitis **(A-II)**. Although some authors have suggested that
examinations should be conducted for 2 weeks after negative findings of
an initial examination, these recommendations are based on small numbers
of patients. The results of large prospective therapy studies that
included careful ophthalmological examinations suggest that onset of
retinal lesions is rare following an otherwise apparently successful
course of systemic therapy (there were no such cases in 441 successfully
treated subjects). The guideline developers thus conclude that
candidemic individuals should have at least 1 careful ophthalmological
examination, preferably at a time when the candidemia appears controlled
and new spread to the eye is unlikely **(B-III)**. These data and
recommendations are based almost entirely on experience in the treatment
of nonneutropenic patients---neutropenic patients may not manifest
visible endophthalmitis until recovery from neutropenia, and, therefore,
ophthalmological examination should be performed after recovery of the
neutrophil count.

**Empirical Treatment of Suspected Disseminated Candidiasis in Febrile
Nonneutropenic Patients**

The utility of antifungal therapy for this syndrome has not been
defined. If therapy is given, its use should be limited to patients with
(1) *Candida* species colonization (preferably at multiple sites), (2)
multiple other risk factors, and (3) absence of any other uncorrected
causes of fever (**C-III)** (Buchner et al, 2002). The absence of
colonization by *Candida* species indicates a lower risk for invasive
candidiasis and warrants delaying empirical therapy.

**Empirical Antifungal Treatment of Neutropenic Patients with Prolonged
Fever Despite Antibacterial Therapy**

Antifungal therapy is appropriate in neutropenic patients who have
persistent unexplained fever, despite receipt of 4 to 7 days of
appropriate antibacterial therapy. Once begun, therapy is continued
until resolution of neutropenia. Amphotericin B deoxycholate (0.5--0.7
mg/kg per day) has traditionally been the preferred agent **(A-II)**.
When compared with amphotericin B deoxycholate (median dose, 0.6 mg/kg
per day), liposomal amphotericin B (median dose, 3 mg/kg per day) showed
similar overall clinical efficacy but demonstrated superior safety and a
decreased rate of documented breakthrough fungal infections,
particularly in recipients of bone marrow transplants **(A-I)** (Walsh
et al, 1999). When compared with amphotericin B deoxycholate (mean daily
dose, 0.7 mg/kg), itraconazole (200 mg intravenously \[iv\] q12h for 2
days, 200 mg iv per day for 12 days, and then 400-mg solution orally
\[po\] per day) showed similar breakthrough fungal infection rates and
mortality but significantly less toxicity **(A-I)** (Boogaerts et al,
2001). Although the data are controversial because some analyses show
that voriconazole was, overall, slightly inferior to liposomal
amphotericin B, voriconazole has been shown to be superior to liposomal
amphotericin B in the prevention of breakthrough fungal infections in
high-risk patients **(A-I)**. Thus, use of this compound should be
limited to allogeneic bone marrow transplant recipients and individuals
with relapsed leukemia. Fluconazole (400 mg/day) has been used
successfully for selected patients **(A-I)** (Malik et al, 1998; Viscoli
et al., 1996; Winston et al, 2000) and could be considered as an
alternative strategy if (1) the patient is at low risk for invasive
aspergillosis, (2) the patient lacks any other signs or symptoms
suggesting aspergillosis, (3) local epidemiologic data suggest that the
patient is at low risk for infection with azole-resistant isolates of
*Candida*, and (4) the patient has not received an azole antifungal
agent as prophylaxis.

**Chronic Disseminated Candidiasis (Hepatosplenic Candidiasis)**

Fluconazole (6 mg/kg per day) is generally preferred for clinically
stable patients **(B-III)**. Amphotericin B deoxycholate (0.6--0.7 mg/kg
per day) or a lipid-associated formulation of amphotericin B (3--5 mg/kg
per day) may be used in acutely ill patients or patients with refractory
disease. Some experts recommend an initial 1- to 2-week course of
amphotericin B for all patients, followed by a prolonged course of
fluconazole. Therapy should be continued until calcification or
resolution of lesions, particularly in patients receiving continued
chemotherapy or immunosuppression. Premature discontinuation of
antifungal therapy may lead to recurrent infection. Patients with
chronic disseminated candidiasis may continue to receive chemotherapy,
including ablative therapy for recipients of bone marrow and/or stem
cell transplants. Treatment of chronic disseminated candidiasis in such
patients continues throughout chemotherapy.

**Disseminated Cutaneous Neonatal Candidiasis**

Prematurely born neonates, neonates with low birth weight, or infants
with prolonged rupture of membranes who demonstrate the clinical
findings associated with disseminated neonatal cutaneous candidiasis
should be considered for systemic therapy. Amphotericin B deoxycholate
(0.5--1 mg/kg per day, for a total dose of 10--25 mg/kg) is generally
used **(B-III)**. Fluconazole may be used as a second-line agent
**(B-III)**. Dosing issues for neonates are discussed in more detail in
the original guideline document.

**Urinary Candidiasis**

Determination of the clinical relevance of candiduria can be difficult.
Asymptomatic candiduria rarely requires therapy **(D-III)**. Candiduria
may, however, be the only microbiological documentation of disseminated
candidiasis. Candiduria should be treated in symptomatic patients,
patients with neutropenia, infants with low birth weight, patients with
renal allografts, and patients who will undergo urologic manipulations
**(B-III)**. However, short courses of therapy are not recommended;
therapy for 7 to 14 days is more likely to be successful. Removal of
urinary tract instruments, including stents and Foley catheters, is
often helpful. If complete removal is not possible, placement of new
devices may be beneficial. Treatment with fluconazole (200 mg/day for
7--14 days) and with amphotericin B deoxycholate at widely ranging doses
(0.3--1.0 mg/kg per day for 1--7 days) has been successful **(B-II)**
(Jacobs et al, 1996). In the absence of renal insufficiency, oral
flucytosine (25 mg/kg four times a day \[q.i.d.\]) may be valuable for
eradicating candiduria in patients with urologic infection due to
non-*albicans* species of *Candida* **(C-III)**. However, emergence of
resistance may occur rapidly when this compound is used as a single
agent. Bladder irrigation with amphotericin B deoxycholate (50--200
micrograms/mL) may transiently clear funguria, but is rarely indicated
**(C-III)**, except as a diagnostic localizing tool. Even with
apparently successful local or systemic antifungal therapy for
candiduria, relapse is frequent, and this likelihood is increased by
continued use of a urinary catheter. Persistent candiduria in
immunocompromised patients warrants ultrasonography or computed
tomography (CT) of the kidney **(C-III)**.

**Lower Respiratory Tract Candidiasis (Pulmonary and Laryngeal
Candidiasis)**

Most patients with primary *Candida* pneumonia and laryngeal candidiasis
have been treated with amphotericin B (0.7--1.0 mg/kg per day)
**(B-III)**. In cases of secondary pneumonia associated with
hematogenously disseminated infection, therapy directed at disseminated
candidiasis, rather than at *Candida* pneumonia in particular, is
indicated (see the section Candidemia and Acute Hematogenously
Disseminated Candidiasis, above). For candidal laryngitis, fluconazole
is a suitable alternative in milder cases **(B-III)**.

**Candidal Osteomyelitis (including Mediastinitis) and Arthritis**

Osteomyelitis is best treated with combined surgical debridement of the
affected area, especially in the case of vertebral osteomyelitis, and
antifungal therapy. Courses of amphotericin B deoxycholate (0.5--1 mg/kg
per day for 6--10 weeks) have been used successfully.

Fluconazole has been used successfully as initial therapy for
susceptible isolates in 3 reports in which doses of 6 mg/kg per day for
6 to 12 months were effective. Addition of amphotericin B deoxycholate
to bone cement appears safe and may be of value in complicated cases.
Taken together, these data suggest that surgical debridement and an
initial course of amphotericin B for 2 to 3 weeks followed by
fluconazole, for a total duration of therapy of 6 to 12 months, would be
rational **(B-III)**.

Definitive information on treatment of native joint arthritis is
limited. Adequate drainage is critical to successful therapy. In
particular, management of *Candida* arthritis of the hip requires open
drainage. Case reports have documented cures with administration of
intravenous amphotericin B and with fluconazole when administered in
conjunction with adequate drainage. Fluconazole has occasionally been
used alone successfully. As parenteral administration of these agents
produces substantial synovial fluid levels, the utility of
intra-articular therapy is discouraged. Prolonged courses of therapy
similar to those used for treating osteomyelitis appear to be required
**(C-III)**.

Although success with medical therapy alone has been described,
*Candida* arthritis that involves a prosthetic joint generally requires
resection arthroplasty. Subsequent medical therapy mirrors that for
native joint disease, and a new prosthesis may be inserted after
successful clearance of the local infection **(C-III)**.

On the basis of a small number of cases, *Candida* mediastinitis may be
treated successfully with surgical debridement followed by either
amphotericin B or fluconazole therapy **(C-III)** (Malani et al, 2002;
Clancy, Nguyen, & Morris, 1997). Irrigation of the mediastinal space
with amphotericin B is not recommended, because it may cause chemical
mediastinitis. Prolonged courses of therapy, similar to those needed for
osteomyelitis at other sites, appear to be appropriate **(C-III)**.

**Candidal Infections of the Gallbladder, Pancreas, and Peritoneum**

Disease of the biliary tree should be treated by mechanical restoration
of functional drainage, combined with therapy with either amphotericin B
or fluconazole **(C-III)**. Both agents achieve therapeutic biliary
concentrations, and local instillation is not needed.
Catheter-associated peritonitis is treated with catheter removal and
systemic treatment with amphotericin B or fluconazole **(B-III)**. After
removal of the peritoneal dialysis catheter and a delay of at least 2
weeks, a new catheter may be placed **(B-III)** (Goldie et al, 1996).
Intraperitoneal amphotericin B has been associated with painful chemical
peritonitis and should, in general, be avoided. *Candida* peritonitis
related to intra-abdominal leakage of fecal material is treated with
surgical repair, drainage, and therapy with either amphotericin B or
fluconazole **(C-III)**. The required duration of therapy for all forms
of *Candida* peritonitis is not well defined and should be guided by the
patient\'s response. In general, 2 to 3 weeks of therapy seems to be
required. Surgical patients with recurrent gastrointestinal perforation
are at increased risk for *Candida* peritonitis and may benefit from
prophylactic antifungal therapy **(B-I)**.

**Candidal Endocarditis, Pericarditis, Suppurative Phlebitis, and
Myocarditis**

Both native valve and prosthetic valve infection should be managed with
surgical replacement of the infected valve. Medical therapy with
amphotericin B with or without flucytosine at maximal tolerated doses
has most often been used **(B-III)**. Total duration of therapy should
be at least 6 weeks after surgery, but possibly much longer **(C-III)**.
*Candida* endocarditis has a propensity for relapse and requires careful
follow-up for at least 1 year. If valve replacement is not possible,
long-term (possibly life-long) suppressive therapy with fluconazole may
be used **(C-III)** (Pierrotti & Baddour, 2002; Baddour, 1995;
Castiglia, Smego, & Sames, 1994). Successful primary therapy with
fluconazole and liposomal amphotericin B has been described for patients
with native valve infections.

Candidal pericarditis requires surgical debridement and/or resection,
depending on the extent of the disease. Cardiac tamponade is possible
and may require an emergency procedure to relieve hemodynamic
compromise. Prolonged therapy with amphotericin B or fluconazole should
be used **(C-III)**.

Suppurative *Candida* thrombophlebitis of a peripheral vein is best
managed with surgical resection of the involved vein segment, followed
by antifungal therapy for 2 weeks **(B-III)**.

After vein resection, the general approach to this disease is similar to
that for other forms of acute hematogenous dissemination.

**Candidal Meningitis**

Amphotericin B deoxycholate (0.7--1 mg/kg per day) plus flucytosine (25
mg/kg q.i.d.) is appropriate as initial therapy **(B-III)**. The
flucytosine dose should be adjusted to produce serum levels of 40 to 60
micrograms/mL. Very few data exist on fluconazole for the treatment of
candidal meningitis---it has been used as both follow-up therapy and
long-term suppressive therapy. Because of the tendency for this disease
to relapse, therapy should be administered for a minimum of 4 weeks
after resolution of all signs and symptoms associated with the
infection. Treatment of *Candida* meningitis associated with
neurosurgical procedures should also include removal of prosthetic
devices.

**Candidal Endophthalmitis**

All patients with candidemia should have at least 1 dilated retinal
examination, preferably by an ophthalmologist **(A-II)**. The
preponderance of clinical experience of treatment is with amphotericin
B, often combined with flucytosine **(B-III)**. Recent data also support
the use of fluconazole for this indication, particularly as follow-up
therapy **(B-III)**. Use of the maximal doses appropriate for other
forms of invasive candidiasis would be appropriate to maximize
penetration into the eye. Therapy should be continued until complete
resolution of visible disease or convincing stabilization. Courses of 6
to 12 weeks of therapy are typically required.

A diagnostic vitreal aspirate is generally recommended for patients
presenting with endophthalmitis of unknown origin. If fungal elements
are observed, some ophthalmologists instill intravitreal amphotericin B
deoxycholate therapy. The utility of vitrectomy has not been
systematically studied. Extrapolation from a study of bacterial
endophthalmitis and from anecdotal experiences with *Candida*
endophthalmitis suggests that initial vitrectomy and intravitreal
amphotericin B therapy may be most appropriate for patients with
substantial vision loss.

**Nongenital Mucocutaneous Candidiasis**

*Oropharyngeal and Esophageal Candidiasis*

Initial episodes of oropharyngeal candidiasis can be treated with
clotrimazole troches (one 10-mg troche 5 times per day) or nystatin
(available as a suspension of 100,000 U/mL \[dosage, 4--6 mL q.i.d.\] or
as flavored 200,000 U pastilles \[dosage, 1 or 2 pastilles 4--5 times
per day for 7--14 days\]) **(B-II)**. Oral fluconazole (100 mg/day for
7--14 days) is as effective as---and, in some studies, superior
to---topical therapy **(A-I)**. Itraconazole solution (200 mg/day for
7--14 days) is as efficacious as fluconazole **(A-I)**. Ketoconazole and
itraconazole capsules are less effective than fluconazole, because of
variable absorption **(A-I)**.

Patients tolerate repeated episodes of oropharyngeal candidiasis without
difficulty, especially if the episodes occur infrequently **(A-I)**.
Suppressive therapy is effective for preventing recurrent infections
**(A-I)**. Although it does the increase the rate of development of
isolates with an increased fluconazole minimal inhibitory concentration
(MIC), the use of continuous suppression (rather than episodic or
intermittent therapy in response to symptomatic relapse) does not
increase the likelihood of developing an infection that fails to respond
to fluconazole **(A-I)**.

Fluconazole-refractory oropharyngeal candidiasis will respond to oral
itraconazole therapy ([\>]{.underline}200 mg/day, preferably in solution
form) approximately two-thirds of the time **(A-II)**. An oral
suspension of amphotericin B (1 mL q.i.d. of the 100 mg/mL suspension)
is sometimes effective in patients who do not respond to itraconazole
**(B-II)**. There have also been anecdotal reports of responses of
refractory disease to use of fluconazole solution (used in a
swish-and-swallow fashion) and to use of chewed itraconazole capsules.
Intravenous caspofungin (50 mg/day) and intravenous amphotericin B
deoxycholate ([\>]{.underline}0.3 mg/kg per day) are usually effective
and may be used in patients with refractory disease **(B-II)**.
Denture-related disease may require extensive and aggressive
disinfection of the denture for definitive cure.

Systemic therapy is required for effective treatment of esophageal
candidiasis **(B-II)**. Although symptoms of esophageal candidiasis may
be mimicked by other pathogens, a diagnostic trial of antifungal therapy
is often appropriate before performing endoscopy **(B-II)**. A 14-- to
21-day course of either oral fluconazole (100 mg/day po) or itraconazole
solution (200 mg/day po) is highly effective **(A-I)**. Ketoconazole and
itraconazole capsules are less effective than fluconazole, because of
variable absorption **(A-I)**. Voriconazole is as effective as
fluconazole but is associated with more adverse events **(A-I)**.
Caspofungin (50 mg/day iv) is as efficacious as amphotericin B or
fluconazole **(A-I)**. Suppressive therapy may be used for patients with
disabling recurrent infections **(A-II)**. Fluconazole-refractory
esophageal candidiasis should be treated with itraconazole solution
([\>]{.underline}200 mg/day po), voriconazole (200 mg b.i.d.), or
caspofungin (50 mg/day) **(A-II)**. Intravenous amphotericin B
deoxycholate (0.3--0.7 mg/kg per day, as needed to produce a response)
may be used for patients with otherwise refractory disease **(B-II)**.

Antifungal susceptibility testing is not generally needed for the
management of either oropharyngeal or esophageal candidiasis, but can be
useful in patients with refractory infection **(B-II)**. In patients
with acquired immune deficiency syndrome (AIDS), treatment of the
underlying HIV infection with highly aggressive antiretroviral therapy
(HAART) is critical for preventing and managing these infections
**(B-II)**.

*Candidal Onychomycosis*

Whereas onychomycosis is usually caused by a dermatophyte, infections
due to *Candida* species also occur. Topical agents are usually
ineffective. For onychomycosis, oral griseofulvin has largely been
replaced by more-effective agents, including oral terbinafine or
itraconazole. With respect to *Candida* onychomycosis, terbinafine has
only limited and unpredictable in vitro activity and has not
demonstrated consistently good activity in clinical trials. Although the
number of reported cases is small, therapy with itraconazole does appear
to be effective. Itraconazole (200 mg b.i.d. for 1 week, repeated
monthly for 3--4 months) appears to be the most appropriate treatment
**(A-II)**.

*Candidal Skin Infections and Paronychia*

Nonhematogenous primary skin infections typically occur as intertrigo in
skin folds, especially in obese and diabetic patients. Topical azoles
and polyenes, including clotrimazole, miconazole, and nystatin, are
effective. Keeping the infected area dry is important. For paronychia,
the most important intervention is drainage.

*Mammary Candidiasis*

Although a clear association remains to be determined, because of the
lack of application of consistent clinical and microbiological criteria,
nipple or breast pain in nursing mothers has been linked to the presence
of *C. albicans*. Nursing worsens or precipitates the pain. Classical
findings of mastitis are absent, as is fever, and the findings of a
local physical examination are often unimpressive. The infant may or may
not have signs of mucosal or cutaneous candidiasis. Microbiological
studies have found both bacteria and *C. albicans*, with bacteria
appearing to predominate. The true cause of the pain associated with
this syndrome is unclear, but treatment of the mother and the infant
with an antifungal agent has produced relief, according to some reports.
Optimal diagnostic criteria and management strategies are not certain,
but both topical nystatin and oral fluconazole are safe for infants and
could be considered as therapy for mother and child if the presentation
is strongly suggestive of candidiasis.

*Chronic Mucocutaneous Candidiasis*

The persistent immunological defect associated with chronic
mucocutaneous candidiasis requires a long-term approach that is
analogous to that used in patients with AIDS and rapidly relapsing
oropharyngeal candidiasis. Systemic therapy is needed, and all of the
azole antifungal agents (ketoconazole, fluconazole, and itraconazole)
have been used successfully. The required dosages are similar to those
used for other forms of mucocutaneous candidiasis. As with HIV-infected
patients, development of resistance to these agents has also been
described.

**Genital Candidiasis**

Vaginal candidiasis may be classified into complicated and uncomplicated
forms (see table 5 in the original guideline document). Uncomplicated
vaginitis is seen in 90% of patients and responds readily to
short-course oral or topical therapy with any of the therapies listed
above, including the single-dose regimens **(A-I)**. In contrast, the
complicated vaginitis seen in approximately 10% of patients requires
antimycotic therapy for [\>]{.underline}7 days, either daily as topical
therapy or as two 150-mg doses of fluconazole administered 72 h apart
**(A-I)** (Sobel et al, 2001) Azole therapy is unreliable for
non-*albicans* species of *Candida* **(B-III)**. Infections with *C.
glabrata*, *C. krusei*, and the other non-*albicans* species frequently
respond to topical boric acid 600 mg/day for 14 days **(B-II)** or
topical flucytosine **(B-II)**. Azole-resistant *C. albicans* infections
are extremely rare.

Recurrent vaginitis is usually due to azole-susceptible *C. albicans*.
After control of causal factors (e.g., uncontrolled diabetes), induction
therapy with 2 weeks of a topical or oral azole should be followed by a
maintenance regimen for 6 months. Suitable maintenance regimens include
fluconazole (150 mg po every week), ketoconazole (100 mg per day),
itraconazole (100 mg q.o.d.) or daily therapy with any topical azole
**(A-I)**. Chronic use of fluconazole in HIV-infected women has been
associated with increased vaginal carriage of non-*albicans* species of
*Candida*, but the significance of this observation is uncertain.

**Prophylaxis**

*HIV-Infected Patients*

See the section on Oropharyngeal and Esophageal Candidiasis, above.

*Neutropenic Patients*

Fluconazole (400 mg/day) or itraconazole solution (2.5 mg/kg q12h po
during the period of risk for neutropenia) are appropriate therapies for
patients who are at significant risk for invasive candidiasis **(A-I)**.
Although not licensed at the time of this writing, micafungin
demonstrated favorable activity, on the basis of results in the recently
reported comparative trial, and may become an option for antifungal
prophylaxis in neutropenic patients. Such patient groups might include
patients receiving standard chemotherapy for acute myelogenous leukemia,
allogeneic bone marrow transplants, or high-risk autologous bone marrow
transplants. However, in this context, it is important to understand
that, among these populations, chemotherapy or bone marrow
transplantation protocols do not all produce equivalent risk and that
local experience with particular chemotherapy and cytokine regimens
should be used to determine the relevance of prophylaxis. The optimal
duration of prophylaxis is not known but should include the period of
risk for neutropenia at a minimum.

*Solid-Organ Transplant Recipients*

High-risk recipients of liver transplants should receive prophylactic
antifungal therapy during the early postoperative period **(A-I)**.

*Patients in Intensive Care Units (ICUs) and Other Care Settings*

Knowledge about this class of infections is evolving. The primary data
showing utility of prophylaxis are from studies at single centers with
high baseline rates of infections. The broader applicability of these
rules in other ICUs remains a subject of significant debate.
Institutions where high rates of invasive candidiasis in the adult or
neonatal ICU persist despite standard infection-control procedures could
consider fluconazole prophylaxis for carefully selected patients in
these care areas **(A-I)**.

**[Definitions]{.underline}**:

**Quality of Evidence**

1.  Evidence from at least one properly randomized, controlled trial

2.  Evidence from at least one well-designed clinical trial without
    randomization, from cohort or case-controlled analytic studies
    (preferably from more than one center), or from multiple time-series
    studies or dramatic results from uncontrolled experiments

3.  Evidence from opinions of respected authorities based on clinical
    experience, descriptive studies, or reports of expert committees

**Strength of Recommendation**

A.  Good evidence to support a recommendation for use

B.  Moderate evidence to support a recommendation for use

C.  Poor evidence to support a recommendation

D.  Moderate evidence to support a recommendation against use

E.  Good evidence to support a recommendation against use

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### REFERENCES SUPPORTING THE RECOMMENDATIONS

[References open in a new
window](http://www.guideline.gov/summary/select_ref.aspx?doc_id=4545)

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for select
recommendations (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Early treatment of fungal infections should reduce fungal
infection--associated morbidity.

**Subgroups Most Likely to Benefit**

The following patients are likely to benefit from aggressive therapy
because of the associated high morbidity and mortality of their
diagnosis:

-   Neutropenic patients with prolonged fever despite antibacterial
    therapy

-   Patients with otolaryngologic candidiasis

-   Patients with candidal osteomyelitis (including mediastinitis) and
    arthritis

-   Patients with candidal endocarditis, pericarditis, and suppurative
    phlebitis

-   Patients with candidal meningitis

-   Patients with candidal endophthalmitis

#### POTENTIAL HARMS

**Antifungal Therapy**

-   Conventional amphotericin B is associated with significant toxicity,
    including infusion-related events, such as chills, fever, headache,
    nausea and vomiting, and dose-limiting nephrotoxicity.

-   Lipid formulations of amphotericin B, although offering several
    therapeutic advantages over conventional amphotericin B, are
    considerably more expensive, ranging from 10- to 20-fold higher in
    cost.

-   One potential limitation of the azole antifungal drugs is the
    frequency of their interactions with coadministered drugs, which
    results in adverse clinical consequences. One type of azole-drug
    interaction may lead to decreased plasma concentration of the azole,
    related to either decreased absorption or increased metabolism of
    the azole. A second type of azole-drug interaction may lead to an
    unexpected toxicity of the coadministered drug, relating to the
    ability of the azoles to increase plasma concentrations of other
    drugs by altering hepatic metabolism via the cytochrome P-450
    system.

-   A second potential limitation of the azoles is the emergence of
    resistance of fungal organisms, especially *Candida* species, to
    fluconazole.

-   Widespread use of inappropriate antifungal therapy may have
    deleterious epidemiological consequences, including selection of
    resistant organisms.

**Subgroups Most Likely to Be Harmed**

Critically ill patients

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

#### IMPLEMENTATION TOOLS

Personal Digital Assistant (PDA) Downloads

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Pappas PG, Rex JH, Sobel JD, Filler SG, Dismukes WE, Walsh TJ, Edwards
JE. Guidelines for treatment of candidiasis. Clin Infect Dis 2004 Jan
15;38(2):161-89. \[344 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14699449)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2004 Jan 15

#### GUIDELINE DEVELOPER(S)

Infectious Diseases Society of America - Medical Specialty Society

#### SOURCE(S) OF FUNDING

Infectious Diseases Society of America (IDSA)

#### GUIDELINE COMMITTEE

Infectious Diseases Society of America (IDSA) Practice Guidelines
Committee

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Authors*: Pappas PG; Rex JH; Sobel JD; Filler SG; Dismukes WE; Walsh
TJ; Edwards JE

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

**Peter G. Pappas** has received grant support from Merck, Fujisawa,
Pfizer, Shering-Plough, Enzon, and Vicuron. He has been a speaker for
Merck, Fujisawa, Enzon, and Pfizer and has served as a consultant for
Merck and Schering-Plough.

**John H. Rex** is employed full time with AstraZeneca Pharmaceuticals.

**Jack D. Sobel** has received grant support from 3M, Pfizer, and
Johnson & Johnson.

**Scott G. Filler** has received grant support from Pfizer, Glaxo-Smith
Kline, Cubist, and Merck. He has been a speaker for Merck, Pfizer, and
3M and has served as a consultant for Merck.

**William E. Dismukes** has received grant support from Fujisawa and
Merck. He has been a speaker for Pfizer and Enzon and has served as a
consultant for Fujisawa, Pfizer, Vicuron, and Bristol-Myers Squibb.

**Thomas J. Walsh** has received grant support from Fujisawa and Merck.

**John E. Edwards** has served as a consultant for Pfizer and Merck.

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Rex JH, Walsh TJ, Sobel JD,
Filler SG, Pappas PG, Dismukes WE, Edwards JE. Practice guidelines for
the treatment of candidiasis. Infections Diseases Society of America.
Clin Infect Dis 2000 Apr;30(4):662-78.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the [Infectious Disease Society of
America (IDSA) Web
site](http://www.journals.uchicago.edu/cgi-bin/resolve?CID32301).

Print copies: Available from Infectious Diseases Society of America,
1300 Wilson Boulevard, Suite 300, Arlington, VA 22209.

#### AVAILABILITY OF COMPANION DOCUMENTS

The following is available:

-   Kish MA. Guide to development of practice guidelines. Clin Infect
    Dis 2001 Mar 15;32(6):851-4.

Electronic copies: Available from the [Clinical Infectious Diseases
Journal Web
site](http://www.journals.uchicago.edu/doi/full/10.1086/319366).

Print copies: Available from Infectious Diseases Society of America,
1300 Wilson Boulevard, Suite 300, Arlington, VA 22209.

A PDA version of the original guideline document is available from
[www.idsaguidelinesforhandhelds.org](http://www.idsaguidelinesforhandhelds.org/).

#### PATIENT RESOURCES

None available

#### NGC STATUS

This summary was completed by ECRI on May 1, 2001. The information was
verified by the guideline developer on June 29, 2001. This summary was
updated by ECRI on April 20, 2004. This summary was updated by ECRI
Institute on February 26, 2008 following the U.S. Food and Drug
Administration advisory/voluntary market withdrawal of the liquid
formulation of Leukine (sargramostim).

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions.

### DISCLAIMER

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