The Nebraska Medical Center Guidelines for Management of Invasive Candidiasis

Purpose
To provide a framework for initial evaluation and management of immunocompetent and immunocompromised patients
with suspected, probable, or proven invasive candidiasis (IC) based on the recent 2009 Clinical Practice Guidelines by the
Infectious Disease Society of America.1 A summary of recommendations for the management of disseminated candidiasis
in the neonatal population are also provided. The new guideline was updated to reflect newer antifungal agents, recent
publications on the treatment of IC or suspected candidiasis as well as prophylaxis in high risk adult populations.

Definition
IC encompasses severe and invasive Candida infections that include candidemia, disseminated candidiasis, endocarditis,
meningitis, endophthalmitis, and other deep tissue involvement. It excludes more superficial and less severe diseases such
as oropharyngeal and esophageal candidiasis.1

Risk Factors
Risk factors for IC include: prolonged and broad-spectrum antibiotics, central venous catheters, total parenteral nutrition,
renal replacement therapy, neutropenia, bone marrow transplant, hematologic malignancies, solid organ transplant (liver
and kidney), premature birth, gastrointestinal surgery, burns, implanted prosthetic devices, immunosuppressive agents
(including glucocorticoids, chemotherapy,and immunomodulators), and prolonged intensive care unit (ICU) stay.1 Risk
factors for non-albicans species include glucocorticosteroid use, central venous catheter placement, prior fluconazole
therapy, and preexisting candiduria.2,3

Antifungal Selection
Selection of an antifungal agent should take into account history of recent azole exposure, history of antifungal
intolerances, the dominant Candida species based on epidemiologic and institution-specific surveillance data,
susceptibility data, severity of illness, relevant comorbidities, and evidence of involvement of the central nervous system
(CNS), cardiac valves, and/or visceral organs. Early antifungal initiation is critical to successful treatment outcomes.
Empiric or prophylactic use of antifungals may reduce morbidity, mortality, and length of stay in critically ill patients, but
widespread use of antifungals must be balanced against the risk of toxicity, costs, and emergence of resistance.1
Currently, the prevalence of IC among adult ICU patients at TNMC is < 2%; thus, routine fungal prophylaxis in non-
neutropenic ICU patients is not recommended at TNMC.

Susceptibility testing of Candida species is performed at TNMC on yeast isolates from sterile sites including blood,
cerebrospinal fluid, synovial fluids, pleural fluids, and pericardial fluids. Candida species grow rather rapidly and can
usually be identified within 3-5 days. Therapy should be guided by susceptibility testing results when available. In the
absence of such results, Table 1 (see below) can be used.

Pharmacologic Considerations1, 4-5 – There are 4 major antifungal categories (polyenes, triazoles, echinocandins,
flucytosine). TNMC formulary antifungals are discussed briefly below.
1. Polyenes (amphotericin B deoxycholate and lipid amphotericin B formulations)1,4
• Antifungal category of choice for use in pregnant individuals with IC.
• AmB-d (amphotericin B deoxycholate) – The most common adverse effects include nephrotoxicity, infusion-
related reactions (chills, rigors, hypotension), and potassium and magnesium wasting.
• LFAmB (lipid amphotericin B formulation) – Three formulations exist with similar spectra to AmB-d (see Table
1 below) but with less nephrotoxicity and higher costs. The TNMC formulary agent is liposomal Amphotericin B
(AmBisome®). LFAmB formulations possess different pharmacological properties and adverse events and should
not be interchanged without careful consideration.
2. Triazoles (fluconazole, itraconazole, voriconazole, posaconazole)1,4 – Triazoles have varied activity against Candida
(see Table 1 below). All triazoles have good oral bioavailability, and the oral formulations are preferred when
possible. Fluconazole is the only azole with clinically significant urinary concentrations. All inhibit CYP450 to
varying degrees, and careful evaluation for drug-drug interactions is warranted. Generally, avoid in pregnancy due to
risks of fetal malformations.
 • Fluconazole is well absorbed orally (~90% bioavailability), is unaffected by food and gastric pH, and among all
triazoles, has the greatest penetration into cerebrospinal fluid (CSF) and vitreous body with concentrations at least
50% of serum. Fluconazole urine concentrations reach 10-20 times serum concentrations. Adjust dose for
creatinine clearance <50mL/min.
• Itraconazole is generally reserved for mucosal candidiasis, and little data exist for IC. GI absorption differs for
capsule versus solution. Acid-reducing agents decrease absorption of the capsule, while food and acidic
beverages (such as carbonated drinks and cranberry juice) enhance absorption. Oral solution is better absorbed on
an empty stomach. Renal elimination is minimal (active drug <0.03%; inactive metabolite 40%).
• Voriconazole is effective for mucosal and IC, but is primarily used for step-down oral therapy for fluconazole-
resistant, voriconazole-susceptible strains of C. krusei and C. glabrata. Voriconazole has good oral
bioavailability, CSF (~50% of serum), and vitreous penetration. Oral bioavailability is not affected by gastric pH
but is decreased when consumed with food. IV voriconazole is complexed to a cyclodextrin molecule, and should
not be used if the CrCl is < 50 mL/min due to risk of accumulation of this molecule. Renal elimination of
unchanged drug is insignificant, and thus dosage adjustment for renal insufficiency is not necessary.
Voriconazole is the only triazole to require dosage reduction for mild-to-moderate hepatic impairment. Serum
levels can vary widely between patients due to common polymorphisms in the primary metabolic enzyme. Drug-
drug interactions are frequent and need careful consideration when beginning, altering, or discontinuing treatment.
Contraindicated in pregnancy.
• Posaconazole does not have an indication for treatment of primary candidiasis but demonstrates in vitro activity
similar to that of voriconazole. Clinical data are inadequate to make evidence-based recommendation for
treatment other than oropharyngeal candidiasis. Available only as oral suspension with high bioavailability
especially when small doses are given frequently and administered with fatty foods and in acidic environments.
Major excretion pathway is feces (~77%) with minimal urinary elimination (~14%). Therefore, dosage adjustment
is not necessary in renal impairment. However, due to variability in posaconazole exposure in patients with
creatinine clearance <20mL/min, patients should be monitored for breakthrough fungal infections.6
3. Echinocandins (caspofungin, anidulafungin, micafungin)1,4-5 The TNMC formulary echinocandin is micafungin. Due
to lack of data, these agents are generally avoided in pregnancy.
• All agents are available parenterally only, dosed once daily, and do not require renal dose adjustment.
Caspofungin requires dosage adjustment for moderate hepatic impairment (Child-Pugh class B). Echinocandins
undergo nonenzymatic degradation and are not metabolized by the CYP450 system, although caspofungin
undergoes phase II metabolism. Echinocandins have negligible distribution into CSF and urine.
• Have a broad spectrum of activity and are similar to each other with respect to in vitro activity against Candida sp
(see Table 1), with micafungin and anidulafungin having similar MICs that are generally lower than the MIC of
capsofungin. C. parapsilosis has demonstrated less in vitro susceptibility to the echinocandins suggesting it may
be less responsive to these drugs. However, the clinical significance of this finding is still unknown.
• Echinocandins are generally well tolerated. Adverse drug reactions are less frequent with micafungin and
anidulafungin compared with caspofungin. Phlebitis (3.5-25% of patients) and elevated liver enzyme levels (1-
15%) occur more often with caspofungin compared with micafungin and anidulafungin (< 8%)
4. Flucytosine has broad antifungal activity against most Candida species except C. krusei.1,4 Available orally only with
good bioavailability. Most (>90%) is excreted unchanged in the urine, and dosage adjustment is necessary for renal
dysfunction. Flucytosine is primarily used in combination with amphotericin B for invasive diseases such as
meningitis or endocarditis and is rarely administered alone due to rapid emergence of resistance. Occasionally,
flucytosine may be used for urinary tract infections when there are no other alternatives. Contraindicated in pregnancy.

Table 1. Spectra of Activity Against Candida Species of Various Antifungals 1,10

Fluconazole Voriconazole Posaconazole Itraconazole Echinocandins Amphotericin Flucytosine
C. albicans S S S S S S S
C. parapsilosis S S S S S to R S S
C. tropicalis S S S S S S S
C. glabrata S-DD to R S-DD to R S-DD to R S-DD to R S S to I S
C. krusei R S S S-DD to R S S to I I to R
C. lusitaniae S S S S S S to R S
C. dubliniensis S S S S S S S
C. guilliermondii S S S S S to I S to I S
I= intermediately susceptible; R= resistant; S= susceptible; S-DD= susceptible dose-dependent
Monitoring 7-9
• Therapeutic drug monitoring for itraconazole and voriconazole is recommended with extended treatment courses
(e.g., ≥4 weeks) to ensure adequate absorption, monitor changes in dosages, monitor the addition of an interacting
agent, and assess adherence. Timing of drug sampling for these agents is ill-defined. This is further complicated
by nonlinear pharmacokinetics exhibited by itraconazole and voriconazole, making use of the half-life less
applicable in determining the time of drug sampling. Therefore, multiple samples are needed to ensure effective
and nontoxic concentrations are maintained.
o Itraconazole blood concentrations vary widely and are generally higher (~30%) with solution than capsule
formulation; however, wide inter-patient variability exists.
o Itraconazole can be measured by high-performance liquid chromatography (HPLC) or bioassay. The
results of bioassay are 2-10 times higher than those of HPLC because the bioassay measures both
itraconazole and its active metabolite, hydroxyitraconazole. Determination of total antifungal activity by
HPLC requires a separate assay for itraconazole and hydroxyitraconazole. The sum of itraconazole and its
metabolite should be used in assessing drug levels.
o Itraconazole levels should only be drawn after steady-state is achieved, which takes ~2 weeks due to its
long half-life. The long half-life results in serum concentrations which vary little and allows for blood
collection at any time in relation to drug administration.
o Voriconazole nonlinear pharmacokinetics and genetic differences in metabolism account for observable
intra-patient and inter-patient variability. Although the reported half-life of voriconazole is ~6 hours, this
varies greatly depending on dose administered. Therefore, the recommendation is to obtain levels after 7
days of therapy to ensure steady state is reached. Drug toxicity has been observed at higher concentrations
as well as reduced clinical response at lower concentrations.
o The upper limit desired therapeutic level for voriconazole is currently 6mg/L, however this is unknown
for itraconazole
• If flucytosine is used in infants, careful drug monitoring is recommended as clearance is directly proportional to
the glomerular filtration rate (GFR). Very low birth weight infants may accumulate high plasma concentrations
due to immaturity.
• Turnaround time for HPLC and liquid chromatography-mass spectrometry (LC-MS) is up to 1 week.

Table 2: Summary of desired reference ranges for antifungal monitoring7-9

Drug Lab assay Desired trough levels When to obtain levels
Prophylaxis (mg/L) Treatment (mg/L)
Itraconazole Bioassay >0.5 >1-2 1-2 weeks
Voriconazole HPLC and LC-MS 0.5-6 1-6 1 week
Flucytosine N/A Peak (2hrs post dose): ≥2 weeks
50-100mg/L
Trough: 25-50mg/L
LC-MS: Liquid chromatography-mass spectrometry; HPLC : High-performance liquid chromatography

Length of therapy1
Without obvious metastatic complications, duration of antifungal therapy for IC is 2 weeks (3 weeks for neonates) after
documented clearance of Candida species from the bloodstream and resolution of symptoms.
Table 3: Treatment Guidelines; All dosages are based on normal renal/hepatic function.1,10
Proven/Suspected Candidiasis Treatment
Preferred General Initial Therapy Alternative Therapy Definitive Therapy/Notes
CANDIDEMIA
• Fluconazole for less critically ill & without • Amphotericin B deoxycholate for intolerance or • Infectious Disease (ID) consult recommended.
recent (≤3 months) azole exposure. limited availability of preferred antifungals. • C. glabrata: micafungin preferred.
• Micafungin for patients with moderately severe AmBisome® may be used if needed due to o Transition to fluconazole or voriconazole not
to severe illness or with recent azole exposure. toxicities associated with amphotericin B recommended without confirmation of isolate
Treatment
Candidemia • Transition from micafungin to fluconazole for deoxycholate. susceptibility.
Nonneutropenic isolates likely susceptible (C. albicans) if patient • Voriconazole effective for candidemia but offers o If initially received fluconazole or voriconazole with
clinically stable. little advantage over fluconazole. clinical improvement and negative follow-up
Patient
• Catheter removal strongly recommended Recommended as step-down therapy for selected cultures, continuation of azole to therapy completion
cases of candidiasis due to susceptible C. krusei is reasonable.
or C. glabrata. Generally reserved for • Candida parapsilosis: fluconazole preferred.
aspergillosis. o If initially received micafungin with clinical
• Micafungin recommended for most. • Fluconazole reasonable for less critically ill improvement and negative follow-up cultures,
• Catheter removal strongly recommended. without recent azole exposure. continuation is reasonable.
• Voriconazole if additional mold coverage • C. krusei: micafungin, Abelcet®, or voriconazole
needed. preferred.
• C. lusitaniae: fluconazole or micafungin preferred over
Treatment amphotericin
Candidemia • Document fungus clearance from bloodstream
Neutropenic Patient • Treat for 2 weeks AFTER documented clearance
from bloodstream and resolution of symptoms
• Ophthalmology evaluation/fundoscopic examination
for all patients
• Consider trans-esophageal echocardiogram if blood
cultures are persistently positive.
CANDIDIASIS
• Similar to proven candidemia. Avoid azoles if • Amphotericin B deoxycholate for intolerance or • Infectious Disease (ID) consult recommended.
Empiric Treatment recent exposure. limited availability of preferred antifungals.
Suspected Invasive • Consider for the critically ill with risk factors for AmBisome® may be used if needed due to
Candidiasis in IC and no other known cause of fever based on toxicities associated with amphotericin B
Nonneutropenic clinical assessment, serologic markers for IC, deoxycholate.
and/or culture data from nonsterile sites.
• Micafungin • Fluconazole: Do not use if recent azole • Infectious Disease (ID) consult recommended.
Empiric Treatment
• Abelcet® exposure.
Suspected Invasive
• Voriconazole • Itraconazole: Do not use if recent azole
Candidiasis in
exposure.
Neutropenic
• Amphotericin B deoxycholate effective but
carries higher risk of toxicity.
• Amphotericin B deoxycholate (1mg/kg daily) • AmBisome® if urinary tract involvement • Infectious Disease (ID) consult recommended.
Neonatal
• Fluconazole (12mg/kg daily) excluded. • Lumbar puncture and ophthalmology evaluation
Disseminated
• Treat for 3 weeks. • Micafungin should be used with caution and recommended with sterile body fluid and/or urine
Candidiasis
Treatment • IV catheter removal strongly recommended. limited to situations in which resistance or cultures positive for Candida species.
toxicity precludes use of other agents. • Imaging of genitourinary tract, liver and spleen should be
 performed if results of sterile body fluid cultures are
persistently positive.

• Stable patients: Fluconazole • Micafungin then step down to fluconazole • Infectious Disease (ID) consult recommended.
• Severely ill: Amphotericin B deoxycholate 0.5- • Transition from amphotericin or micafungin to
0.7mg/kg daily or AmBisome®, then switch to fluconazole is preferred after several weeks of treatment.
Chronic
fluconazole once stable • Duration of treatment: until lesions resolved (usually
disseminated
months)
• Treatment should be continued through periods of
immunosuppression (chemotherapy or transplant).
• AmBisome® ± flucytosine for several weeks, • Fluconazole (if patient cannot tolerate • Infectious Disease (ID) consult recommended.
then fluconazole daily AmBisome®) • Treat until signs and symptoms, CSF abnormalities, and
CNS
radiologic abnormalities have resolved.
• Remove intraventricular devices if possible.
• AmBisome® ± flucytosine • Stable patients with susceptible organisms and • Infectious Disease (ID) consult recommended.
• Amphotericin B deoxycholate 0.6-1mg/kg daily negative blood culture: step down to fluconazole • Valve replacement, including prosthetic valves, strongly
Endocarditis ± flucytosine recommended.
• Micafungin • If valvular replacement not feasible, chronic suppression
with fluconazole is recommended.
• AmBisome® • If AmBisome® or micafungin used: step down • Infectious Disease (ID) consult recommended.
• Fluconazole to fluconazole once stable • Several months of therapy is usually warranted for
Pericarditis, • Micafungin pericarditis or myocarditis. Pericardial window or
pericardiectomy recommended.
myocarditis,
• At least 2 weeks of treatment after 1st negative blood
suppurative
thrombophlebitis culture is recommended for suppurative
thrombophlebitis. Adjunctive surgical incision and
drainage or vein resection is recommended for
thrombophlebitis.
• Fluconazole • Micafungin • Infectious Disease (ID) consult recommended.
• AmBisome® for several weeks, then fluconazole • Amphotericin B deoxycholate • Transition from amphotericin or micafungin to
Osteomyelitis fluconazole is preferred after several weeks of treatment.
• Duration: 6-12 months
• Surgical debridement often necessary.
• Fluconazole • Micafungin • Infectious Disease (ID) consult recommended.
• AmBisome® for several weeks, then fluconazole • Amphotericin B deoxycholate • Transition from amphotericin or micafungin to
fluconazole is preferred after several weeks of treatment.
Septic arthritis
• Duration: 6 weeks
• Surgical debridement for all cases and removal of
infected prosthesis is recommended in most cases.
• Amphotericin B deoxycholate 0.7-1mg/kg + • AmBisome® • Infectious Disease (ID) consult recommended.
flucytosine • Voriconazole • Surgical intervention is desired for patients with severe
• Fluconazole • Micafungin disease or vitreitis.
Endopthalmitis • Duration: at least 4-6 weeks with resolution of infection
based on serial ocular exams.
• Diagnostic vitreal aspiration required if etiology
unknown.
 • Rarely indicates invasive candidiasis and should • Candida pneumonia and lung abscess are very
Candida from not be treated. uncommon, however colonization of bronchial tree is
respiratory common in patients on ventilator.
secretions • Diagnosis of Candida pneumonia requires
histopathological confirmation.
• Treatment is generally not indicated with few • Remove urinary catheter if present.
exceptions noted below. • Treat only high risk patients: neutropenic patients, infants
• Neutropenic and neonates: manage as per with low birth weight, and patients who will undergo
Candiduria:
invasive candidiasis outlined above urologic manipulations.
asymptomatic
• Urologic procedures: fluconazole 200- 400 mg • Urologic procedures: Amphotericin B • If persistent or recurrent, image kidneys and collecting
(3–6 mg/kg) daily for several days before and deoxycholate 0.3–0.6 mg/kg daily for several system to exclude abscess, fungus ball, or urologic
after procedure days before and after the procedure abnormality.
• Complicated by disseminated candidiasis: treat • Cystitis: • Remove urinary catheter if present.
as described for candidemia. o Fluconazole resistant: Amphotericin B • Amphotericin B deoxycholate bladder irrigation,
• Cystitis: deoxycholate IV 0.3–0.6 mg/kg IV daily for although not recommended, may be useful for
o Fluconazole susceptible: Fluconazole 200 1–7 days OR flucytosine for 7–10 days fluconazole-resistant C. glabrata or C. krusei.
mg (3 mg/kg) PO daily for 2 weeks • Pyelonephritis: • Fluconazole is mainstay. No other currently available
• Pyelonephritis: o Fluconazole-resistant: Amphotericin B azole is useful, because of minimal excretion of active
Candiduria: o Fluconazole-susceptible: fluconazole PO deoxycholate IV 0.5–0.7 mg/kg daily ± drug into urine.
symptomatic 200–400 mg (3–6 mg/kg) daily for 2 weeks flucytosine OR flucytosine for 2 weeks. • Echinocandins are not useful because of minimal
• Fungus balls • Fungus ball: excretion into urine.
o Surgical intervention strongly recommended o Amphotericin B deoxycholate IV 0.5–0.7 • Alternatives are oral flucytosine, systemic amphotericin
in non-neonates. mg/kg daily ± flucytosine B deoxycholate, and bladder irrigation with amphotericin
o Fluconazole 200–400 mg (3–6 mg/kg) daily o Adjunct to systemic therapy: amphotericin B B deoxycholate.
o Treat until symptoms resolved and urine deoxycholate 50 mg/L of sterile water • Avoid lipid amphotericin B formulations.
cultures no longer yield Candida species. irrigation.
• Micafungin (preferred if critically ill) • Amphotericin B deoxycholate ± flucytosine • Infectious Disease (ID) consult recommended.
• Fluconazole • Use of antifungals for empiric therapy of peritonitis
usually not warranted. Consider in the setting of
recurrent peritonitis following recent antibiotic treatment
for bacterial peritonitis.
Peritonitis11-13
• Peritoneal dialysis catheter removal with temporary
hemodialysis is strongly recommended.
• If C. parapsilosis is isolated, fluconazole preferred.
• If C. glabrata is isolated, micafungin is preferred until
fluconazole susceptibility can be confirmed.

ADULT DOSING (unless otherwise specified above) All doses are for normal renal/hepatic function.

• Micafungin: 100mg IV q24hr

• Fluconazole: loading dose 12mg/kg [800mg], then 6mg/kg [400mg] IV/PO daily • Amphotericin B deoxycholate (conventional): 0.5-1 mg/kg IV daily
• Itraconazole 200mg [3mg/kg] PO q12hr—acidic environment enhances absorption of capsule • Liposomal amphotericin B (AmBisome®): 3mg/kg IV daily (doses up
• Voriconazole: 6mg/kg [400mg] q12hr x 2 doses, then 3mg/kg [200mg] q12hr thereafter IV/PO to 5mg/kg/day are allowed only for NICU patients)
• Flucytosine: 25 mg/kg PO QID
 References:
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Infect Dis. 2009;48:503-35.
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risk factors and outcome. Anesth Analg. 2008;106(2):523-9,
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2001;47:308–313.
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6. Courtney R, Sansone A, Smith W, et al. Posaconazole pharmacokinetics, safety, and tolerability in subjects with varying degrees of chronic renal disease. J Clin Pharmacol.
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outcomes. Clin Infect Dis. 2008;46:201-11.
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10. The Sanford Guide to Antimicrobial Therapy, 2009.
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Compiled by:
Elizabeth D. Hermsen, Pharm.D., M.B.A., BCPS-ID, Jessica Njoku, Pharm.D., BCPS, and Rachel Pfeifer, Pharm.D.

Reviewed by:
Antimicrobial Subcommittee – January 2010