Clinical Practice Guideline For The Management of

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Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by

the Infectious Diseases Society of America
Article in Clinical Infectious Diseases · December 2015

DOI: 10.1093/cid/civ933
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Clinical
Clinical Infectious Infectious Diseases Advance Access published December 16, 2015
Diseases
IDSA GUIDELINE
Clinical Practice Guideline for the Management of

Candidiasis: 2016 Update by the Infectious Diseases
Society of America
Peter G. Pappas,1 Carol A. Kauffman,2 David R. Andes,3 Cornelius J. Clancy,4 Kieren A. Marr,5 Luis Ostrosky-Zeichner,6 Annette C. Reboli,7 Mindy G. Schuster,8
Jose A. Vazquez,9 Thomas J. Walsh,10 Theoklis E. Zaoutis,11 and Jack D. Sobel12
1
University of Alabama at Birmingham; 2Veterans Affairs Ann Arbor Healthcare System and University of Michigan Medical School, Ann Arbor; 3University of Wisconsin, Madison; 4University of
Pittsburgh, Pennsylvania; 5Johns Hopkins University School of Medicine, Baltimore, Maryland; 6University of Texas Health Science Center, Houston; 7Cooper Medical School of Rowan University,
Camden, New Jersey; 8University of Pennsylvania, Philadelphia; 9Georgia Regents University, Augusta; 10Weill Cornell Medical Center and Cornell University, New York, New York; 11Children’s
Hospital of Pennsylvania, Philadelphia; and 12Harper University Hospital and Wayne State University, Detroit, Michigan
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to
supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these
guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light
of each patient’s individual circumstances.
Keywords. candidemia; invasive candidiasis; fungal diagnostics; azoles; echinocandins.
Downloaded from http://cid.oxfordjournals.org/ by guest on January 15, 2016

EXECUTIVE SUMMARY endorsed by the American Academy of Pediatrics (AAP) and
Background the Pediatric Infectious Diseases Society (PIDS). The Mycoses
Invasive infection due to Candida species is largely a condition Study Group (MSG) has also endorsed these guidelines. The
associated with medical progress, and is widely recognized as a panel followed a guideline development process that has been
major cause of morbidity and mortality in the healthcare envi- adopted by the Infectious Diseases Society of America
ronment. There are at least 15 distinct Candida species that cause (IDSA), which includes a systematic method of grading both
human disease, but >90% of invasive disease is caused by the the quality of evidence (very low, low, moderate, and high)
5 most common pathogens, C. albicans, C. glabrata, C. tropicalis, and the strength of the recommendation (weak or strong) [2]
C. parapsilosis, and C. krusei. Each of these organisms has uni- (Figure 1). [3] The guidelines are not intended to replace clin-
que virulence potential, antifungal susceptibility, and epidemi- ical judgment in the management of individual patients. A de-
ology, but taken as a whole, significant infections due to these tailed description of the methods, background, and evidence
organisms are generally referred to as invasive candidiasis. summaries that support each recommendation can be found
Mucosal Candida infections—especially those involving the in the full text of the guideline.
oropharynx, esophagus, and vagina—are not considered to I. What Is the Treatment for Candidemia in Nonneutropenic Patients?
be classically invasive disease, but they are included in these Recommendations
guidelines. Since the last iteration of these guidelines in 2009 1. An echinocandin (caspofungin: loading dose 70 mg, then
[1], there have been new data pertaining to diagnosis, pre- 50 mg daily; micafungin: 100 mg daily; anidulafungin: load-
vention, and treatment for proven or suspected invasive candi- ing dose 200 mg, then 100 mg daily) is recommended as ini-
diasis, leading to significant modifications in our treatment tial therapy (strong recommendation; high-quality evidence).
recommendations. 2. Fluconazole, intravenous or oral, 800-mg (12 mg/kg) load-
Summarized below are the 2016 revised recommendations ing dose, then 400 mg (6 mg/kg) daily is an acceptable alter-
for the management of candidiasis. Due to the guideline’s rele- native to an echinocandin as initial therapy in selected
vance to pediatrics, the guideline has been reviewed and patients, including those who are not critically ill and who
are considered unlikely to have a fluconazole-resistant Can-
dida species (strong recommendation; high-quality evidence).
Received 28 October 2015; accepted 2 November 2015. 3. Testing for azole susceptibility is recommended for all blood-
Correspondence: P. G. Pappas, University of Alabama at Birmingham, Division of Infectious
Disease, 229 Tinsley Harrison Tower, 1900 University Blvd, Birmingham, AL 35294-0006
stream and other clinically relevant Candida isolates. Testing
( pappas@uab.edu). for echinocandin susceptibility should be considered in pa-
Clinical Infectious Diseases® tients who have had prior treatment with an echinocandin
© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of
America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
and among those who have infection with C. glabrata or
DOI: 10.1093/cid/civ933 C. parapsilosis (strong recommendation; low-quality evidence).
Clinical Practice Guideline for the Management of Candidiasis • CID • 1

Figure 1. Approach and implications to rating the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development
and Evaluation (GRADE) methodology (unrestricted use of the figure granted by the US GRADE Network) [3].
4. Transition from an echinocandin to fluconazole (usually repeat cultures on antifungal therapy are negative (strong rec-
within 5–7 days) is recommended for patients who are clin- ommendation; high-quality evidence).
ically stable, have isolates that are susceptible to fluconazole 8. Among patients with suspected azole- and echinocandin-
(eg, C. albicans), and have negative repeat blood cultures fol- resistant Candida infections, lipid formulation AmB (3–5
lowing initiation of antifungal therapy (strong recommenda- mg/kg daily) is recommended (strong recommendation;
tion; moderate-quality evidence). low-quality evidence).
5. For infection due to C. glabrata, transition to higher-dose 9. Voriconazole 400 mg (6 mg/kg) twice daily for 2 doses, then
fluconazole 800 mg (12 mg/kg) daily or voriconazole 200– 200 mg (3 mg/kg) twice daily is effective for candidemia, but
300 (3–4 mg/kg) twice daily should only be considered offers little advantage over fluconazole as initial therapy
among patients with fluconazole-susceptible or voricona- (strong recommendation; moderate-quality evidence). Vorico-
zole-susceptible isolates (strong recommendation; low-quality nazole is recommended as step-down oral therapy for selected
evidence). cases of candidemia due to C. krusei (strong recommendation;
6. Lipid formulation amphotericin B (AmB) (3–5 mg/kg daily) low-quality evidence).
is a reasonable alternative if there is intolerance, limited 10. All nonneutropenic patients with candidemia should have
availability, or resistance to other antifungal agents (strong a dilated ophthalmological examination, preferably per-
recommendation; high-quality evidence). formed by an ophthalmologist, within the first week after
7. Transition from AmB to fluconazole is recommended after diagnosis (strong recommendation; low-quality evidence).
5–7 days among patients who have isolates that are suscepti- 11. Follow-up blood cultures should be performed every day
ble to fluconazole, who are clinically stable, and in whom or every other day to establish the time point at which
2 • CID • Pappas et al
candidemia has been cleared (strong recommendation; low- 21. Ophthalmological findings of choroidal and vitreal infec-
quality evidence). tion are minimal until recovery from neutropenia; therefore,
12. Recommended duration of therapy for candidemia without dilated funduscopic examinations should be performed with-
obvious metastatic complications is for 2 weeks after docu- in the first week after recovery from neutropenia (strong rec-
mented clearance of Candida species from the bloodstream ommendation; low-quality evidence).
and resolution of symptoms attributable to candidemia 22. In the neutropenic patient, sources of candidiasis other
(strong recommendation; moderate-quality evidence). than a CVC (eg, gastrointestinal tract) predominate. Catheter
removal should be considered on an individual basis (strong
II. Should Central Venous Catheters Be Removed in Nonneutropenic recommendation; low-quality evidence).
Patients With Candidemia? 23. Granulocyte colony-stimulating factor (G-CSF)–mobilized
Recommendation granulocyte transfusions can be considered in cases of persis-
13. Central venous catheters (CVCs) should be removed as tent candidemia with anticipated protracted neutropenia
early as possible in the course of candidemia when the source (weak recommendation; low-quality evidence).
is presumed to be the CVC and the catheter can be removed
safely; this decision should be individualized for each patient IV. What Is the Treatment for Chronic Disseminated (Hepatosplenic)
(strong recommendation; moderate-quality evidence). Candidiasis?
Recommendations
III. What Is the Treatment for Candidemia in Neutropenic Patients? 24. Initial therapy with lipid formulation AmB, 3–5 mg/kg daily

Recommendations OR an echinocandin (micafungin: 100 mg daily; caspofungin:
14. An echinocandin (caspofungin: loading dose 70 mg, then 70-mg loading dose, then 50 mg daily; or anidulafungin: 200-
50 mg daily; micafungin: 100 mg daily; anidulafungin: loading mg loading dose, then 100 mg daily), for several weeks is rec-
dose 200 mg, then 100 mg daily) is recommended as initial ommended, followed by oral fluconazole, 400 mg (6 mg/kg)
therapy (strong recommendation; moderate-quality evidence). daily, for patients who are unlikely to have a fluconazole-
15. Lipid formulation AmB, 3–5 mg/kg daily, is an effective resistant isolate (strong recommendation; low-quality evidence).
but less attractive alternative because of the potential for 25. Therapy should continue until lesions resolve on repeat
toxicity (strong recommendation; moderate-quality evidence). imaging, which is usually several months. Premature discon-
16. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 tinuation of antifungal therapy can lead to relapse (strong
mg (6 mg/kg) daily, is an alternative for patients who are recommendation; low-quality evidence).
not critically ill and have had no prior azole exposure 26. If chemotherapy or hematopoietic cell transplantation is
(weak recommendation; low-quality evidence). required, it should not be delayed because of the presence of
17. Fluconazole, 400 mg (6 mg/kg) daily, can be used for step- chronic disseminated candidiasis, and antifungal therapy
down therapy during persistent neutropenia in clinically sta- should be continued throughout the period of high risk to pre-
ble patients who have susceptible isolates and documented vent relapse (strong recommendation; low-quality evidence).
bloodstream clearance (weak recommendation; low-quality 27. For patients who have debilitating persistent fevers,
evidence). short-term (1–2 weeks) treatment with nonsteroidal anti-
18. Voriconazole, 400 mg (6 mg/kg) twice daily for 2 doses, inflammatory drugs or corticosteroids can be considered
then 200–300 mg (3–4 mg/kg) twice daily, can be used in sit- (weak recommendation; low-quality evidence).
uations in which additional mold coverage is desired (weak
recommendation; low-quality evidence). Voriconazole can V. What Is the Role of Empiric Treatment for Suspected Invasive
also be used as step-down therapy during neutropenia in Candidiasis in Nonneutropenic Patients in the Intensive Care Unit?
clinically stable patients who have had documented blood- Recommendations
stream clearance and isolates that are susceptible to voricona- 28. Empiric antifungal therapy should be considered in critically
zole (weak recommendation; low-quality evidence). ill patients with risk factors for invasive candidiasis and no
19. For infections due to C. krusei, an echinocandin, lipid other known cause of fever and should be based on clinical
formulation AmB, or voriconazole is recommended (strong assessment of risk factors, surrogate markers for invasive can-
recommendation; low-quality evidence). didiasis, and/or culture data from nonsterile sites (strong rec-
20. Recommended minimum duration of therapy for can- ommendation; moderate-quality evidence). Empiric antifungal
didemia without metastatic complications is 2 weeks after therapy should be started as soon as possible in patients who
documented clearance of Candida from the bloodstream, have the above risk factors and who have clinical signs of sep-
provided neutropenia and symptoms attributable to candide- tic shock (strong recommendation; moderate-quality evidence).
mia have resolved (strong recommendation; low-quality 29. Preferred empiric therapy for suspected candidiasis in
evidence). nonneutropenic patients in the intensive care unit (ICU) is

an echinocandin (caspofungin: loading dose of 70 mg, then 39. Lipid formulation AmB, 3–5 mg/kg daily, is an alternative,
50 mg daily; micafungin: 100 mg daily; anidulafungin: load- but should be used with caution, particularly in the presence
ing dose of 200 mg, then 100 mg daily) (strong recommenda- of urinary tract involvement (weak recommendation; low-
tion; moderate-quality evidence). quality evidence).
30. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 40. Echinocandins should be used with caution and generally
mg (6 mg/kg) daily, is an acceptable alternative for patients limited to salvage therapy or to situations in which resistance
who have had no recent azole exposure and are not colonized or toxicity preclude the use of AmB deoxycholate or flucon-
with azole-resistant Candida species (strong recommenda- azole (weak recommendation; low-quality evidence).
tion; moderate-quality evidence). 41. A lumbar puncture and a dilated retinal examination are
31. Lipid formulation AmB, 3–5 mg/kg daily, is an alternative recommended in neonates with cultures positive for Candida
if there is intolerance to other antifungal agents (strong rec- species from blood and/or urine (strong recommendation;
ommendation; low-quality evidence). low-quality evidence).
32. Recommended duration of empiric therapy for suspected 42. Computed tomographic or ultrasound imaging of the gen-
invasive candidiasis in those patients who improve is 2 itourinary tract, liver, and spleen should be performed
weeks, the same as for treatment of documented candidemia if blood cultures are persistently positive for Candida species
(weak recommendation; low-quality evidence). (strong recommendation; low-quality evidence).
33. For patients who have no clinical response to empiric an- 43. CVC removal is strongly recommended (strong recommen-
tifungal therapy at 4–5 days and who do not have subsequent dation; moderate-quality evidence).

evidence of invasive candidiasis after the start of empiric 44. The recommended duration of therapy for candidemia
therapy or have a negative non-culture-based diagnostic without obvious metastatic complications is for 2 weeks
assay with a high negative predictive value, consideration after documented clearance of Candida species from the
should be given to stopping antifungal therapy (strong rec- bloodstream and resolution of signs attributable to candide-
ommendation; low-quality evidence). mia (strong recommendation; low-quality evidence).
What Is the Treatment for Central Nervous System Infections in
VI. Should Prophylaxis Be Used to Prevent Invasive Candidiasis in the
Neonates?
Intensive Care Unit Setting?
Recommendations Recommendations
34. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 45. For initial treatment, AmB deoxycholate, 1 mg/kg intrave-
mg (6 mg/kg) daily, could be used in high-risk patients in nous daily, is recommended (strong recommendation; low-
adult ICUs with a high rate (>5%) of invasive candidiasis quality evidence).
(weak recommendation; moderate-quality evidence). 46. An alternative regimen is liposomal AmB, 5 mg/kg daily
35. An alternative is to give an echinocandin (caspofungin: (strong recommendation; low-quality evidence).
70-mg loading dose, then 50 mg daily; anidulafungin: 47. The addition of flucytosine, 25 mg/kg 4 times daily, may be
200-mg loading dose and then 100 mg daily; or micafun- considered as salvage therapy in patients who have not had a
gin: 100 mg daily) (weak recommendation; low-quality clinical response to initial AmB therapy, but adverse effects
evidence). are frequent (weak recommendation; low-quality evidence).
36. Daily bathing of ICU patients with chlorhexidine, which 48. For step-down treatment after the patient has responded to
has been shown to decrease the incidence of bloodstream in- initial treatment, fluconazole, 12 mg/kg daily, is recommend-
fections including candidemia, could be considered (weak ed for isolates that are susceptible to fluconazole (strong rec-
recommendation; moderate-quality evidence). ommendation; low-quality evidence).
49. Therapy should continue until all signs, symptoms, and cere-
VII. What Is the Treatment for Neonatal Candidiasis, Including Central brospinal fluid (CSF) and radiological abnormalities, if present,
Nervous System Infection? have resolved (strong recommendation; low-quality evidence).
What Is the Treatment for Invasive Candidiasis and Candidemia?
50. Infected central nervous system (CNS) devices, including
Recommendations ventriculostomy drains and shunts, should be removed if at
37. AmB deoxycholate, 1 mg/kg daily, is recommended for all possible (strong recommendation; low-quality evidence).
neonates with disseminated candidiasis (strong recommenda-
What Are the Recommendations for Prophylaxis in the Neonatal
tion; moderate-quality evidence).
Intensive Care Unit Setting?
38. Fluconazole, 12 mg/kg intravenous or oral daily, is a rea-
sonable alternative in patients who have not been on flucon- Recommendations
azole prophylaxis (strong recommendation; moderate-quality 51. In nurseries with high rates (>10%) of invasive candidiasis,
evidence). intravenous or oral fluconazole prophylaxis, 3–6 mg/kg twice
weekly for 6 weeks, in neonates with birth weights <1000 g is 61. Oral voriconazole, 200–300 mg (3–4 mg/kg) twice daily, or
recommended (strong recommendation; high-quality evidence). posaconazole tablets, 300 mg daily, can be used as step-down
52. Oral nystatin, 100 000 units 3 times daily for 6 weeks, is an therapy for isolates that are susceptible to those agents but
alternative to fluconazole in neonates with birth weights not susceptible to fluconazole (weak recommendation; very
<1500 g in situations in which availability or resistance low-quality evidence).
preclude the use of fluconazole (weak recommendation; 62. Valve replacement is recommended; treatment should con-
moderate-quality evidence). tinue for at least 6 weeks after surgery and for a longer duration
53. Oral bovine lactoferrin (100 mg/day) may be effective in in patients with perivalvular abscesses and other complications
neonates <1500 g but is not currently available in US hospi- (strong recommendation; low-quality evidence).
tals (weak recommendation; moderate-quality evidence). 63. For patients who cannot undergo valve replacement, long-
term suppression with fluconazole, 400–800 mg (6–12 mg/
VIII. What Is the Treatment for Intra-abdominal Candidiasis? kg) daily, if the isolate is susceptible, is recommended (strong
Recommendations recommendation; low-quality evidence).
54. Empiric antifungal therapy should be considered for pa- 64. For prosthetic valve endocarditis, the same antifungal reg-
tients with clinical evidence of intra-abdominal infection imens suggested for native valve endocarditis are recom-
and significant risk factors for candidiasis, including recent mended (strong recommendation; low-quality evidence).
abdominal surgery, anastomotic leaks, or necrotizing pancre- Chronic suppressive antifungal therapy with fluconazole,
atitis (strong recommendation; moderate-quality evidence). 400–800 mg (6–12 mg/kg) daily, is recommended to pre-

55. Treatment of intra-abdominal candidiasis should include vent recurrence (strong recommendation; low-quality
source control, with appropriate drainage and/or debride- evidence).
ment (strong recommendation; moderate-quality evidence).
What Is the Treatment for Candida Infection of Implantable
56. The choice of antifungal therapy is the same as for the
Cardiac Devices?
treatment of candidemia or empiric therapy for nonneutro-
penic patients in the ICU (See sections I and V) (strong rec- Recommendations
ommendation; moderate-quality evidence). 65. For pacemaker and implantable cardiac defibrillator infec-
57. The duration of therapy should be determined by adequacy tions, the entire device should be removed (strong recommen-
of source control and clinical response (strong recommenda- dation; moderate-quality evidence).
tion; low-quality evidence). 66. Antifungal therapy is the same as that recommended for
native valve endocarditis (strong recommendation; low-
IX. Does the Isolation of Candida Species From the Respiratory Tract quality evidence).
Require Antifungal Therapy? 67. For infections limited to generator pockets, 4 weeks of an-
Recommendation tifungal therapy after removal of the device is recommended
58. Growth of Candida from respiratory secretions usually indi- (strong recommendation; low-quality evidence).
cates colonization and rarely requires treatment with antifungal 68. For infections involving the wires, at least 6 weeks of anti-
therapy (strong recommendation; moderate-quality evidence). fungal therapy after wire removal is recommended (strong
recommendation; low-quality evidence).
X. What Is the Treatment for Candida Intravascular Infections, Including 69. For ventricular assist devices that cannot be removed, the an-
Endocarditis and Infections of Implantable Cardiac Devices? tifungal regimen is the same as that recommended for native
What Is the Treatment for Candida Endocarditis? valve endocarditis (strong recommendation; low-quality evi-
dence). Chronic suppressive therapy with fluconazole if the iso-
Recommendations late is susceptible, for as long as the device remains in place is
59. For native valve endocarditis, lipid formulation AmB, 3–5 recommended (strong recommendation; low-quality evidence).
mg/kg daily, with or without flucytosine, 25 mg/kg 4 times
What Is the Treatment for Candida Suppurative Thrombophlebitis?
daily, OR high-dose echinocandin (caspofungin 150 mg
daily, micafungin 150 mg daily, or anidulafungin 200 mg Recommendations
daily) is recommended for initial therapy (strong recommen- 70. Catheter removal and incision and drainage or resection of
dation; low-quality evidence). the vein, if feasible, is recommended (strong recommenda-
60. Step-down therapy to fluconazole, 400–800 mg (6–12 mg/ tion; low-quality evidence).
kg) daily, is recommended for patients who have susceptible 71. Lipid formulation AmB, 3–5 mg/kg daily, OR fluconazole,
Candida isolates, have demonstrated clinical stability, and 400–800 mg (6–12 mg/kg) daily, OR an echinocandin (cas-
have cleared Candida from the bloodstream (strong recom- pofungin 150 mg daily, micafungin 150 mg daily, or anidu-
mendation; low-quality evidence). lafungin 200 mg daily) for at least 2 weeks after candidemia

(if present) has cleared is recommended (strong recommen- within the first week of therapy in nonneutropenic patients
dation; low-quality evidence). to establish if endophthalmitis is present (strong recommen-
72. Step-down therapy to fluconazole, 400–800 mg (6–12 mg/ dation; low-quality evidence). For neutropenic patients, it is
kg) daily, should be considered for patients who have initially recommended to delay the examination until neutrophil re-
responded to AmB or an echinocandin, are clinically stable, covery (strong recommendation; low-quality evidence).
and have a fluconazole-susceptible isolate (strong recommen- 83. The extent of ocular infection (chorioretinitis with or with-
dation; low-quality evidence). out macular involvement and with or without vitritis) should
73. Resolution of the thrombus can be used as evidence to dis- be determined by an ophthalmologist (strong recommenda-
continue antifungal therapy if clinical and culture data are tion; low-quality evidence).
supportive (strong recommendation; low-quality evidence). 84. Decisions regarding antifungal treatment and surgical in-
tervention should be made jointly by an ophthalmologist and
XI. What Is the Treatment for Candida Osteoarticular Infections? an infectious diseases physician (strong recommendation;
What Is the Treatment for Candida Osteomyelitis? low-quality evidence).
Recommendations What Is the Treatment for Candida Chorioretinitis Without
74. Fluconazole, 400 mg (6 mg/kg) daily, for 6–12 months OR Vitritis?
an echinocandin (caspofungin 50–70 mg daily, micafungin
Recommendations
100 mg daily, or anidulafungin 100 mg daily) for at least 2
weeks followed by fluconazole, 400 mg (6 mg/kg) daily, for 85. For fluconazole-/voriconazole-susceptible isolates, flu-

6–12 months is recommended (strong recommendation; conazole, loading dose, 800 mg (12 mg/kg), then 400–800
low-quality evidence). mg (6–12 mg/kg) daily OR voriconazole, loading dose 400
75. Lipid formulation AmB, 3–5 mg/kg daily, for at least 2 mg (6 mg/kg) intravenous twice daily for 2 doses, then
weeks followed by fluconazole, 400 mg (6 mg/kg) daily, for 300 mg (4 mg/kg) intravenous or oral twice daily is recom-
6–12 months is a less attractive alternative (weak recommen- mended (strong recommendation; low-quality evidence).
dation; low-quality evidence). 86. For fluconazole-/voriconazole-resistant isolates, liposomal
76. Surgical debridement is recommended in selected cases AmB, 3–5 mg/kg intravenous daily, with or without oral flu-
(strong recommendation; low-quality evidence). cytosine, 25 mg/kg 4 times daily is recommended (strong rec-
ommendation; low-quality evidence).
What Is the Treatment for Candida Septic Arthritis? 87. With macular involvement, antifungal agents as noted
77. Fluconazole, 400 mg (6 mg/kg) daily, for 6 weeks OR an above PLUS intravitreal injection of either AmB deoxycho-
echinocandin (caspofungin 50–70 mg daily, micafungin 100 late, 5–10 µg/0.1 mL sterile water, or voriconazole, 100 µg/
mg daily, or anidulafungin 100 mg daily) for 2 weeks followed 0.1 mL sterile water or normal saline, to ensure a prompt
by fluconazole, 400 mg (6 mg/kg) daily, for at least 4 weeks is high level of antifungal activity is recommended (strong rec-
recommended (strong recommendation; low-quality evidence). ommendation; low-quality evidence).
78. Lipid formulation AmB, 3–5 mg/kg daily, for 2 weeks, fol- 88. The duration of treatment should be at least 4–6 weeks,
lowed by fluconazole, 400 mg (6 mg/kg) daily, for at least 4 with the final duration depending on resolution of the lesions
weeks is a less attractive alternative (weak recommendation; as determined by repeated ophthalmological examinations
low-quality evidence). (strong recommendation; low-quality evidence).
79. Surgical drainage is indicated in all cases of septic arthritis What Is the Treatment for Candida Chorioretinitis With Vitritis?
(strong recommendation; moderate-quality evidence).
80. For septic arthritis involving a prosthetic device, device re- Recommendations
moval is recommended (strong recommendation; moderate- 89. Antifungal therapy as detailed above for chorioretinitis
quality evidence). without vitritis, PLUS intravitreal injection of either am-
81. If the prosthetic device cannot be removed, chronic sup- photericin B deoxycholate, 5–10 µg/0.1 mL sterile water, or
pression with fluconazole, 400 mg (6 mg/kg) daily, if the iso- voriconazole, 100 µg/0.1 mL sterile water or normal saline
late is susceptible, is recommended (strong recommendation; is recommended (strong recommendation; low-quality
low-quality evidence). evidence).
90. Vitrectomy should be considered to decrease the burden of
XII. What Is the Treatment for Candida Endophthalmitis?
organisms and to allow the removal of fungal abscesses that
What Is the General Approach to Candida Endophthalmitis?
are inaccessible to systemic antifungal agents (strong recom-
Recommendations mendation; low-quality evidence).
82. All patients with candidemia should have a dilated retinal 91. The duration of treatment should be at least 4–6 weeks,
examination, preferably performed by an ophthalmologist, with the final duration dependent on resolution of the lesions
as determined by repeated ophthalmological examinations kg 4 times daily for 7–10 days is recommended (strong rec-
(strong recommendation; low-quality evidence). ommendation; low-quality evidence).
103. For C. krusei, AmB deoxycholate, 0.3–0.6 mg/kg daily, for
XIII. What Is the Treatment for Central Nervous System Candidiasis? 1–7 days is recommended (strong recommendation; low-
Recommendations quality evidence).
92. For initial treatment, liposomal AmB, 5 mg/kg daily, with 104. Removal of an indwelling bladder catheter, if feasible, is
or without oral flucytosine, 25 mg/kg 4 times daily is recom- strongly recommended (strong recommendation; low-quality
mended (strong recommendation; low-quality evidence). evidence).
93. For step-down therapy after the patient has responded to ini- 105. AmB deoxycholate bladder irrigation, 50 mg/L sterile
tial treatment, fluconazole, 400–800 mg (6–12 mg/kg) daily, is water daily for 5 days, may be useful for treatment of cystitis
recommended (strong recommendation; low-quality evidence). due to fluconazole-resistant species, such as C. glabrata and
94. Therapy should continue until all signs and symptoms and C. krusei (weak recommendation; low-quality evidence).
CSF and radiological abnormalities have resolved (strong rec-
What Is the Treatment for Symptomatic Ascending Candida
Pyelonephritis?
95. Infected CNS devices, including ventriculostomy drains,
shunts, stimulators, prosthetic reconstructive devices, and bio- Recommendations
polymer wafers that deliver chemotherapy should be removed 106. For fluconazole-susceptible organisms, oral fluconazole,
if possible (strong recommendation; low-quality evidence). 200–400 mg (3–6 mg/kg) daily for 2 weeks is recommended

96. For patients in whom a ventricular device cannot be re- (strong recommendation; low-quality evidence).
moved, AmB deoxycholate could be administered through 107. For fluconazole-resistant C. glabrata, AmB deoxycholate,
the device into the ventricle at a dosage ranging from 0.01 0.3–0.6 mg/kg daily for 1–7 days with or without oral flucy-
mg to 0.5 mg in 2 mL 5% dextrose in water (weak recommen- tosine, 25 mg/kg 4 times daily, is recommended (strong rec-
dation; low-quality evidence). ommendation; low-quality evidence).
108. For fluconazole-resistant C. glabrata, monotherapy with
XIV. What Is the Treatment for Urinary Tract Infections Due to Candida oral flucytosine, 25 mg/kg 4 times daily for 2 weeks, could
Species? be considered (weak recommendation; low-quality evidence).
What Is the Treatment for Asymptomatic Candiduria? 109. For C. krusei, AmB deoxycholate, 0.3–0.6 mg/kg daily, for
Recommendations 1–7 days is recommended (strong recommendation; low-
97. Elimination of predisposing factors, such as indwelling quality evidence).
bladder catheters, is recommended whenever feasible (strong 110. Elimination of urinary tract obstruction is strongly rec-
recommendation; low-quality evidence). ommended (strong recommendation; low-quality evidence).
98. Treatment with antifungal agents is NOT recommended 111. For patients who have nephrostomy tubes or stents in
unless the patient belongs to a group at high risk for dissem- place, consider removal or replacement, if feasible (weak rec-
ination; high-risk patients include neutropenic patients, very ommendation; low-quality evidence).
low-birth-weight infants (<1500 g), and patients who will What Is the Treatment for Candida Urinary Tract Infection As-
undergo urologic manipulation (strong recommendation; sociated With Fungus Balls?
low-quality evidence).
99. Neutropenic patients and very low–birth-weight infants Recommendations
should be treated as recommended for candidemia (see sections 112. Surgical intervention is strongly recommended in adults
III and VII) (strong recommendation; low-quality evidence). (strong recommendation; low-quality evidence).
100. Patients undergoing urologic procedures should be treated 113. Antifungal treatment as noted above for cystitis or pyelo-
with oral fluconazole, 400 mg (6 mg/kg) daily, OR AmB deox- nephritis is recommended (strong recommendation; low-
ycholate, 0.3–0.6 mg/kg daily, for several days before and after quality evidence).
the procedure (strong recommendation; low-quality evidence). 114. Irrigation through nephrostomy tubes, if present, with
AmB deoxycholate, 25–50 mg in 200–500 mL sterile water,
What Is the Treatment for Symptomatic Candida Cystitis?
is recommended (strong recommendation; low-quality
Recommendations evidence).
101. For fluconazole-susceptible organisms, oral fluconazole,
200 mg (3 mg/kg) daily for 2 weeks is recommended (strong XV. What Is the Treatment for Vulvovaginal Candidiasis?
recommendation; moderate-quality evidence). Recommendations
102. For fluconazole-resistant C. glabrata, AmB deoxycholate, 115. For the treatment of uncomplicated Candida vulvovagini-
0.3–0.6 mg/kg daily for 1–7 days OR oral flucytosine, 25 mg/ tis, topical antifungal agents, with no one agent superior to

another, are recommended (strong recommendation; high- alternatives for refractory disease (weak recommendation;
quality evidence). moderate-quality evidence).
116. Alternatively, for the treatment of uncomplicated Can- 128. Chronic suppressive therapy is usually unnecessary. If re-
dida vulvovaginitis, a single 150-mg oral dose of fluconazole quired for patients who have recurrent infection, fluconazole,
is recommended (strong recommendation; high-quality 100 mg 3 times weekly, is recommended (strong recommen-
evidence). dation; high-quality evidence).
117. For severe acute Candida vulvovaginitis, fluconazole, 150 129. For HIV-infected patients, antiretroviral therapy is
mg, given every 72 hours for a total of 2 or 3 doses, is recom- strongly recommended to reduce the incidence of recurrent
mended (strong recommendation; high-quality evidence). infections (strong recommendation; high-quality evidence).
118. For C. glabrata vulvovaginitis that is unresponsive to oral 130. For denture-related candidiasis, disinfection of the den-
azoles, topical intravaginal boric acid, administered in a gel- ture, in addition to antifungal therapy is recommended
atin capsule, 600 mg daily, for 14 days is an alternative (strong recommendation; moderate-quality evidence).
(strong recommendation; low-quality evidence).
119. Another alternative agent for C. glabrata infection is nys- XVII. What Is the Treatment for Esophageal Candidiasis?
tatin intravaginal suppositories, 100 000 units daily for 14 Recommendations
days (strong recommendation; low-quality evidence). 131. Systemic antifungal therapy is always required. A diag-
120. A third option for C. glabrata infection is topical 17% flu- nostic trial of antifungal therapy is appropriate before
cytosine cream alone or in combination with 3% AmB cream performing an endoscopic examination (strong recommenda-

administered daily for 14 days (weak recommendation; low- tion; high-quality evidence).
quality evidence). 132. Oral fluconazole, 200–400 mg (3–6 mg/kg) daily, for 14–
121. For recurring vulvovaginal candidiasis, 10–14 days of 21 days is recommended (strong recommendation; high-qual-
induction therapy with a topical agent or oral fluconazole, ity evidence).
followed by fluconazole, 150 mg weekly for 6 months, is rec- 133. For patients who cannot tolerate oral therapy, intravenous
ommended (strong recommendation; high-quality evidence). fluconazole, 400 mg (6 mg/kg) daily, OR an echinocandin
(micafungin, 150 mg daily, caspofungin, 70-mg loading
XVI. What Is the Treatment for Oropharyngeal Candidiasis? dose, then 50 mg daily, or anidulafungin, 200 mg daily) is rec-
Recommendations ommended (strong recommendation; high-quality evidence).
122. For mild disease, clotrimazole troches, 10 mg 5 times 134. A less preferred alternative for those who cannot tolerate
daily, OR miconazole mucoadhesive buccal 50-mg tablet ap- oral therapy is AmB deoxycholate, 0.3–0.7 mg/kg daily
plied to the mucosal surface over the canine fossa once daily (strong recommendation; moderate-quality evidence).
for 7–14 days are recommended (strong recommendation; 135. Consider de-escalating to oral therapy with fluconazole
high-quality evidence). 200–400 mg (3–6 mg/kg) daily once the patient is able to tol-
123. Alternatives for mild disease include nystatin suspension erate oral intake (strong recommendation; moderate-quality
(100 000 U/mL) 4–6 mL 4 times daily, OR 1–2 nystatin pas- evidence).
tilles (200 000 U each) 4 times daily, for 7–14 days (strong 136. For fluconazole-refractory disease, itraconazole solution,
recommendation; moderate-quality evidence). 200 mg daily, OR voriconazole, 200 mg (3 mg/kg) twice
124. For moderate to severe disease, oral fluconazole, 100–200 daily either intravenous or oral, for 14–21 days is recom-
mg daily, for 7–14 days is recommended (strong recommen- mended (strong recommendation; high-quality evidence).
dation; high-quality evidence). 137. Alternatives for fluconazole-refractory disease include an
125. For fluconazole-refractory disease, itraconazole solution, echinocandin (micafungin: 150 mg daily; caspofungin: 70-
200 mg once daily OR posaconazole suspension, 400 mg mg loading dose, then 50 mg daily; or anidulafungin: 200
twice daily for 3 days then 400 mg daily, for up to 28 days mg daily) for 14–21 days, OR AmB deoxycholate, 0.3–0.7
are recommended (strong recommendation; moderate-quality mg/kg daily, for 21 days (strong recommendation; high-
evidence). quality evidence).
126. Alternatives for fluconazole-refractory disease include 138. Posaconazole suspension, 400 mg twice daily, or extend-
voriconazole, 200 mg twice daily, OR AmB deoxycholate ed-release tablets, 300 mg once daily, could be considered for
oral suspension, 100 mg/mL 4 times daily (strong recommen- fluconazole-refractory disease (weak recommendation; low-
dation; moderate-quality evidence). quality evidence).
127. Intravenous echinocandin (caspofungin: 70-mg loading 139. For patients who have recurrent esophagitis, chronic sup-
dose, then 50 mg daily; micafungin: 100 mg daily; or anidu- pressive therapy with fluconazole, 100–200 mg 3 times week-
lafungin: 200-mg loading dose, then 100 mg daily) OR intra- ly, is recommended (strong recommendation; high-quality
venous AmB deoxycholate, 0.3 mg/kg daily, are other evidence).
140. For HIV-infected patients, antiretroviral therapy is common cause of healthcare–associated bloodstream infection.
strongly recommended to reduce the incidence of recurrent A recent multicenter point-prevalence survey identified Candi-
infections (strong recommendation; high-quality evidence). da species as the most commonly isolated healthcare-associated
bloodstream pathogen [4]. Among patients with candidemia
and other forms of invasive candidiasis, non-albicans Candida
INTRODUCTION
species constitute approximately 50% of all relevant isolates,
In the first section, the panel summarizes background informa- representing a steady trend in many regions throughout the
tion relevant to the topic. In the second section, the panel poses world for more than a decade [5–12].
questions regarding the management of candidiasis, evaluates Among the many clinical manifestations of candidiasis, can-
applicable clinical trial and observational data, and makes rec- didemia and invasive candidiasis have been given the most
ommendations using the Grading of Recommendations Assess- attention in clinical trials. Candidemia is associated with up
ment, Development and Evaluation (GRADE) framework [2]. to 47% attributable mortality [5–13], and this is even higher
The following 17 questions were answered: among persons with septic shock [14]. Several authors have
demonstrated that mortality is closely linked to both timing
I. What is the treatment for candidemia in nonneutropenic
of therapy and/or source control [14–19]. That is, earlier inter-
patients?
vention with appropriate antifungal therapy and removal of a
II. Should central venous catheters be removed in nonneutro-
contaminated central venous catheter (CVC) or drainage of in-
penic patients with candidemia?
fected material is generally associated with better overall out-
III. What is the treatment for candidemia in neutropenic

comes [14–19]. CVCs are commonly linked with candidemia,
patients?
but catheters are not always the source, especially among
IV. What is the treatment for chronic disseminated (hepatos-
neutropenic patients in whom the gastrointestinal tract is a
plenic) candidiasis?
common source. Most experts agree that thoughtful patient-
V. What is the role of empiric treatment for suspected invasive
specific management of CVCs is critical in the overall manage-
candidiasis in nonneutropenic patients in the intensive care
ment of the infection [19].
unit?
The continued reliance on blood cultures, which are notori-
VI. Should prophylaxis be used to prevent invasive candidiasis
ously insensitive as markers of disease, remains a significant ob-
in the intensive care unit setting?
stacle to early intervention for this condition. The development
VII. What is the treatment for neonatal candidiasis, including
of reliable nonculture assays is critical to providing the oppor-
central nervous system infection?
tunity for earlier intervention and more targeted antifungal
VIII. What is the treatment for intra-abdominal candidiasis?
therapy among large numbers of patients in whom traditional
IX. Does the isolation of Candida species from the respiratory
blood cultures are insensitive or provide untimely results [20].
tract require antifungal therapy?
Species distribution is also a significant challenge for all
X. What is the treatment for Candida intravascular infections,
forms of candidiasis, and there is considerable geographic, cen-
including endocarditis and infections of implantable cardiac
ter-to-center, and even unit-to-unit variability in the prevalence
devices?
of pathogenic Candida species [8–12]. Indeed, candidiasis is not
XI. What is the treatment for Candida osteoarticular
one but rather several diseases, with each Candida species pre-
infections?
senting its own unique characteristics with respect to tissue tro-
XII. What is the treatment for Candida endophthalmitis?
pism, propensity to cause invasive disease, virulence, and
XIII. What is the treatment for central nervous system
antifungal susceptibility. A working knowledge of the local ep-
candidiasis?
idemiology and rates of antifungal resistance is critical in mak-
XIV. What is the treatment for urinary tract infections due to
ing informed therapeutic decisions while awaiting culture and
Candida species?
susceptibility data.
XV. What is the treatment for vulvovaginal candidiasis?
Despite the overall robust nature of the randomized con-
XVI. What is the treatment for oropharyngeal candidiasis?
trolled trials examining treatment of candidemia and other
XVII. What is the treatment for esophageal candidiasis?
forms of invasive candidiasis [21–34], no single trial has dem-
Infections due to Candida species are major causes of mor- onstrated clear superiority of one therapeutic agent over anoth-
bidity and mortality in humans, causing a diverse spectrum of er. Careful analysis of these clinical data sometimes leads to
clinical disease ranging from superficial and mucosal infections conflicting conclusions. For instance, the use of amphotericin
to invasive disease associated with candidemia and metastatic B (AmB) plus fluconazole is as least as effective as higher-
organ involvement. As an entity, candidemia is one of the dose (800 mg daily) fluconazole given alone for patients with
most common healthcare-associated bloodstream infections in candidemia [22], but there is little role for this combination
US hospitals, typically ranking as the third or fourth most in current practice, especially as echinocandins are such a safe

and effective alternative. Similarly, voriconazole is as effective as studies for the Candida guideline PICO ( population/patient, in-
the strategy of sequential AmB and fluconazole for candidemia, tervention/indicator, comparator/control, outcome) questions.
but few would choose voriconazole in this setting as there is lit- Search strategies were developed and built by 2 independent
tle advantage and potentially greater toxicity associated with health sciences librarians from the Health Sciences Library Sys-
using this agent compared to other therapies [23]. tem, University of Pittsburgh. For each PICO question, the li-
The echinocandins have emerged as preferred agents for brarians developed the search strategies using PubMed’s
most episodes of candidemia and invasive candidiasis, with command language and appropriate search fields. Medical Sub-
the exception of central nervous system (CNS), eye, and urinary ject Headings (MeSH) terms and keywords were used for the
tract infections due to these organisms. This preference is based main search concepts of each PICO question. Articles in all lan-
on a strong safety profile, convenience, early fungicidal activity, guages and all publication years were included. Initial searches
a trend toward better outcomes based on data from individual were created and confirmed with input from the guideline com-
studies and combined analyses of candidemia studies [19, 25], mittee chairs and group leaders from August to November
and the emergence of azole-resistant Candida species. The re- 2013. The searches were finalized and delivered between late
cent emergence of multidrug-resistant Candida species further November 2013 and January 2014. After the literature searches
complicates the selection of antifungal therapy for the immedi- were performed, authors continued to review the literature and
ate future [10, 12, 35–38] as there are no good prospective data added relevant articles as needed.
to guide therapy.
Process Overview
There is an abundance of clinical data generated from large The panel met face-to-face twice and conducted a series of con-

randomized clinical trials for candidemia, Candida esophagitis, ference calls over a 2-year period. The panel reviewed and dis-
oropharyngeal candidiasis, and prophylaxis studies in special cussed all recommendations, their strength, and the quality of
populations, such as patients in intensive care units (ICUs), ne- evidence. Discrepancies were discussed and resolved, and all
onates, and selected transplant recipients, and these studies final recommendations represent a consensus opinion of the en-
have led to important insights into optimal therapeutic ap- tire panel. For the final version of these guidelines, the panel as a
proaches in these vulnerable populations. For those with less group reviewed all individual sections.
common manifestations of disease, such as osteomyelitis,
endophthalmitis, and infective endocarditis, treatment recom- Evidence Review: The GRADE Method
mendations are largely based on extrapolation from random- GRADE is a systematic approach to guideline development that
ized studies of patients with other forms of disease, small has been described in detail elsewhere [2, 39]. The IDSA adopt-
retrospective series, and anecdotal reports. Thus, there is a crit- ed GRADE in 2008. In the GRADE system, the guideline panel
ical need to assess these data in an ongoing manner to provide assigns each recommendation with separate ratings for the un-
timely recommendations pertaining to the management of pa- derlying quality of evidence supporting the recommendation
tients with these less common forms of candidiasis. and for the strength with which the recommendation is made
(Figure 1). Data from randomized controlled trials begin as
METHODS “high” quality, and data from observational studies begin as
“low” quality. However, the panel may judge that specific fea-
Panel Composition
tures of the data warrant decreasing or increasing the quality
The most recent version of the Infectious Diseases Society of
of evidence rating, and GRADE provides guidance on how
America (IDSA) guideline on the management of patients with
such factors should be weighed [39]. The strength assigned to
candidiasis was published in 2009 [1]. For this update, the IDSA
a recommendation chiefly reflects the panel’s confidence that
Standards and Practice Guidelines Committee (SPGC) con-
the benefits of following the recommendation are likely to out-
vened a multidisciplinary panel of 12 experts in the manage-
weigh potential harms. While the quality of evidence is an im-
ment of patients with candidiasis. The panel consisted of 12
portant factor in choosing recommendation strength, it is not
members of IDSA, and included 11 adult infectious diseases
prescriptive.
physicians and 1 pediatric infectious diseases physician. All
panel members were selected on the basis of their expertise in Guidelines and Conflicts of Interest
clinical and/or laboratory mycology with a focus on candidiasis. The expert panel complied with the IDSA policy on conflicts of
interest, which requires disclosure of any financial or other inter-
Literature Review and Analysis est that may be construed as constituting an actual, potential, or
Panel members were each assigned to review the recent litera- apparent conflict. Panel members were provided IDSA’s conflicts
ture for at least 1 topic, evaluate the evidence, determine the of interest disclosure statement and were asked to identify ties to
strength of recommendations, and develop written evidence companies developing products that may be affected by promul-
in support of these recommendations. PubMed, which includes gation of the guideline. Information was requested regarding em-
Medline (1946 to present), was searched to identify relevant ployment, consultancies, stock ownership, honoraria, research
funding, expert testimony, and membership on company advi- considered for invasive Candida infections caused by less sus-
sory committees. Decisions were made on a case-by-case basis ceptible species, such as C. glabrata and C. krusei. The typical
as to whether an individual’s role should be limited as a result dosage for lipid formulation AmB is 3–5 mg/kg daily when used
of a conflict. Potential conflicts of interests are listed in the for invasive candidiasis. Nephrotoxicity is the most common se-
Acknowledgments section. rious adverse effect associated with AmB deoxycholate therapy,
resulting in acute kidney injury in up to 50% of recipients and
Consensus Development Based on Evidence
The panel obtained feedback from 3 external peer reviewers. an electrolyte-wasting tubular acidosis in a majority of patients
The guidelines were reviewed and endorsed by the MSG, the [40, 41]. Lipid formulations of AmB are more expensive than
American Academy of Pediatrics (AAP) and the Pediatric In- AmB deoxycholate, but all have considerably less nephrotoxici-
fectious Diseases Society (PIDS). The guideline was reviewed ty [42, 43]. Most observers agree that lipid formulations, with
and approved by the IDSA SPGC and the IDSA Board of Direc- the exception of ABCD, have fewer infusion-related reactions
tors prior to dissemination. than AmB deoxycholate. The impact of the pharmacokinetics
and differences in toxicity of lipid formulations of AmB have
Revision Dates not been formally examined in clinical trials. We are not
At annual intervals, the panel chairs will be asked for their input aware of any forms of candidiasis for which lipid formulations
on the need to update the guideline based on an examination of of AmB are superior to AmB deoxycholate in terms of clinical
the current literature. The IDSA SPGC will consider this input efficacy. In addition, we are not aware of any situation in which
and determine the necessity and timing of an update. If war- lipid formulations should not be used, with the exception of uri-

ranted, the entire panel or a subset thereof will be convened nary tract infections, because of reduced renal excretion of these
to discuss potential changes. formulations. Animal model studies suggest a pharmacokinetic
BACKGROUND and therapeutic advantage for liposomal AmB in the CNS [44].
Data demonstrating that AmB deoxycholate–induced nephro-
Antifungal Agents
toxicity is associated with a 6.6-fold increase in mortality have
Pharmacologic Considerations for Therapy for Candidiasis
led many clinicians to use lipid formulations of AmB in proven
Systemic antifungal agents shown to be effective for the treat-
or suspected candidiasis, especially among patients in a high-
ment of invasive candidiasis comprise 4 major categories: the
risk environment, such as an ICU [45].
polyenes (amphotericin B [AmB] deoxycholate, liposomal
AmB, AmB lipid complex [ABLC], and amphotericin B colloi-
Triazoles
dal dispersion [ABCD, not available in the United States]), the
Fluconazole, itraconazole, voriconazole, posaconazole, and a
triazoles (fluconazole, itraconazole, voriconazole, and posaco-
new expanded-spectrum triazole, isavuconazole, demonstrate
nazole), the echinocandins (caspofungin, anidulafungin, and
similar activity against most Candida species [46–51]. Each of
micafungin), and flucytosine. Data from a recently completed
the azoles has less activity against C. glabrata and C. krusei
clinical trial comparing isavuconazole to an echinocandin for
than against other Candida species. All of the azole antifungals
treatment of invasive candidiasis are unavailable at this time.
inhibit cytochrome P450 enzymes to some degree [52]. Thus,
Clinicians should become familiar with strategies to optimize
clinicians must carefully consider the influence on a patient’s
efficacy through an understanding of relevant pharmacokinetic
drug regimen when adding or removing an azole. In large clin-
properties.
ical trials, fluconazole demonstrated efficacy comparable to that
Amphotericin B of AmB deoxycholate for the treatment of candidemia [21, 22]
Most experience with AmB is with the deoxycholate prepara- and is also considered to be standard therapy for oropharyngeal,
tion. Three lipid formulations of AmB have been developed esophageal, and vaginal candidiasis, as well as urinary tract in-
and approved for use in humans: ABLC, ABCD, and liposomal fections [53, 54]. Fluconazole is readily absorbed, with oral bio-
AmB. These agents possess the same spectrum of activity as availability resulting in concentrations equal to approximately
AmB deoxycholate, but daily dosing regimens and toxicity pro- 90% of those achieved by intravenous administration [55]. Ab-
files differ for each agent. The 3 lipid formulation AmB agents sorption is not affected by food consumption, gastric pH, or dis-
have different pharmacological properties and rates of treat- ease state. Among the triazoles, fluconazole has the greatest
ment-related adverse events and should not be interchanged penetration into the cerebrospinal fluid (CSF) and vitreous,
without careful consideration. In this document, a reference achieving concentrations of >70% of those in serum [56–59].
to AmB, without a specific dose or other discussion of form, For this reason, it is often used in the treatment of CNS and in-
should be taken to be a reference to the general use of any of traocular Candida infections. Fluconazole achieves urine con-
the AmB preparations. For most forms of invasive candidiasis, centrations that are 10–20 times the concentrations in serum
the typical intravenous dosage for AmB deoxycholate is 0.5–0.7 and, thus, is the preferred treatment option for symptomatic
mg/kg daily, but dosages as high as 1 mg/kg daily should be cystitis [59]. For patients with invasive candidiasis, fluconazole

should be administered with an average loading dose of 800 mg discontinuing treatment with this compound [52]. Voricona-
(12 mg/kg), followed by an average daily dose of 400 mg (6 mg/ zole has not been studied systematically in fluconazole-resistant
kg). The higher-dose level (800 mg daily, 12 mg/kg) is often rec- Candida species, and with the exception of C. krusei, use is cur-
ommended for therapy of susceptible C. glabrata infections, but rently discouraged. Each of the triazoles can be associated with
this has not been validated in clinical trials. Fluconazole elimi- uncommon side effects. However, several effects are unique to
nation is almost entirely renal; thus, a dose reduction is needed voriconazole or more commonly associated with higher vorico-
in patients with creatinine clearance <50 mL/minute. nazole concentrations, including hepatic injury, visual side ef-
Itraconazole is only available in oral formulations. It has not fects, photosensitivity, periostitis, and CNS side effects [73–75].
been well studied for invasive candidiasis, and is generally re- Posaconazole does not have an indication for primary candi-
served for patients with mucosal candidiasis, especially those diasis therapy. It demonstrates in vitro activity against Candida
who have experienced treatment failure with fluconazole [60]. species that is similar to that of voriconazole, but clinical data
Gastrointestinal absorption is variable among patients and is are inadequate to make an evidence-based recommendation
greater for the oral solution compared with the capsule formu- for treatment of candidiasis other than oropharyngeal candidi-
lation. Histamine receptor antagonists and proton pump inhib- asis [76]. Posaconazole is currently available as an extended-re-
itors result in decreased absorption of the capsule formulation, lease tablet, an oral suspension, and an intravenous solution.
whereas acidic beverages enhance absorption [61]. Administra- The tablet formulation, given as 300 mg twice daily for 2 doses,
tion of the capsule formulation with food increases absorption, then 300 mg daily produces predictable serum concentrations
but the oral solution is better absorbed on an empty stomach and excellent drug exposure and requires only once-daily dos-

[62]. Oral formulations are dosed in adults at 200 mg 3 times ing [77, 78]. The oral suspension has unpredictable bioavailabil-
daily for 3 days, then 200 mg once or twice daily thereafter. ity [79–81]. Intravenous posaconazole is given as 300 mg twice
Voriconazole has demonstrated effectiveness for both muco- daily for 2 doses, then 300 mg daily.
sal and invasive candidiasis [23, 63]. Its clinical use has been pri- Isavuconazole is a recently approved expanded-spectrum tri-
marily for step-down oral therapy in patients with infection due azole antifungal with excellent in vitro activity against Candida
to C. krusei and fluconazole-resistant, voriconazole-susceptible species. Preliminary analysis of the recently completed large in-
C. glabrata. CSF and vitreous concentrations are >50% of serum ternational double-blind trial comparing isavuconazole to an
concentration, and voriconazole has been shown to be effica- echinocandin for invasive candidiasis suggests that isavucona-
cious in case series for these infection sites [64–66]. Voricona- zole did not meet criteria for noninferiority ( personal commu-
zole does not accumulate in active form in the urine and thus nication, Astellas US).
should not be used for urinary candidiasis. The oral bioavail-
ability of voriconazole is excellent and is not affected by gastric Echinocandins
pH, but it decreases when the drug is administered with food Caspofungin, anidulafungin, and micafungin are available only
[67, 68]. In adults, the recommended oral dosing regimen for can- as parenteral preparations [82–84]. The minimum inhibitory
didiasis includes a loading dose of 400 mg (6 mg/kg) twice daily concentrations (MICs) of the echinocandins are low for most
for 2 doses, followed by 200–300 mg (3–4 mg/kg) twice daily. Candida species, including C. glabrata and C. krusei [48–50].
Intravenous voriconazole is complexed to a cyclodextrin mol- However, recent case series have described treatment failure as-
ecule; after 2 loading doses of 6 mg/kg every 12 hours, a main- sociated with resistant strains of C. glabrata [85, 86]. Candida
tenance dosage of 3–4 mg/kg every 12 hours is recommended. parapsilosis demonstrates innately higher MICs to the echino-
Because of the potential for cyclodextrin accumulation and candins than do most other Candida species, which raises the
possible nephrotoxicity among patients with significant renal concern that C. parapsilosis may be less responsive to the
dysfunction, intravenous voriconazole is not currently recom- echinocandins.
mended for patients with a creatinine clearance <50 mL/minute. Each of these agents has been studied for the treatment of
However, retrospective examination of intravenous voricona- esophageal candidiasis [24, 87, 88] and invasive candidiasis
zole use in patients with varying degrees of renal function [25–34], and each has demonstrated efficacy in these situations.
below this cutoff value has not identified toxic effects, mitigat- Recent pooled analyses of almost exclusively nonneutropenic
ing some of these concerns [69, 70]. Oral voriconazole does not patients included in randomized invasive candidiasis treatment
require dosage adjustment for renal insufficiency, but it is the trials suggest a survival advantage associated with initial echino-
only triazole that requires dosage reduction for patients with candin therapy [19].
mild to moderate hepatic impairment [71]. All echinocandins have minimal adverse effects. The phar-
Common polymorphisms in the gene encoding the primary macologic properties in adults are also very similar, and each
metabolic enzyme for voriconazole result in wide variability of is administered once daily intravenously [82–84]. Echino-
serum levels [72]. Drug–drug interactions are common with candins achieve therapeutic concentrations in all infection
voriconazole and should be considered when initiating and sites with the exception of the eye, CNS, and urine [59]. The
major route of elimination is nonenzymatic degradation. None Fluconazole pharmacokinetics vary with age, and the drug
of the echinocandins require dosage adjustment for renal insuf- is rapidly cleared in children. Thus, a daily fluconazole dose
ficiency or dialysis. Both caspofungin and micafungin undergo of 12 mg/kg is necessary for neonates and children [102–105].
minimal hepatic metabolism, but neither drug is a major sub- Voriconazole pharmacokinetics are also highly variable in chil-
strate for cytochrome P450. Caspofungin is the only echinocan- dren [106–108]. To attain plasma exposures comparable to
din for which dosage reduction is recommended for patients those in adults receiving 4 mg/kg every 12 hours, a loading
with moderate to severe hepatic dysfunction. The usual intrave- dose of intravenous voriconazole of 9 mg/kg twice daily, fol-
nous dosing regimens for invasive candidiasis are as follows: lowed by 8 mg/kg twice daily is recommended in children.
caspofungin: loading dose 70 mg, then 50 mg daily; anidulafun- The recommended oral dose is 9 mg/kg twice daily (maximum
gin: loading dose 200 mg, then 100 mg daily; and micafungin: dose 350 mg) [95, 107]. There are no data on voriconazole dos-
100 mg daily (no loading dose needed). ing in children <2 years old, and there are no pediatric studies
examining the pharmacokinetics of the intravenous formula-
Flucytosine
tion, the oral suspension, or the extended-release tablets of
Flucytosine demonstrates broad antifungal activity against most
posaconazole.
Candida species, with the exception of C. krusei. The com-
Caspofungin and micafungin are approved by the US Food
pound is available in the United States only as an oral for-
and Drug Administration (FDA) for use in children. Caspofun-
mulation. The drug has a short half-life (2.4–4.8 hours) and
gin dosing is based on body surface area rather than weight. Dos-
is ordinarily administered at a dosage of 25 mg/kg 4 times
ing in children is a loading dose of 70 mg/m2, followed by 50 mg/
daily for patients with normal renal function. Flucytosine

m2/day. Preliminary studies suggest an optimal dose of caspofun-
demonstrates excellent absorption after oral administration
gin in neonates of 25 mg/m2/day. The current recommendation
(80%–90%), and most of the drug is excreted unchanged
for micafungin for invasive candidiasis is 2 mg/kg/day, with the
(microbiologically active) in the urine [89, 90]; dose adjustment
option to increase to 4 mg/kg/day in children <40 kg. The opti-
is necessary for patients with renal dysfunction [91, 92].The
mal dose of micafungin in neonates is unknown, but likely to be
compound exhibits high penetration into the CNS and eye.
10 mg/kg/day or greater [109]. Anidulafungin should be dosed at
Concentration-dependent toxicity results in bone marrow sup-
1.5 mg/kg/day for neonates and children [110–112].
pression and hepatitis.
Flucytosine is usually given in combination with another an- Considerations During Pregnancy
tifungal agent due to a high rate of emergence of resistance dur- AmB is the treatment of choice for invasive candidiasis in preg-
ing monotherapy [93]. The most common use of flucytosine in nant women [113]. Fluconazole, itraconazole, posaconazole,
the setting of Candida infection is in combination with AmB for and isavuconazole should be avoided in pregnant women, espe-
patients with more refractory infections, such as Candida endo- cially those in the first trimester, because of the possibility of
carditis, meningitis, or endophthalmitis. Occasionally, it is used birth defects associated with their use. Voriconazole is con-
for the treatment of symptomatic urinary tract candidiasis due traindicated during pregnancy because of fetal abnormalities
to fluconazole-resistant C. glabrata [94]. observed in animals. There are few data concerning the echino-
candins; thus, their use is cautioned during pregnancy. Flucyto-
Pediatric Dosing
sine is contraindicated during pregnancy because of fetal
There is considerable variation in the pharmacokinetics of an-
abnormalities observed in animals.
tifungal agents between adult and pediatric patients, and the
data on dosing in pediatric patients are limited. The pharmaco- Therapeutic Drug Monitoring
logical properties of antifungal agents in children and infants Therapeutic drug monitoring (TDM) for itraconazole, vorico-
have been reviewed in detail [95]. The optimal dose of AmB de- nazole, posaconazole, and flucytosine has been shown to be use-
oxycholate in neonates has not been clearly defined; a dosage of ful for optimizing efficacy and limiting toxicity in patients
1 mg/kg is generally used [96–98]. The safety, efficacy, area receiving therapy for a variety of invasive fungal infections, in-
under the curve, and maximal concentration of ABLC 2–5 cluding mucosal and invasive candidiasis [114]. The basis for
mg/kg day are similar in adults and children [99]. The pharma- TDM is widely variable concentrations among patients and a
cokinetics of liposomal AmB in neonates and children suggest strong relationship between concentration and efficacy and/or
that both volume and clearance are affected by weight [100]. toxicity.
Flucytosine clearance is directly proportional to glomerular For itraconazole, when measured by high-pressure liquid
filtration rate, and infants with a very low birth weight may chromatography (HPLC), both itraconazole and its bioactive
accumulate high plasma concentrations because of poor renal hydroxy-itraconazole metabolite are reported, the sum of
function due to immaturity [101]. Thus, the use of flucytosine which should be considered in assessing drug levels. Treatment
without careful monitoring of serum drug levels is discouraged success has been associated with concentrations ≥1 mg/L and
in this group of patients. toxicity with concentrations >5 mg/L. Bioassay levels are 3- to

7-fold higher than those measured by HPLC. Because of non- Table 1. Clinical Breakpoints for Antifungal Agents Against Common
linear pharmacokinetics in adults and genetic differences in me- Candida Species
tabolism, there is both intrapatient and interpatient variability

Clinical Breakpoint, µg/mLa
in serum voriconazole concentrations [115–118]. TDM should
be considered for patients receiving voriconazole, because drug Candida Antifungal
Organism Agent S SDD I R
toxicity has been observed at higher serum concentrations and
C. albicans Fluconazole ≤2 4 ≥8
reduced clinical response has been observed at lower concentra-
Itraconazole ≤0.12 0.25–0.5 ≥1
tions [117, 118]. The therapeutic trough concentration window Voriconazole ≤0.12 0.25–0.5 ≥1
for voriconazole is 1–5.5 mg/L. Few data are available to sup- Posaconazole
port a specific concentration to optimize posaconazole efficacy. Anidulafungin ≤0.25 0.5 ≥1
Flucytosine monitoring is predominantly used to prevent con- Caspofungin ≤0.25 0.5 ≥1
Micafungin ≤0.25 0.5 ≥1
centration-associated toxicity. Peak concentrations <100 mg/L
C. glabrata Fluconazole 32 ≥64
are recommended to avoid the predictable liver and bone mar- Itraconazole
row effects [119]. Voriconazole
Posaconazole
Antifungal Susceptibility Testing Anidulafungin ≤0.12 0.25 ≥0.5
Caspofungin ≤0.12 0.25 ≥0.5
Intensive efforts to develop standardized, reproducible, and rel-
Micafungin ≤0.06 0.12 ≥0.25
evant susceptibility testing methods for fungi have resulted in
C. parapsilosis Fluconazole ≤2 4 ≥8

the development of the Clinical and Laboratory Standards Insti- Itraconazole
tute (CLSI) M27-A3 and the European Committee on Antimi- Voriconazole ≤0.12 0.25–0.5 ≥1
crobial Susceptibility Testing (EUCAST) methodologies for Posaconazole
susceptibility testing of yeasts [120]. Interpretive breakpoints Anidulafungin ≤2 4 ≥8
Caspofungin ≤2 4 ≥8
for susceptibility take into account the MIC, as well as pharma-
Micafungin ≤2 4 ≥8
cokinetic/pharmacodynamic data and animal model data. They C. tropicalis Fluconazole ≤2 4 ≥8
are reported for each species. Breakpoints have been established Itraconazole
for most, but not all, drugs for the 5 most common Candida Voriconazole ≤0.12 0.25–0.5 ≥1
species [47, 50, 121, 122] (Table 1). Posaconazole
Anidulafungin ≤0.25 0.5 ≥1
In many instances, clinical breakpoints have decreased from
Caspofungin ≤0.25 0.5 ≥1
those used previously. For example, the prior Candida clinical
Micafungin ≤0.25 0.5 ≥1
breakpoint for susceptibility to fluconazole was ≤8 mg/L. With C. krusei Fluconazole
the new interpretation, the susceptible value has been reduced to Itraconazole
≤2 mg/L for C. albicans. For C. glabrata, there is no breakpoint Voriconazole ≤0.5 1 ≥2
established for susceptibility to fluconazole, itraconazole, posa- Posaconazole
Anidulafungin ≤0.25 0.5 ≥1
conazole, or voriconazole (Table 1).
Caspofungin ≤0.25 0.5 ≥1
When there is no clinical breakpoint established, the epide- Micafungin ≤0.25 0.5 ≥1
miologic cutoff value (ECV) based on an examination of the
Where no values are entered, there are insufficient data to establish clinical breakpoints.
distribution of MICs within a species can be used. The ECV Abbreviations: I, intermediate; MIC, minimum inhibitory concentration; R, resistant; S,
is defined as the MIC value that excludes non–wild type strains, susceptible; SDD, susceptible dose-dependent.
a
Clinical breakpoints adopted by the Clinical and Laboratory Standards Institute.
notably isolates that are likely to contain a resistant mutant [50,
123]. The addition of the ECV method is particularly useful for
detecting emergence of resistance in a Candida species at an
institution. 125]. The value of susceptibility testing for other Candida spe-
The susceptibility of Candida to the currently available anti- cies is less clear, although resistance among C. tropicalis and
fungal agents is generally predictable if the species of the in- C. parapsilosis has been reported from tertiary care institutions
fecting isolate is known. Currently, antifungal resistance in that have extensive use of antifungal agents [127, 128]. Because
C. albicans is uncommon. However, individual isolates may of these trends, susceptibility testing is increasingly used to
not necessarily follow this general pattern [124]. Recent surveil- guide the management of candidemia and invasive candidiasis.
lance studies suggest that triazole resistance among C. glabrata
isolates has increased to a degree that is it difficult to rely upon Diagnosis of Candidiasis
these agents for therapy in the absence of susceptibility testing Cultures of blood or other samples collected under sterile con-
[12, 125, 126]. A similar trend has begun to emerge for a smaller ditions have long been considered diagnostic gold standards for
proportion of C. glabrata isolates and the echinocandins [35, 85, invasive candidiasis. Nonculture diagnostic tests, such as
antigen, antibody, or β-D-glucan detection assays, and poly- but not the United States (Platelia Candida Ag and Ab; Bio-
merase chain reaction (PCR) are now entering clinical prac- Rad). In a meta-analysis of 14 studies, the sensitivity/specificity
tice as adjuncts to cultures. If used and interpreted for the diagnosis of invasive candidiasis of mannan and anti-
judiciously, these tests can identify more patients with inva- mannan IgG individually were 58%/93% and 59%/83%, respec-
sive candidiasis and better direct antifungal therapy. To tively [140]. Values for the combined assay were 83% and 86%,
fully realize the benefits of combining culture and nonculture with best performances for C. albicans, C. glabrata, and C. tro-
tests, however, clinicians must carefully consider the types of picalis infections. In one study of candidemia, at least one test
invasive candidiasis, understand the strengths and limitations was positive before blood culture in 73% of patients [141]. In a
of each assay, and interpret test results in the context of the study of hepatosplenic candidiasis, at least one test was positive
clinical setting. before radiographic changes in 86% of patients [142]. This assay
is not used widely in the United States, and its role in the diag-
Use of Cultures in the Diagnosis of Invasive Candidiasis
nosis and management of invasive candidiasis is unclear.
Invasive candidiasis encompasses 3 entities: candidemia in the
absence of deep-seated candidiasis, candidemia associated with
β-D-Glucan detection
deep-seated candidiasis, and deep-seated candidiasis in the ab-
β-D-glucan is a cell wall constituent of Candida species, Asper-
sence of candidemia [20]. The distribution of these entities is
gillus species, Pneumocystis jiroveci, and several other fungi. A
likely to differ among centers; on balance, data suggest that
serum β-D-glucan assay (Fungitell; Associates of Cape Cod,
the groups are approximately equal in size [129].
East Falmouth, Massachusetts) has been approved by the
The overall sensitivity of blood cultures for diagnosing inva-

FDA as an adjunct to cultures for the diagnosis of invasive fun-
sive candidiasis is roughly 50% [20]. The limit of detection of
gal infections. True-positive results are not specific for invasive
blood cultures is ≤1 colony-forming unit/mL [130, 131]. The
candidiasis, but rather suggest the possibility of an invasive fun-
limit of detection for cultures is at or below that of PCR
gal infection. For this reason, among patient populations that
[132–135]. As such, blood cultures should be positive during
are also at risk for invasive mold infections, such as hematopoi-
the vast majority of active Candida bloodstream infections.
etic cell transplant recipients, β-D-glucan offers a theoretical ad-
They may be negative in cases of extremely low-level candide-
vantage over more narrow assays for candidiasis. β-D-glucan
mia, intermittent candidemia, deep-seated candidiasis that per-
detection can identify cases of invasive candidiasis days to
sists after sterilization of the bloodstream, or deep-seated
weeks prior to positive blood cultures, and shorten the time
candidiasis resulting from direct inoculation of Candida in
to initiation of antifungal therapy [143]. Prophylactic or empiric
the absence of candidemia. Blood cultures are limited by slow
antifungal treatment is likely to impact test performance. On
turnaround times (median time to positivity of 2–3 days, rang-
the one hand, antifungal agents may reduce diagnostic sensitiv-
ing from 1 to ≥7 days), and the fact that they may become pos-
ity [144–146], but decreasing β-D-glucan levels may also corre-
itive relatively late in the disease course [130, 136]. Cultures of
late with responses to antifungal therapy [147].
tissues or fluid recovered from infected sites during deep-seated
In meta-analyses of β-D-glucan studies, the pooled sensitivity
candidiasis also exhibit poor sensitivity (often <50%) and slow
and specificity for diagnosing invasive candidiasis were 75%–
turnaround times, and require invasive sampling procedures
80% and 80%, respectively [144–146]. A number of issues com-
that may be dangerous or contraindicated due to underlying
plicate the interpretation of these data, including uncertainties
medical conditions [137].
about the best cutoff value for a positive result, number of pos-
Antigen and Antibody Detection itive tests required to establish a diagnosis, and optimal timing
Candida antigen and anti-Candida antibody detection has and frequency of testing among at-risk patients. There is
gained greater acceptance in Europe than the United States. marked heterogeneity among studies in how they address
In general, antigen detection is limited by rapid clearance these issues, as well as in patient and control populations,
from the bloodstream [138]. Concerns have been expressed range and type of fungal pathogens targeted, invasive candidi-
about the reliability of antibody detection in immunosup- asis disease entities, distributions of Candida species, prior an-
pressed hosts, but assays have performed well in patients with tifungal use, specific β-D-glucan assays employed, and other
neutropenia and cell-mediated immune defects (including he- aspects of study design and statistical interpretation.
matopoietic cell and solid organ transplant recipients) [138, The major concern about β-D-glucan detection is the poten-
139]. Serum immunoglobulin G (IgG) responses against specific tial for poor specificity and false positivity, which may be par-
antigens have typically performed better than immunoglobulin ticularly problematic in the patient populations for which
M (IgM) responses, suggesting that many patients mount am- nonculture diagnostics would be most helpful. For example,
nestic responses or have ongoing, subclinical tissue invasion false-positive results are rare in healthy controls, but decidedly
[139]. The best-studied test is a combined mannan/antimannan more common among patients in an ICU [148]. Causes of
antibody assay, which is currently approved for use in Europe, false positivity include other systemic infections, such as

gram-positive and gram-negative bacteremia, certain antibiot- A multicenter US study assessing the performance of a self-con-
ics, such as intravenous amoxicillin-clavulanate (not available tained instrument that amplifies and detects Candida DNA by
in the United States), hemodialysis, fungal colonization, receipt PCR and T2 magnetic resonance (T2 Biosystems, Lexington,
of albumin or immunoglobulin, use of surgical gauze or other Massachusetts), respectively, has been completed [163]. This
material containing glucan, and mucositis or other disruptions assay is FDA approved, but its role in the early diagnosis and
of gastrointestinal mucosa [149–154]. The specificity of β-D- management of candidemia remains unclear until more data
glucan can be improved by requiring consecutive positive re- are available. PCR has potential advantages over β-D-glucan
sults rather than a single result, but false positivity remains a or antigen-antibody assays, including the capacity for species
significant limitation if the above-listed factors are common identification, detection of molecular markers for drug resis-
in the population tested. As an extreme example, the per-patient tance, and multiplex formatting. In Europe, a whole-blood,
sensitivity/specificity and positive and negative predictive values multiplex real-time PCR assay (SeptiFast, Roche) that detects
of routine surveillance β-D-glucan testing in a recent study of 19 bacteria and 6 fungi (C. albicans, C. glabrata, C. parapsilosis,
lung transplant recipients were 64%/9% and 14%/50%, respec- C. tropicalis, C. krusei, and Aspergillus fumigatus) has been in-
tively [155]. Moreover, 90% of patients had at least one positive vestigated in several studies of sepsis and neutropenic fever.
β-D-glucan result. Therefore, the test will be most useful if tar- Among patients with candidemia in one study, the sensitivity
geted to subgroups of patients whose clinical course or risk fac- of the test was 94%; the only negative result was observed
tors are particularly suggestive of invasive candidiasis or other with C. famata candidemia [164]. The role of PCR in testing
fungal infection. samples other than blood is not established.

The role of β-D-glucan testing of samples other than serum
in the diagnosis of invasive candidiasis is not established. Stud- Nonculture Diagnostic Testing for Blood Culture–Negative
ies of β-D-glucan testing of CSF reported sensitivity and specif- Invasive Candidiasis
icity of 100% and 95%–98%, respectively, for the diagnosis of The overwhelming majority of studies have examined noncul-
non-Candida fungal CNS infections [156, 157]. β-D-glucan de- ture diagnostics in the setting of candidemia. More limited
tection was highly sensitive and specific in a rabbit model of he- data on deep-seated candidiasis demonstrate how these tests
matogenous C. albicans meningoencephalitis [158]. Limited may identify cases that are currently missed by blood cultures.
data suggest that positive predictive values of β-D-glucan in In a single-center study of prospectively enrolled patients, the
bronchoalveolar lavage fluid are poor for diagnosing fungal sensitivities/specificities of the Fungitell β-D-glucan assay and
pneumonia [159]. There are case reports for testing of samples a real-time quantitative PCR assay (ViraCor-IBT, Lee’s Summit,
collected from other sites of invasive Candida infection [160]. Missouri) for invasive candidiasis were 56%/73% and 80%/70%,
Limited data exist pertaining to the usefulness of β-D-glucan respectively [132]. More importantly, the sensitivities of con-
testing in children [161]. The optimal threshold for positivity of temporaneously collected blood cultures, β-D-glucan assay,
β-D-glucan testing in children is not known. In studies of un- and PCR samples among patients with deep-seated candidiasis
infected immunocompetent individuals, mean β-D-glucan lev- (mostly intra-abdominal candidiasis) were 21%, 67%, and 88%,
els are slightly higher in children than adults [162]. Currently, it respectively. The combination of either a positive blood culture
is not recommended to use β-D-glucan testing to guide pediat- or positive β-D-glucan assay had sensitivity for invasive candi-
ric clinical decision making. diasis of 79%; a positive blood culture or positive PCR sample
was 98% sensitive. A second study investigated the serum β-D-
Polymerase Chain Reaction glucan assay, Candida score (a predictive score for invasive can-
Candida PCR shares many of the potential benefits and short- didiasis based on clinical parameters and burden of Candida
comings of β-D-glucan detection. Compared to cultures, PCR colonization), and Candida colonization indices ( predictive
assays of various blood fractions have been shown to shorten scores based on burden of colonization) among prospectively
the time to diagnosis of invasive candidiasis and initiation of enrolled patients who were in surgical ICUs at 2 hospitals and
antifungal therapy [134, 135]. The pooled sensitivity and specif- who were at particularly high risk for intra-abdominal candidi-
icity of PCR for suspected invasive candidiasis in a recent meta- asis [143]. The sensitivity/specificity of 2 consecutive positive β-
analysis were 95% and 92%, respectively [134]. In probable in- D-glucan results was 65%/78%. In contrast, the sensitivity of
vasive candidiasis, sensitivity of PCR and blood cultures was blood cultures was only 7%. In addition to identifying cases
85% and 38%, respectively. The impact of antifungal agents missed by blood cultures, the β-D-glucan assay was positive a
on diagnostic sensitivity was unclear. Data among patients col- median of 5 and 6 days prior to positive intra-abdominal cul-
onized with Candida were surprisingly limited, but there was a tures and institution of antifungal therapy, respectively. The
trend toward lower specificity. sensitivities of Candida scores and colonization indices were
A major limitation of PCR studies is the lack of standardized comparable to β-D-glucan, but specificities were poorer
methodologies and multicenter validation of assay performance. (≤43%).
The interpretation of specificity in these studies was compli- kg daily) is recommended (strong recommendation; low-
cated by the fact that negative controls were also at risk for in- quality evidence).
vasive candidiasis. Therefore, it is unclear if positive test results 9. Voriconazole 400 mg (6 mg/kg) twice daily for 2 doses, then
for controls were false positives (as defined in the studies) or 200 mg (3 mg/kg) twice daily is effective for candidemia, but
true positives that were missed due to the poor sensitivity of offers little advantage over fluconazole as initial therapy
intra-abdominal and blood cultures. Indeed, this is a central (strong recommendation; moderate-quality evidence). Vorico-
challenge in assessing new diagnostics for invasive candidiasis: nazole is recommended as step-down oral therapy for selected
How can test performance be accurately measured when the cases of candidemia due to C. krusei (strong recommendation;
gold standard is inadequate? low-quality evidence).
10. All nonneutropenic patients with candidemia should have
I. What Is the Treatment for Candidemia in Nonneutropenic Patients? a dilated ophthalmological examination, preferably per-
Recommendations formed by an ophthalmologist, within the first week after di-
1. An echinocandin (caspofungin: loading dose 70 mg, then agnosis (strong recommendation; low-quality evidence).
50 mg daily; micafungin: 100 mg daily; anidulafungin: load- 11. Follow-up blood cultures should be performed every day or
ing dose 200 mg, then 100 mg daily) is recommended as ini- every other day to establish the time point at which candide-
tial therapy (strong recommendation; high-quality evidence). mia has been cleared (strong recommendation; low-quality
2. Fluconazole, intravenous or oral, 800-mg (12 mg/kg) load- evidence).
ing dose, then 400 mg (6 mg/kg) daily is an acceptable alter- 12. Recommended duration of therapy for candidemia without

native to an echinocandin as initial therapy in selected obvious metastatic complications is for 2 weeks after docu-
patients, including those who are not critically ill and who mented clearance of Candida species from the bloodstream
are considered unlikely to have a fluconazole-resistant Can- and resolution of symptoms attributable to candidemia
dida species (strong recommendation; high-quality evidence). (strong recommendation; moderate-quality evidence).
3. Testing for azole susceptibility is recommended for all
bloodstream and other clinically relevant Candida isolates. Evidence Summary
Testing for echinocandin susceptibility should be considered Candidemia has emerged as one of the most common causes of
in patients who have had prior treatment with an echinocan- healthcare-associated bloodstream infections, and in many US
din and among those who have infection with C. glabrata hospitals, candidemia represents the third or fourth most com-
or C. parapsilosis (strong recommendation; low-quality mon hospital-acquired bloodstream isolate. In most clinical set-
evidence). tings, C. albicans is the most commonly isolated species, but the
4. Transition from an echinocandin to fluconazole (usually non-albicans Candida species together represent approximately
within 5–7 days) is recommended for patients who are clin- 50% of the bloodstream isolates, and this has been a growing
ically stable, have isolates that are susceptible to fluconazole trend in many hospitals throughout the world for more than
(eg, C. albicans), and have negative repeat blood cultures fol- a decade [8–12].
lowing initiation of antifungal therapy (strong recommenda- There are significant challenges in treating candidemia and in-
tion; moderate-quality evidence). vasive candidiasis. First, the infection is associated with high
5. For infection due to C. glabrata, transition to higher-dose mortality. Earlier therapy is associated with better overall out-
fluconazole 800 mg (12 mg/kg) daily or voriconazole 200– comes [14–18], but there remain significant limitations to early
300 (3–4 mg/kg) twice daily should only be considered diagnosis. The development of rapid diagnostic assays has been
among patients with fluconazole-susceptible or voricona- slow; thus, clinicians continue to rely on cultures to establish a
zole-susceptible isolates (strong recommendation; low-quality diagnosis [20]. Second, there is considerable geographic, center-
evidence). to-center, and even unit-to-unit variability of species causing
6. Lipid formulation AmB (3–5 mg/kg daily) is a reasonable candidemia [12]; each Candida species presents its own unique
alternative if there is intolerance, limited availability, or resis- challenges with respect to virulence, pathogenicity, and antifun-
tance to other antifungal agents (strong recommendation; gal susceptibility. Third, despite the overall robust nature of the
high-quality evidence). randomized controlled trials examining treatment of candidemia
7. Transition from AmB to fluconazole is recommended after and other forms of invasive candidiasis, no single trial has demon-
5–7 days among patients who have isolates that are suscepti- strated the clear superiority of one therapeutic agent over another
ble to fluconazole, who are clinically stable, and in whom re- [19, 21–34]. Fourth, the recent emergence of multidrug-resistant
peat cultures on antifungal therapy are negative (strong Candida species will complicate the selection of antifungal therapy
recommendation; high-quality evidence). in the immediate future [10, 12, 35–38].
8. Among patients with suspected azole- and echinocandin- The selection of any particular agent for the treatment of
resistant Candida infections, lipid formulation AmB (3–5 mg/ candidemia should take into account a history of recent azole or

echinocandin exposure, a history of intolerance to an antifungal anidulafungin for at least 5 days followed by step-down therapy
agent, the dominant Candida species and current susceptibility to oral fluconazole or voriconazole (if the infecting organism
data in a particular clinical unit, severity of illness, relevant co- was susceptible) when they were clinically stable and blood cul-
morbidities, and evidence of involvement of the CNS, cardiac tures had become negative [34]. There was no difference noted
valves, and/or visceral organs. The risk of mortality among pa- in outcomes among patients who continued on anidulafungin
tients with candidemia ranges from 10% to 47% [6–8, 13], but throughout the treatment course compared with those who
the actual disease-associated mortality is more likely 10%–20%, were changed to an oral azole. Smaller pilot studies from
with the risk of death being related to increasing age, higher Latin America and Asia demonstrated similar findings [33,
Acute Physiology and Chronic Health Evaluation II (APACHE 171]. Thus, on the basis of these data and other clinical trials
II) scores, infecting Candida species, immunosuppressive [22, 23, 25, 26, 28, 33, 34, 171], the Expert Panel favors step-
agents, preexisting renal dysfunction, venous catheter retention, down therapy to fluconazole or voriconazole for patients who
and antifungal selection [8, 19, 165–167]. Early initiation of ef- have improved clinically following initial therapy with an echi-
fective antifungal therapy and source control is critical in the nocandin, have documented clearance of Candida from the
successful treatment of candidemia, as demonstrated by data bloodstream, and who are infected with an organism that is
suggesting significantly higher mortality rates among patients susceptible to fluconazole (eg, C. albicans, C. parapsilosis, and
with candidemia in whom antifungal therapy was delayed or C. tropicalis) or voriconazole (eg, C. krusei). This transition usu-
considered inadequate, and/or in whom source control was ally occurs within 5–7 days, but this time is variable and ulti-
not promptly attained [14, 16–18, 168]. mately dependent on patient response and clinician preference.

The echinocandins demonstrate significant fungicidal activi- In many parts of the world, based on success rates reported
ty against most Candida species, and each of these agents has from well-designed clinical trials, fluconazole remains standard
demonstrated success in approximately 70%–75% of patients therapy for patients with candidemia [21–23, 27]. However, in
in randomized, comparative clinical trials [24–28, 31, 32]. De- light of recent data on the efficacy of echinocandins and increas-
spite the need for intravenous administration, their superb effi- ing resistance to fluconazole, the Expert Panel believes that flu-
cacy, favorable safety profile, limited drug interactions, and conazole should be considered first-line therapy only in patients
concerns about fluconazole resistance have led many experts who are hemodynamically stable, who have had no previous ex-
to favor the echinocandins as initial therapy for most adult pa- posure to azoles, and who do not belong in a group at high risk
tients with candidemia. Few studies comparing different echi- for C. glabrata infection, including those who are elderly, have
nocandins have been performed [28, 169], but most experts underlying malignancy, or are diabetic.
agree that these agents are sufficiently similar to be considered In previous iterations of these guidelines, the Expert Panel fa-
interchangeable. vored fluconazole over an echinocandin for treatment of candi-
Only one study comparing an echinocandin to fluconazole demia due to C. parapsilosis based on reports of decreased in
has been performed, and the results from this study suggest a vitro activity of echinocandins against this species and of echi-
strong trend toward more favorable outcomes with anidulafungin nocandin resistance among some isolates [11, 12, 172–175]. In
compared with fluconazole as primary therapy for candidemia spite of these laboratory observations, there have been no clin-
[27]. In a subanalysis of patients with C. albicans infections, ical studies that have demonstrated superiority of fluconazole
there was a significant improvement in global response among over the echinocandins for the treatment of C. parapsilosis in-
those receiving anidulafungin [31]. In another subanalysis of crit- fections. Moreover, recent observational data from Spain among
ically ill patients from this trial, those receiving anidulafungin had almost 200 patients with candidemia due to C. parapsilosis sug-
significantly better responses at end of therapy compared with gested no difference in outcome among patients who received
fluconazole-treated patients [170]. A combined analysis of 7 of initial treatment with an echinocandin compared with those
the largest randomized clinical trials comparing treatment for who received other regimens [176]. Any recommendation sup-
candidemia and invasive candidiasis and involving almost porting fluconazole over an echinocandin is generally based on
2000 patients found that initial therapy with an echinocandin theoretical concerns rather than on observed therapeutic failure
was a significant predictor of survival [19]. This same analysis of the echinocandins in these patients.
identified higher APACHE II score, older age, and infection Voriconazole was shown to be as effective for candidemia
with C. tropicalis to be associated with worse outcomes and and invasive candidiasis as the comparator regimen of sequen-
higher mortality [19]. tial therapy with AmB for 4–7 days followed by fluconazole
It has become common practice for clinicians treating pa- [23]. Voriconazole possesses activity against most Candida spe-
tients with candidemia to initiate an echinocandin, then change cies, including C. krusei [177, 178], but the need for more fre-
to an oral azole (typically fluconazole) once the patient has be- quent administration, less predictable pharmacokinetics, more
come clinically stable [1]. A recent open-label noncomparative drug interactions, and poor tolerance to the drug make it less
trial assessed outcomes of patients who were treated with attractive for initial therapy. Parenteral voriconazole appears
to be safe when administered to those with baseline renal dys- with candidemia, but the potential benefit of early identifica-
function, despite concerns based on possible nephrotoxicity tion of endophthalmitis and prevention of visual loss far out-
of its vehicle (sulfobutylether β-cyclodextrin) [70]. Voricona- weighs the expense of performing a dilated funduscopic
zole does not provide predictable activity against fluconazole- examination.
resistant C. glabrata [47, 177–179]. It does, however, fill an Follow-up blood cultures every day or every other day until
important niche for patients who have fluconazole-resistant iso- demonstration of clearance of Candida from the bloodstream
lates of C. krusei, C. guilliermondii, or C. glabrata that are vor- are helpful to establish the appropriate duration of antifungal
iconazole susceptible and who are ready for transition from an therapy. If there are no metastatic complications of candidemia,
echinocandin or AmB to oral therapy. the duration of therapy with systemic antifungal agents should be
There is little role for oral itraconazole for the treatment of 14 days following documented clearance of Candida species from
candidemia, given the similar antifungal spectrum, ease of ad- the bloodstream and resolution of signs and symptoms attribut-
ministration, superior pharmacokinetics, and better tolerability able to infection. This recommendation is based on the results of
of fluconazole. Posaconazole has excellent in vitro activity several prospective, randomized trials in which this rule has been
against most Candida species. The extended-release tablet and universally and successfully applied, and it is generally associated
the intravenous formulation could prove useful in the future, with few complications and relapses [21–23, 26–28, 30, 32–34].
but currently there is no role for posaconazole in the treatment
II. Should Central Venous Catheters Be Removed in Nonneutropenic
of candidemia. The broad-spectrum azole isavuconazole dem-
Patients With Candidemia?
onstrates similar in vitro activity against Candida species, as
Recommendation

do voriconazole and posaconazole, and could prove useful in
13. CVCs should be removed as early as possible in the course
the future [180].
of candidemia when the source is presumed to be the CVC
AmB has broad activity against all Candida species with the
and the catheter can be removed safely; this decision should
exception of C. lusitaniae, which is frequently resistant. Lipid
be individualized for each patient (strong recommendation;
formulations of AmB are preferred to AmB deoxycholate and
moderate-quality evidence).
should be considered when there is a history of intolerance to
echinocandins and/or azoles, the infection is refractory to Evidence Summary
other therapy, the organism is resistant to other agents, or Central venous catheters and other intravascular devices are im-
there is a suspicion of infection due to non-Candida yeasts, portant risk factors in the development and persistence of can-
such as Cryptococcus neoformans or Histoplasma capsulatum. didemia in nonneutropenic patients [5, 7–9, 184]. A CVC is
Liposomal AmB, 3 mg/kg daily, has been shown to be as effec- present in at least 70% of nonneutropenic patients with candi-
tive as micafungin for treatment of candidemia [26]. demia at the time that the diagnostic blood culture is obtained
The emergence of echinocandin-resistant and echinocan- [5, 7–9, 170, 184–187]. The relationship of candidemia to CVCs
din-/azole-resistant Candida isolates, especially C. glabrata, has been assumed on the basis of observation, clinical experi-
clearly has been documented, and this finding appears to be as- ence, and an understanding of the role of biofilm in the genesis
sociated with worse clinical outcomes [10, 12, 35–37, 181, 182]. of bloodstream infections [188, 189]. That candidemia in non-
Fluconazole resistance is a frequent finding among echinocan- neutropenic patients is commonly due to contaminated CVCs
din-resistant isolates [9, 10], further complicating therapeutic is undeniable, but there remains controversy as to how best to
choices. There are currently no prospective data to inform a de- distinguish a catheter-associated candidemia from one that is
cision, but the Expert Panel favors lipid formulation AmB for related to another source, such as the gastrointestinal tract.
treatment of patients with candidemia due to proven or suspect- There have been no prospective clinical studies designed to
ed fluconazole and echinocandin-resistant (multidrug resistant) examine CVC management as a primary measurement related
strains until more data become available. to outcome. Moreover, several retrospective analyses have led to
Recent data suggest that as many as 16% of patients with can- very different conclusions regarding the necessity and timing of
didemia have some manifestation of ocular involvement, and CVC removal in the candidemic patient [19, 190–193]. Thus,
some of these patients will develop severe, sight-threatening en- the controversy continues, with some groups arguing for a
dophthalmitis [70]. Thus, for all patients with candidemia, the strictly individualized approach to each patient [190] and others
Expert Panel strongly advises a dilated funduscopic examina- for an approach that removes CVCs in all nonneutropenic can-
tion, preferably performed by an ophthalmologist, within the didemic patients in whom it is safe and feasible to do so [19]. No
first week after initiation of specific antifungal therapy. Some prospective study has demonstrated a survival benefit to early
groups have suggested that it is possible to stratify patients ac- CVC removal in patients who have candidemia, but most stud-
cording to risk in an effort to avoid performing ophthalmologic ies have demonstrated a shorter duration of candidemia and/or
examinations on all candidemic patients [183]. This approach is a trend toward improved outcomes [14, 21–23, 27, 28, 168, 192–
possibly more cost-effective than examining all patients 200]. The recent combined analysis of 7 candidemia trials

observed a survival benefit among those who underwent CVC 20. Recommended minimum duration of therapy for candide-
removal at some time during treatment for candidemia [19]. mia without metastatic complications is 2 weeks after docu-
The survival benefit applied to patients across all levels of se- mented clearance of Candida from the bloodstream, provided
verity of illness as determined by APACHE II scores. neutropenia and symptoms attributable to candidemia have re-
The Expert Panel members strongly believe that CVCs solved (strong recommendation; low-quality evidence).
should be removed if this can be performed safely when candi- 21. Ophthalmological findings of choroidal and vitreal infec-
demia is documented in the nonneutropenic patient. It is intu- tion are minimal until recovery from neutropenia; therefore,
itive that each patient with candidemia must be managed dilated funduscopic examinations should be performed with-
individually with respect to CVC removal or retention, but on in the first week after recovery from neutropenia (strong rec-
balance, the bulk of data supports an approach that leads to ommendation; low-quality evidence).
early removal among nonneutropenic patients in whom the 22. In the neutropenic patient, sources of candidiasis other
catheter is a likely source of infection. than a CVC (eg, gastrointestinal tract) predominate. Catheter
Among neutropenic patients, the role of the gastrointestinal removal should be considered on an individual basis (strong
tract as a source for disseminated candidiasis is evident from recommendation; low-quality evidence).
autopsy studies, but in an individual patient, it is difficult to de- 23. Granulocyte colony-stimulating factor (G-CSF)–mobilized
termine the relative contributions of the gastrointestinal tract vs granulocyte transfusions can be considered in cases of persis-
the CVC as the primary source of candidemia [195, 201]. An tent candidemia with anticipated protracted neutropenia
exception is made for candidemia due to C. parapsilosis, (weak recommendation; low-quality evidence).

which is very frequently associated with CVCs [188, 189, 200,
202]. A recent retrospective analysis that included mostly non- Evidence Summary
neutropenic patients underscored the influence of early CVC Candidemia that develops in neutropenic patients is a life-
removal, specifically among patients with C. parapsilosis blood- threatening infection associated with acute disseminated candi-
stream infection, on clinical outcome [176]. diasis, a sepsis-like syndrome, multiorgan failure, and death.
Outcomes are particularly poor in people with protracted neu-
III. What Is the Treatment for Candidemia in Neutropenic Patients? tropenia, such as that which develops after induction therapy
Recommendations for hematologic malignancies [190, 203, 204]. Candidemia asso-
14. An echinocandin (caspofungin: loading dose 70 mg, then ciated with C. tropicalis is associated with particularly poor out-
50 mg daily; micafungin: 100 mg daily; anidulafungin: loading comes in neutropenic hosts. Chronic disseminated candidiasis
dose 200 mg, then 100 mg daily) is recommended as initial (hepatosplenic candidiasis) can ensue as a complication of can-
therapy (strong recommendation; moderate-quality evidence). didemia in neutropenic patients, especially when patients with
15. Lipid formulation AmB, 3–5 mg/kg daily, is an effective gastrointestinal tract mucositis do not receive antifungal pro-
but less attractive alternative because of the potential for tox- phylaxis. There are no adequately powered randomized con-
icity (strong recommendation; moderate-quality evidence). trolled trials of treatment of candidemia in neutropenic
16. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 patients. The data are largely derived from single-arm studies,
mg (6 mg/kg) daily, is an alternative for patients who are small subsets of randomized controlled studies that have en-
not critically ill and have had no prior azole exposure rolled mostly nonneutropenic patients, and pooled outcomes
(weak recommendation; low-quality evidence). from randomized trials [205, 206].
17. Fluconazole, 400 mg (6 mg/kg) daily, can be used for step- Historically, candidemia in neutropenic patients was treated
down therapy during persistent neutropenia in clinically stable with an AmB formulation. The availability of voriconazole and
patients who have susceptible isolates and documented blood- the echinocandins has led to greater use of these agents, but
stream clearance (weak recommendation; low-quality evidence). without compelling clinical data. The extensive use of flucona-
18. Voriconazole, 400 mg (6 mg/kg) twice daily for 2 doses, zole for prophylaxis to prevent invasive candidiasis in neutrope-
then 200–300 mg (3–4 mg/kg) twice daily, can be used in sit- nic patients and the lack of meaningful prospective data has led
uations in which additional mold coverage is desired (weak to a diminished therapeutic role for this agent among these pa-
recommendation; low-quality evidence). Voriconazole can tients, except for use as maintenance, or step-down therapy
also be used as step-down therapy during neutropenia in after organism species and susceptibilities are obtained in clin-
clinically stable patients who have had documented blood- ically stable patients [207].
stream clearance and isolates that are susceptible to voricona- The numbers of neutropenic patients included in candidemia
zole (weak recommendation; low-quality evidence). treatment studies are small. In these trials, 50% of caspofungin
19. For infections due to C. krusei, an echinocandin, lipid for- recipients vs 40% of AmB deoxycholate recipients [25], 68% of
mulation AmB, or voriconazole is recommended (strong rec- micafungin recipients vs 61% of liposomal AmB recipients [26],
ommendation; low-quality evidence). and 69% of micafungin recipients vs 64% of caspofungin
recipients [28] with neutropenia at onset of therapy were suc- problems. An analysis of 842 patients enrolled in 2 phase 3 treat-
cessfully treated. The randomized controlled trial of anidulafun- ment trials failed to demonstrate significant clinical benefits of
gin vs fluconazole enrolled too few neutropenic patients with catheter removal in multivariable analyses that adjusted for other
candidemia to generate meaningful data regarding efficacy measures of prognostic significance [190]. The Expert Panel sug-
[27]. In 2 retrospective studies, successful outcomes for primary gests that catheter removal should be considered on an individual
treatment of neutropenic patients were reported in 64% of those basis, taking into account feasibility and risk of removal.
receiving AmB deoxycholate, 64% of those receiving flucona- An extremely important factor influencing the outcome of
zole, and 68% of those receiving caspofungin [29, 208]. candidemia in neutropenic patients is the recovery of neutro-
Additional insights can be gleaned from data derived from phils during therapy. In multiple cohort studies of patients
studies of empiric antifungal therapy involving febrile patients with cancer who had candidemia, and pooled analyses of ran-
with neutropenia who had candidemia at baseline. In these stud- domized trials, persistent neutropenia was associated with a
ies, baseline candidemia was cleared in 73% of those treated with greater chance of treatment failure [190, 203, 204, 212]. This
AmB deoxycholate vs 82% of those treated with liposomal AmB has led to improvement of strategies to harvest granulocytes
[209] and in 67% of those treated with caspofungin vs 50% of from donors (including community volunteers), using G-CSF
those treated with liposomal AmB [210]. Data from a large ran- mobilization, which has been shown to be safe and feasible
domized trial also suggest that voriconazole is a reasonable choice [213]. Analysis of subsets of people within phase 1/2 granulo-
for febrile patients with neutropenia and suspected invasive can- cyte infusion studies, retrospective observations, and small co-
didiasis for whom additional mold coverage is desired [211]. hort studies suggest that G-CSF–mobilized granulocyte

A systematic review was conducted to analyze available data transfusions may be of benefit in patients with persistent candi-
generated in treatment trials and empiric therapy trials that en- demia and prolonged neutropenia [213–215]. In a randomized
rolled neutropenic patients [205]. This included 17 trials that ran- controlled trial, granulocyte infusions were associated with few
domized 342 neutropenic patients with documented invasive toxicities, but small numbers of patients in infection subgroups
candidiasis. Pooling of results favored use of nonpolyenes to limited conclusions of efficacy [216]. The panel recommends
AmB-containing comparators. Another pooled analysis that consideration of granulocyte infusions in select situations,
summarized results of treating with micafungin or comparators when such technology is feasible.
(liposomal AmB or caspofungin) for candidemia in the setting
IV. What Is the Treatment for Chronic Disseminated (Hepatosplenic)
of malignancy-associated neutropenia from 2 randomized trials
Candidiasis?
demonstrated success rates ranging from 53% to 85%, but no sig-
Recommendations
nificant differences among treatment groups [206].
24. Initial therapy with lipid formulation AmB, 3–5 mg/kg daily
On the basis of these limited data, the success rates of anti-
OR an echinocandin (micafungin: 100 mg daily; caspofungin:
fungal therapy for candidemia in patients with neutropenia do
70-mg loading dose, then 50 mg daily; or anidulafungin: 200-
not appear to be substantially different from those reported in the
mg loading dose, then 100 mg daily), for several weeks is rec-
large randomized trials of nonneutropenic patients. However, con-
ommended, followed by oral fluconazole, 400 mg (6 mg/kg)
clusions may be limited by significant enrollment bias of selected
daily, for patients who are unlikely to have a fluconazole-
patients. Although these data do not suggest less favorable out-
resistant isolate (strong recommendation; low-quality evidence).
comes associated with fluconazole and voriconazole, many experts
25. Therapy should continue until lesions resolve on repeat
prefer lipid formulation AmB or an echinocandin, which are
imaging, which is usually several months. Premature discon-
fungicidal, as first-line agents. Similar to the approach in nonneu-
tinuation of antifungal therapy can lead to relapse (strong
tropenic patients, the recommended duration of therapy for candi-
recommendation; low-quality evidence).
demia in neutropenic patients is for 14 days after resolution of
26. If chemotherapy or hematopoietic cell transplantation is
attributable signs and symptoms and clearance of the bloodstream
required, it should not be delayed because of the presence of
of Candida species, provided that there has been recovery from
chronic disseminated candidiasis, and antifungal therapy
neutropenia. When neutropenia is protracted, an antifungal drug
should be continued throughout the period of high risk to pre-
should be continued until engraftment. This recommendation is
vent relapse (strong recommendation; low-quality evidence).
based on limited data from prospective randomized trials and
27. For patients who have debilitating persistent fevers, short
has been associated with few complications and relapses [209, 210].
term (1–2 weeks) treatment with nonsteroidal anti-inflam-
The management of intravascular catheters in neutropenic pa-
matory drugs or corticosteroids can be considered (weak rec-
tients with candidemia is less straightforward than in their non-
neutropenic counterparts. Distinguishing gut-associated from
vascular catheter–associated candidemia can be difficult in these Evidence Summary
patients [201]. The data for catheter removal are less compelling, Chronic disseminated candidiasis is an uncommon syn-
and catheter removal often creates significant intravenous access drome seen almost entirely in patients who have hematologic

malignancies and who have just recovered from neutropenia several weeks, given as a tapering dose [232, 233]. However,
[217–219]. Candida albicans is the species most commonly iso- the role of corticosteroids in this disease is still not clear.
lated, but C. tropicalis, C. glabrata, C. krusei, and other Candida
V. What Is the Role of Empiric Treatment for Suspected Invasive
species also have been implicated. Fever, right upper quadrant
Candidiasis in Nonneutropenic Patients in the Intensive Care Unit?
discomfort, nausea, and elevation of liver enzymes occur follow-
Recommendations
ing return of neutrophils and persist for months unless treat-
28. Empiric antifungal therapy should be considered in criti-
ment is initiated. Contrast-enhanced computed tomography
cally ill patients with risk factors for invasive candidiasis and
(CT), magnetic resonance imaging (MRI), positron emission
no other known cause of fever and should be based on clin-
tomography-CT (PET-CT), and sometimes ultrasound have
ical assessment of risk factors, surrogate markers for invasive
all been shown to be useful for diagnosis and for follow-up
candidiasis, and/or culture data from nonsterile sites (strong
[217, 218, 220, 221]. Biopsy of lesions may reveal budding yeasts
recommendation; moderate-quality evidence). Empiric anti-
and hyphae, but organisms may not be seen on biopsy speci-
fungal therapy should be started as soon as possible in pa-
mens and often do not grow in culture, leading some to suggest
tients who have the above risk factors and who have
that chronic disseminated candidiasis represents an immune re-
clinical signs of septic shock (strong recommendation; mod-
constitution syndrome [219].
erate-quality evidence).
Approaches to the treatment of chronic disseminated candi-
29. Preferred empiric therapy for suspected candidiasis in
diasis are based on anecdotal case reports and open-label se-
nonneutropenic patients in the ICU is an echinocandin (cas-
ries. Early experience with AmB was discouraging; as many as
pofungin: loading dose of 70 mg, then 50 mg daily; micafun-

one-third of patients died within 3 months with active infec-
gin: 100 mg daily; anidulafungin: loading dose of 200 mg,
tion, and the overall mortality was 74% [222]. With the use of
then 100 mg daily) (strong recommendation; moderate-
newer antifungal agents, mortality has decreased to 21% over-
quality evidence).
all and is highly linked to relapse of leukemia [223]. Lipid for-
30. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400
mulations of AmB have proved more efficacious, perhaps
mg (6 mg/kg) daily, is an acceptable alternative for patients
related to better tissue concentrations [217, 218, 224, 225]. Flu-
who have had no recent azole exposure and are not colonized
conazole alone or following AmB induction has been shown to
with azole-resistant Candida species (strong recommenda-
be effective [226, 227]. Increasingly, patients are receiving flu-
tion; moderate-quality evidence).
conazole prophylaxis, and thus have an increased risk of devel-
31. Lipid formulation AmB, 3–5 mg/kg daily, is an alternative
oping infection with a fluconazole-resistant organism. In this
if there is intolerance to other antifungal agents (strong rec-
population, a broader-spectrum azole or an echinocandin is
more appropriate therapy. Only a few reports note experience
32. Recommended duration of empiric therapy for suspected
with voriconazole or posaconazole for this condition, but echi-
invasive candidiasis in those patients who improve is 2
nocandins are increasingly used to treat this infection [219,
weeks, the same as for treatment of documented candidemia
223, 228–231].
(weak recommendation; low-quality evidence).
Antifungal therapy should be given until all lesions have re-
33. For patients who have no clinical response to empiric an-
solved radiographically in order to prevent relapse. MRI or
tifungal therapy at 4–5 days and who do not have subsequent
PET-CT appear to be the most sensitive follow-up modalities,
evidence of invasive candidiasis after the start of empiric
but are expensive [220, 221]; standard contrast-enhanced CT
therapy or have a negative non-culture-based diagnostic
is less expensive and is adequate for follow-up. Additional che-
assay with a high negative predictive value, consideration
motherapy and hematopoietic cell transplant should be pursued
should be given to stopping antifungal therapy (strong rec-
when clinically appropriate and not delayed because of candidi-
asis. However, antifungal therapy must be continued during the
period of immunosuppression to prevent relapse of infection Evidence Summary
[219, 223, 228–231]. Candida species are an increasing cause of invasive infection in
There is evidence that this syndrome could possibly be a form nonneutropenic patients in the ICU; half to two-thirds of all ep-
of immune reconstitution and that corticosteroids or anti- isodes of candidemia occur in an ICU [5, 14, 167, 170, 234]. Can-
inflammatory agents might have a role in selected patients. Sev- dida bloodstream infections are associated with increased ICU
eral investigators have reported rapid defervescence and im- and hospital stay [129, 235]. Most estimates of attributable mor-
provement in liver enzyme tests when corticosteroids have tality rates for invasive candidiasis in this setting are 30%–40%
been given in conjunction with antifungal agents [219, 223, [167, 170]. In those patients who have septic shock due to Can-
232, 233]. The dosage of corticosteroids has generally been dida species and who do not have adequate source control or
0.5–1 mg/kg daily of oral prednisone. The duration of steroid antifungal therapy begun within 24 hours, the mortality ap-
treatment, although highly variable, in most cases has been proaches 100% [14]. Prompt initiation of appropriate antifungal
therapy has been associated with as much as a 50% reduction in other forms of invasive candidiasis [132]. Tests using magnet-
mortality [14, 17, 18, 236]. Prompt and appropriate antifungal ic biosensor technology for the rapid detection of Candida
therapy is often delayed because of the relative insensitivity of species from whole-blood samples (T2 Biosystems) are also
blood cultures, the time needed for blood cultures to yield growth, promising [163]. Recommendations for the clinical use of
the possibility of negative blood cultures with invasive abdominal these tests are challenging without robust data in the at-risk
candidiasis, and the lack of specific clinical signs and symptoms. ICU population.
Strategies for initiating empiric antifungal therapy include an Limited clinical studies have evaluated the efficacy of empiric
evaluation of risk factors and use of surrogate markers. strategies. Retrospective studies indicate potential for higher
Optimal utilization of risk factors and colonization status to de- survival when empiric antifungal therapy is given to high-risk
rive clinical scoring systems and the interpretation of non-culture- patients [254]. Prospective clinical trials of empiric antifungal
based diagnostic tests to identify patients with invasive candidiasis therapy in the ICU are difficult to conduct and have yielded
to initiate early empiric antifungal therapy have been the subjects of conflicting results. Selected older studies, including those in
many investigations. Retrospective and single-center studies have specific patient populations, such as those with prior gastroin-
yielded conflicting results, depending on unique patient popula- testinal surgery or bowel perforation, demonstrated potential
tions. Well-designed prospective clinical trials in this area have benefit [255, 256]. In a randomized clinical trial of ICU patients
been difficult to perform, and many unanswered questions remain. at risk for invasive candidiasis and with unexplained fever, em-
Risk factors for development of invasive candidiasis include piric fluconazole (800 mg daily for 14 days) was not associated
Candida colonization, severity of illness, exposure to broad- with better outcomes when compared with placebo [257]. A re-

spectrum antibiotics, recent major surgery, particularly abdom- cent study comparing caspofungin to placebo among ICU pa-
inal surgery, necrotizing pancreatitis, dialysis, parenteral nutri- tients with signs of infection, Candida colonization, and clinical
tion, corticosteroids, and the use of CVCs [237, 238]. Empiric risk factors for invasive candidiasis was stopped prematurely
therapy based solely on colonization with Candida species ap- due to poor patient accrual, confirming the difficulty in con-
pears inadequate [16, 239]. Prospective studies evaluating the ducting these trials [249].
extent of Candida colonization with scores or indices have Widespread use of antifungal agents must be balanced
not been shown to change management, and they are labor in- against the cost, the risk of toxicity, and the emergence of resis-
tensive and expensive [234]. tance. None of the existing clinical trials have been adequately
Several studies have looked at prediction models to identify powered to assess the risk of the emergence of azole or echino-
patients at highest risk. These studies are characterized by candin resistance. Empiric antifungal therapy should be consid-
high specificity, but low sensitivity, thus missing many patients ered in critically ill patients with risk factors for invasive
with candidiasis [240–242]. A subset of postsurgical patients, candidiasis and no other known cause of fever. Preference
particularly those with recurrent gastrointestinal perforation, should be given to an echinocandin in hemodynamically unsta-
anastomotic leaks, or acute necrotizing pancreatitis may be at ble patients, those previously exposed to an azole, and in those
uniquely high risk for candidiasis [238, 240, 243, 244]. The colonized with azole-resistant Candida species. Fluconazole
most important combination of factors in an individual patient may be considered in hemodynamically stable patients who
has not been established. are colonized with azole-susceptible Candida species or who
Surrogate markers that have been evaluated in the ICU set- have no prior exposure to azoles. There are no data guiding
ting include β-D-glucan, mannan-antimannan antibodies, and the appropriate duration of empiric antifungal therapy among
PCR testing. β-D-glucan appears to be more sensitive than Can- patients who have a clinical response to therapy, but it is logical
dida colonization scores or indices, but appears to have low pos- that it should not differ from the treatment of documented can-
itive predictive value [245–248]. False-positive results are a didemia. Conversely, therapy can be stopped after several days
problem, as noted in the Background section. The optimal tim- in the absence of clinical response if cultures and surrogate
ing and number of samples is unknown. In a recent prophylaxis markers are negative.
trial of high-risk ICU patients, β-D-glucan testing performed
twice weekly identified 87% of patients with proven candidiasis VI. Should Prophylaxis Be Used to Prevent Invasive Candidiasis in the
[249]. Small studies basing preemptive therapy on β-D-glucan ICU Setting?
testing suggest that the high negative predictive value of this Recommendations
test could be useful in excluding invasive candidiasis in the 34. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400
ICU setting [151, 248, 250–252]. mg (6 mg/kg) daily, could be used in high-risk patients in
Combined mannan-antimannan testing has variable sensi- adult ICUs with a high rate (>5%) of invasive candidiasis
tivity and specificity [142, 253]. Real-time PCR appears to (weak recommendation; moderate-quality evidence).
have similar sensitivity to β-D-glucan for the diagnosis of 35. An alternative is to give an echinocandin (caspofungin: 70-
candidemia, but may be more sensitive for the diagnosis of mg loading dose, then 50 mg daily; anidulafungin: 200-mg

loading dose and then 100 mg daily; or micafungin: 100 mg importance in the ICU setting. A Cochrane analysis confirmed
daily) (weak recommendation; low-quality evidence). the importance of focusing prophylactic efforts on high-risk pa-
36. Daily bathing of ICU patients with chlorhexidine, which tients, noting that the number needed to treat to prevent one
has been shown to decrease the incidence of bloodstream in- case of invasive candidiasis in the ICU setting varied from 9
fections including candidemia, could be considered (weak in high-risk patients to 188 in low-risk patients [269].
recommendation; moderate-quality evidence). Few data exist on risk factors for candidemia in pediatric in-
tensive care unit (PICU) patients. A population-based, case-
Evidence Summary control study conducted in a large tertiary care pediatric center
Time to appropriate therapy in candidemia appears to have a sig- found an incidence of candidemia of 3.5 per 1000 PICU admis-
nificant impact on the outcome of patients with this infection [14, sions [270]. The presence of a CVC, a diagnosis of malignancy,
17, 18]. However, insensitivity and significant delays using culture and receipt of either vancomycin or an antianaerobic antimi-
techniques, as well as limitations of rapid diagnostic tests, remain crobial agent for >3 days were independently associated with
for this common cause of bloodstream infection among patients the development of candidemia. Children who had ≥3 of
in the ICU [258, 259]. A safe and effective prophylactic strategy to these risk factors in different combinations had a predicted
prevent candidemia among high-risk patients could be of great probability of developing candidemia of between 10% and 46%.
benefit [260]. The approach to prophylaxis has been either Data are accruing on the use of skin decolonization with an-
broad, in which all patients within the ICU setting are treated tiseptic agents in the ICU to decrease bloodstream infections,
[261, 262], or selective, in which only specific high-risk groups including those caused by Candida species [271–274]. Several

of patients are targeted for prophylaxis [249, 263, 264]. multicenter randomized clinical trials have shown that daily
For ICUs that show very high rates of invasive candidiasis, in bathing of ICU patients with chlorhexidine decreases the inci-
excess of the expected rates of <5% of patients, antifungal pro- dence of both catheter-associated and non-catheter-associated
phylaxis may be warranted in selected patients who are at high- hospital-acquired bloodstream infections [271–273]. These
est risk [260]. Two randomized, placebo-controlled trials have studies were aimed primarily at evaluating the impact on
shown a reduction in the incidence of invasive candidiasis in multidrug-resistant bacterial infections and provide few data
single units or single hospitals when fluconazole prophylaxis on Candida infections. However, at least one of these trials
was used broadly in the ICU; one study targeted all patients found a significant reduction in catheter associated Candida
in a surgical ICU [262] and, in the other, all patients receiving bloodstream infections [272]. A meta-analysis on the effects
mechanical ventilation [261]. In both studies, Candida urinary of daily chlorhexidine bathing included 10 studies performed
tract infections, as well as invasive candidiasis and candidemia, in an ICU setting, only one of which was a randomized con-
were included as endpoints. trolled trial. The conclusion was that chlorhexidine bathing re-
In a blinded placebo-controlled trial that enrolled a small duced the incidence of bloodstream infections, including
number of patients, fluconazole prophylaxis was shown to de- catheter-associated bacterial infections [274]. Although not
crease Candida intra-abdominal infections in high-risk patients proven to prevent candidemia, there is little risk to the use of
in the surgical ICU [263]. A noncomparative, open-label trial chlorhexidine in ICU patients, and this practice may prove
using caspofungin prophylaxis in a small number of similar beneficial.
high-risk surgical patients also showed benefit [264]. A recent
VII. What Is the Treatment for Neonatal Candidiasis, Including Central
multicenter placebo-controlled, blinded clinical trial of caspo-
Nervous System Infection?
fungin prophylaxis targeting only those ICU patients who
What Is the Treatment for Neonatal Invasive Candidiasis and
met specific criteria for high risk for invasive candidiasis
Candidemia?
showed a trend toward reduction of invasive candidiasis, but
was limited by the sample size [249]. Recommendations
Several meta-analyses have assessed the issue of fluconazole 37. AmB deoxycholate, 1 mg/kg daily, is recommended for ne-
prophylaxis in ICU patients [265–268]. Not surprisingly, there onates with disseminated candidiasis (strong recommenda-
were methodological differences among the studies, and there tion; moderate-quality evidence).
was variation among the study populations. All 4 meta-analyses 38. Fluconazole, 12 mg/kg intravenous or oral daily, is a rea-
showed that fluconazole prophylaxis was associated with a re- sonable alternative in patients who have not been on flucon-
duction in invasive candidiasis, but only 2 showed a reduction in azole prophylaxis (strong recommendation; moderate-quality
candidemia [267, 268]. Importantly, only one analysis showed a evidence).
reduction in mortality from invasive candidiasis [268]. None of 39. Lipid formulation AmB, 3–5 mg/kg daily, is an alternative,
the meta-analyses assessed the issues of adverse effects of anti- but should be used with caution, particularly in the presence
fungal agents, the emergence of resistance to fluconazole, or of urinary tract involvement (weak recommendation; low-
major ecological shifts in Candida species, topics of great quality evidence).
40. Echinocandins should be used with caution and generally Extremely low-birth-weight infants with candiduria are at a
limited to salvage therapy or to situations in which resistance substantial risk of death or neurodevelopmental impairment.
or toxicity preclude the use of AmB deoxycholate or flucon- Candiduria in this population should prompt an evaluation
azole (weak recommendation; low-quality evidence). (blood cultures, lumbar puncture, and abdominal ultrasound)
41. A lumbar puncture and a dilated retinal examination are for disseminated Candida infection and warrants treatment.
recommended in neonates with cultures positive for Candida The recommendation to treat neonatal candidiasis with AmB
species from blood and/or urine (strong recommendation; deoxycholate or fluconazole is based on small, single-center tri-
low-quality evidence). als and 2 multicenter cohort studies [279, 289–291]. In contrast
42. CT or ultrasound imaging of the genitourinary tract, liver, to adults and older children, AmB deoxycholate is well tolerated
and spleen should be performed if blood cultures are persis- in neonates and does not seem to be associated with a high risk
tently positive for Candida species (strong recommendation; for nephrotoxicity. A recent comparative effectiveness study
low-quality evidence). found that neonates treated with AmB lipid formulations had
43. CVC removal is strongly recommended (strong recommen- higher mortality than infants treated with AmB deoxycholate
dation; moderate-quality evidence). or fluconazole [291]. The difference in outcomes seen with
44. The recommended duration of therapy for candidemia lipid AmB formulations may be related to inadequate penetra-
without obvious metastatic complications is for 2 weeks tion of these drugs into the kidneys, inadequate dosing for pre-
after documented clearance of Candida species from the mature neonates, or unknown confounders. Based on the
bloodstream and resolution of signs attributable to candide- current evidence, fluconazole and AmB deoxycholate are accept-

mia (strong recommendation; low-quality evidence). able choices for therapy, and lipid formulations of AmB should
be used with caution. There are few data on the use of echino-
Evidence Summary candins in neonates. There are concerns with echinocandins be-
Neonatal candidiasis occurs predominately in the neonatal inten- cause concentrations in the CNS and in the urinary tract are low.
sive care unit (NICU). Candida species are the third most com- Dosing of antifungal agents is substantially different for ne-
mon pathogen associated with bloodstream infection in NICUs onates than it is for older children and adults. Limited pharma-
in the United States [275]. However, the incidence of neonatal cokinetic data exist regarding dosing of AmB deoxycholate in
candidiasis has decreased dramatically over the past decade neonates, and the pharmacokinetics appear to be highly vari-
[276–278]. Neonatal candidiasis is associated with significant able in this population [96, 97, 101]. The recommended dose
risk of death, neurodevelopmental impairment in extremely of 1 mg/kg daily results in higher estimates of clearance in in-
low-birth-weight infants who weigh ≤1000 g, and increased fants compared with older children and may partially explain
healthcare costs [279–284]. The primary risk factor for neonatal why the drug is better tolerated in neonates [98]. The duration
candidiasis is prematurity with those neonates who have an ex- of therapy is based primarily on adult and pediatric data, and
tremely low birth weight at greatest risk. These infants are at high there are no data to guide duration specifically in neonates.
risk to have CNS involvement as a complication of candidemia Population pharmacokinetic studies have provided dosing in-
[285, 286]. Candida albicans and C. parapsilosis account for formation for fluconazole in the neonatal population [105, 292].
80%–90% of neonatal invasive candidiasis [278, 287]. Based on these studies, fluconazole, 12/mg/kg daily, can be used
Neonatal candidiasis differs from invasive disease in older pa- to treat neonatal candidiasis. More recent data suggest that a
tients in that neonates are more likely to present with nonspecific loading dose of fluconazole of 25 mg/kg achieves the therapeu-
or subtle signs and symptoms of infection. Candida species in- tic target more rapidly than traditional dosing [292]. However,
vade virtually all tissues, including the retina, brain, heart, lung, further studies of this dosing scheme are required before it can
liver, spleen, and joints [288]. Endocarditis is an uncommon com- be recommended. Failure to promptly remove or replace CVCs
plication of candidiasis in neonates. Although meningitis is seen in infants with candidemia places the infant at increased risk of
frequently in association with candidemia, approximately half of prolonged infection, mortality, and long-term irreversible neu-
neonates with Candida meningitis do not have a positive blood rodevelopmental impairment [198, 279]. Removal and replace-
culture [285]. CNS disease in the neonate typically manifests as ment of the catheter at an anatomically distinct site should be
meningoencephalitis and should be assumed to be present in performed unless contraindicated.
the neonate who has candidemia and signs and symptoms sug- What Is the Treatment for Central Nervous System Infections
gesting meningoencephalitis, as CSF findings of Candida infec- in Neonates?
tion may be unreliable. Neurodevelopmental impairment is
common in survivors; therefore, careful follow-up of neurodeve- Recommendations
lopmental parameters is important [279, 281, 282, 284]. 45. For initial treatment, AmB deoxycholate, 1 mg/kg intrave-
Recent studies have highlighted the significance of candiduria nous daily, is recommended (strong recommendation; low-
in the absence of candidemia in this population [281]. quality evidence).

46. An alternative regimen is liposomal AmB, 5 mg/kg daily Recommendations
(strong recommendation; low-quality evidence). 51. In nurseries with high rates (>10%) of invasive candidia-
47. The addition of flucytosine, 25 mg/kg 4 times daily, may be sis, intravenous or oral fluconazole prophylaxis, 3–6 mg/kg
considered as salvage therapy in patients who have not had a twice weekly for 6 weeks, in neonates with birth weights
clinical response to initial AmB therapy, but adverse effects <1000 g is recommended (strong recommendation; high-
are frequent (weak recommendation; low-quality evidence). quality evidence).
48. For step-down treatment after the patient has responded to 52. Oral nystatin, 100 000 units 3 times daily for 6 weeks, is an
initial treatment, fluconazole, 12 mg/kg daily, is recommend- alternative to fluconazole in neonates with birth weights
ed for isolates that are susceptible to fluconazole (strong rec- <1500 g in situations in which availability or resistance pre-
ommendation; low-quality evidence). clude the use of fluconazole (weak recommendation; moder-
49. Therapy should continue until all signs, symptoms, and ate-quality evidence).
CSF and radiological abnormalities, if present, have resolved 53. Oral bovine lactoferrin (100 mg/day) may be effective in
(strong recommendation; low-quality evidence). neonates <1500 g but is not currently available in US hospi-
50. Infected CNS devices, including ventriculostomy drains tals (weak recommendation; moderate-quality evidence).
and shunts, should be removed if at all possible (strong rec-
ommendation; low-quality evidence). Evidence Summary
Numerous studies examining fluconazole prophylaxis for the
Evidence Summary prevention of invasive candidiasis in neonates have consistent-

There are limited data to guide therapy for CNS Candida infec- ly demonstrated efficacy and possibly reduced mortality [300–
tions in the neonate. All AmB preparations, including the lipid 310]. Fluconazole, 3 mg/kg or 6 mg/kg twice weekly, signifi-
formulations, penetrate the CNS and have fungicidal activity in cantly reduced rates of invasive candidiasis in premature
the CNS [44]. AmB deoxycholate and liposomal AmB were neonates weighing <1000 g in nurseries with a very high inci-
found to have greater antifungal efficacy when studied in a rab- dence of Candida infections [300, 302]. A 2007 Cochrane
bit model of Candida meningoencephalitis compared with the review of clinical trials of fluconazole prophylaxis demonstrat-
other formulations [44]. The clinician must weigh the benefits ed efficacy, with a typical relative risk of 0.23 and number
and drawbacks of using liposomal AmB with its good CSF pen- needed to treat of 9. The number needed to treat varied sub-
etration but poor urine levels vs using AmB deoxycholate with stantially depending on the incidence of invasive candidiasis
less good CSF levels but better urine levels. in a particular ICU. The majority of studies have demonstrated
The benefit of adding flucytosine for neonates with CNS can- the safety of fluconazole prophylaxis and lack of emergence of
didiasis is uncertain. In the largest prospective study evaluating resistance.
treatment outcomes of CNS candidiasis in neonates, the median Enteral or orally administered nystatin has been shown to be
time to clear CSF was longer for those who received flucytosine effective in reducing invasive candidiasis in preterm infants
plus AmB deoxycholate (17.5 days; 6 infants), compared with [303, 311–313]. In one study, nystatin prophylaxis was also as-
those who received only AmB deoxycholate (6 days; 18 infants) sociated with a reduction in all-cause mortality [313]. However,
[279]. In addition, flucytosine is poorly tolerated, and gastroin- there remains a paucity of data on nystatin prophylaxis in in-
testinal side effects may hinder oral feeding in neonates. In ge- fants <750 grams (the group at highest risk), and nystatin
neral, flucytosine is used only in neonates who have not may not always be able to be administered when there is an
responded to AmB alone. ileus, gastrointestinal disease, feeding intolerance, or hemody-
Data supporting the use of echinocandins in neonates are namic instability. These clinical situations are very common
emerging; however, several key issues require further clarifica- in low-gestational-age premature infants and limit the broad
tion. The optimal dose of echinocandins in neonates remains applicability of nystatin prophylaxis as a preventive strategy.
uncertain [109, 284, 293–297]. Furthermore, there are concerns Lactoferrin is a mammalian milk glycoprotein involved in in-
regarding the penetration of echinocandins into the CSF. Echi- nate immunity. In a randomized trial of bovine lactoferrin in
nocandins appear to penetrate brain tissue, but not the CSF, and infants <1500 g, the incidence of late-onset sepsis was signifi-
achieve concentrations in brain shown to be effective in animal cantly lower in the lactoferrin group than in the placebo
models when dosages higher than those recommended for hu- group [314]. A secondary analysis of the clinical trial showed
mans have been used [298, 299]. Limited clinical data suggest that lactoferrin also reduced the incidence of invasive fungal in-
that the echinocandins may be effective for the treatment of fections compared with placebo [314]. Further confirmation of
CNS infections in neonates, but are not adequate to recommend the efficacy and safety of oral bovine lactoferrin for the preven-
their use at this time [293]. tion of invasive candidiasis is needed, especially in infants <750
What Are the Recommendations for Prophylaxis in the Neo- g, because there were only a few neonates in this category in this
natal Intensive Care Unit Setting? trial.
VIII. What Is the Treatment for Intra-abdominal Candidiasis? value for distinguishing colonization from intra-abdominal in-
Recommendations vasive candidiasis and performed better than Candida coloniza-
54. Empiric antifungal therapy should be considered for pa- tion scores or indices [143].
tients with clinical evidence of intra-abdominal infection Clinical evidence for the use of antifungal therapy for pa-
and significant risk factors for candidiasis, including recent tients with suspected intra-abdominal invasive candidiasis is
abdominal surgery, anastomotic leaks, or necrotizing pancre- limited. Most studies are small, uncontrolled, single-center, or
atitis (strong recommendation; moderate-quality evidence). performed in specific populations. Patients who have Candida
55. Treatment of intra-abdominal candidiasis should include species isolated from normally sterile abdominal cultures or
source control, with appropriate drainage and/or debride- drains placed within 24 hours and who have clinical evidence
ment (strong recommendation; moderate-quality evidence). of infection should be treated for intra-abdominal candidiasis.
56. The choice of antifungal therapy is the same as for the Patients who have had gastroduodenal perforations, anastomot-
treatment of candidemia or empiric therapy for nonneutro- ic leaks, necrotizing pancreatitis, or other intra-abdominal
penic patients in the ICU (See sections I and V) (strong rec- events without the isolation of Candida species and who are
ommendation; moderate-quality evidence). doing poorly despite treatment for bacterial infections may ben-
57. The duration of therapy should be determined by adequacy efit from empiric antifungal therapy. Several meta-analyses of
of source control and clinical response (strong recommenda- antifungal prophylaxis in high-risk surgical ICU patients have
tion; low-quality evidence). yielded conflicting results [265–268].
Source control with adequate drainage and/or debridement is

Evidence Summary an important part of therapy of intra-abdominal candidiasis
Intra-abdominal candidiasis in patients who have had recent [14]. The choice of antifungal agent should be guided by the
abdominal surgery or intra-abdominal events refers to a hetero- Candida species isolated and knowledge of the local epidemiol-
geneous group of infections that includes peritonitis, abdominal ogy, including antifungal susceptibility patterns. Duration of
abscess, and purulent or necrotic infection at sites of gastroin- antifungal therapy should be guided by clinical response and
testinal perforation or anastomotic leak. Up to 40% of patients the adequacy of source control.
with secondary or tertiary peritonitis, as defined by a multina-
IX. Does the Isolation of Candida Species From the Respiratory Tract
tional consensus panel, may develop intra-abdominal candidi-
Require Antifungal Therapy?
asis with a high mortality rate [243, 244, 315, 316]. A subset of
Recommendation
postsurgical patients, particularly those with recurrent gastro-
58. Growth of Candida from respiratory secretions usually
duodenal perforation, anastomotic leaks, or acute necrotizing
indicates colonization and rarely requires treatment with anti-
pancreatitis, are at uniquely high risk for invasive candidiasis
fungal therapy (strong recommendation; moderate-quality
[243, 244, 263, 316–320]. In other settings, such as perforated
evidence).
appendicitis, invasive candidiasis appears to be a rare complica-
tion [316, 319]. Infections are often polymicrobial, with yeast Evidence Summary
noted in as high as 20% of all cases and 40% in patients with The isolation of Candida species from the respiratory tract is
a recent gastroduodenal perforation [319, 320]. commonly encountered among patients who are in the ICU
Diagnosis is hampered by the lack of specific clinical signs and and are intubated or have a chronic tracheostomy. This almost
symptoms. Blood cultures are often negative [321]. A laboratory always reflects colonization of the airways and not infection.
report of yeast isolated from an abdominal specimen must be Candida pneumonia and lung abscess are very uncommon
evaluated to distinguish between contamination, colonization, [322, 323]. Only rarely after aspiration of oropharyngeal mate-
and invasive infection. Swabs of superficial wounds and speci- rial has primary Candida pneumonia or abscess been docu-
mens taken from intra-abdominal catheters that have been in mented [324, 325]. Pneumonia due to Candida species is
place for >24 hours do not provide useful information and generally limited to severely immunocompromised patients
should not be performed. In contrast, the presence of yeast ob- who develop infection following hematogenous spread to the
tained from normally sterile intra-abdominal specimens (opera- lungs. CT scan of the thorax usually shows multiple pulmonary
tive room specimens, and/or drains that have been placed within nodules. Isolation of Candida species from respiratory samples
24 hours) in patients with clinical evidence for infection should in a patient who is severely immunosuppressed should trigger a
be considered indicative of intra-abdominal candidiasis. search for evidence of invasive candidiasis.
The role of surrogate markers and Candida risk scores in this Although the diagnosis of Candida pneumonia is supported
setting has not been established. There are limited data on the by isolation of the organism from a bronchoalveolar lavage
utility of using β-D-glucan in postsurgical patients with suspect- (BAL) specimen, a firm diagnosis requires histopathological evi-
ed intra-abdominal candidiasis. In one study, β-D-glucan had a dence of invasive disease. Multiple prospective and retrospective
72% positive predictive value and an 80% negative predictive autopsy studies consistently demonstrate the poor predictive

value of the growth of Candida from respiratory secretions, in- Evidence Summary
cluding BAL fluid [326–328]. In one prospective study, none of The incidence of Candida endocarditis has increased concurrent
77 patients who died in an ICU and who had clinical and radio- with the general increase in Candida infections [337]. Endocardi-
logic evidence of pneumonia and a positive culture for Candida tis should be suspected when blood cultures are persistently pos-
species from BAL or sputum demonstrated evidence of Candida itive, when a patient with candidemia has persistent fever despite
pneumonia at autopsy [328]. Because of the rarity of Candida appropriate treatment, or when a new heart murmur, heart fail-
pneumonia, the extremely common finding of Candida in respi- ure, or embolic phenomena occur in the setting of candidemia
ratory secretions, and the lack of specificity of this finding [329– [338]. Most cases occur following cardiac valvular surgery, but
331], a decision to initiate antifungal therapy should not be made other risk factors include injection drug use, cancer chemothera-
on the basis of respiratory tract culture results alone. py, prolonged presence of CVCs, and prior bacterial endocarditis.
Recent observations suggest that colonization of the airway The signs, symptoms, and complications are generally similar to
with Candida species is associated with the development of bac- those of bacterial endocarditis, except for the frequent occurrence
terial colonization and pneumonia [332–336]. Candida airway of large emboli to major vessels. Cases are fairly evenly divided
colonization was also associated with worse clinical outcomes between C. albicans and non-albicans Candida species [339].
and higher mortality in these studies. However, it is not clear Medical therapy of Candida endocarditis has occasionally
if Candida airway colonization has a causal relationship to been curative [340–348], but the optimum therapy for both na-
poorer outcomes or is simply a marker of disease severity. tive and prosthetic valve endocarditis in adults is a combination
of valve replacement and a long course of antifungal therapy

X. What Is the Treatment for Candida Intravascular Infections, Including
Endocarditis and Infections of Implantable Cardiac Devices? based on case reports, case series, cohort studies, a meta-
What Is the Treatment for Candida Endocarditis? analysis, and clinical experience [339, 349]. Valve repair and ve-
getectomy are alternatives to valve replacement. Most of the
Recommendations cases reported in the literature have been treated with AmB de-
59. For native valve endocarditis, lipid formulation AmB, 3–5 oxycholate, with or without flucytosine [339, 342, 349–355].
mg/kg daily, with or without flucytosine, 25 mg/kg 4 times Fluconazole monotherapy is associated with an unacceptably
daily, OR high-dose echinocandin (caspofungin 150 mg daily, high rate of relapse and mortality [354]. However, fluconazole
micafungin 150 mg daily, or anidulafungin 200 mg daily) is is useful for step-down therapy.
recommended for initial therapy (strong recommendation; AmB deoxycholate and azoles have decreased activity when
low-quality evidence). compared with echinocandins against biofilms formed by Candi-
60. Step-down therapy to fluconazole, 400–800 mg (6–12 mg/ da in vitro, and they penetrate poorly into vegetations. Echinocan-
kg) daily, is recommended for patients who have flucona- dins and lipid formulations of AmB demonstrate more potent
zole-susceptible Candida isolates, have demonstrated clinical activity against Candida biofilms [356]. A prospective, open-
stability, and have cleared Candida from the bloodstream label clinical trial, cohort studies, and several case reports show
(strong recommendation; low-quality evidence). a role for the echinocandins in the treatment of endocarditis
61. Oral voriconazole, 200–300 mg (3–4 mg/kg) twice daily, or [228, 346, 348, 357–365]. Higher dosages of the echinocandins
posaconazole tablets, 300 mg daily, can be used as step-down are thought to be necessary to treat endocarditis [228, 365]. Cas-
therapy for isolates that are susceptible to those agents but pofungin has been used as monotherapy and in combination with
not susceptible to fluconazole (weak recommendation; very AmB, azoles, or flucytosine in single case reports, but data are lim-
low-quality evidence). ited for the other echinocandins [346, 360, 361, 363, 365, 366].
62. Valve replacement is recommended; treatment should con- Lifelong suppressive therapy with fluconazole has been used
tinue for at least 6 weeks after surgery and for a longer duration successfully after a course of primary therapy in patients for
in patients with perivalvular abscesses and other complications whom cardiac surgery is contraindicated; it has also been advo-
(strong recommendation; low-quality evidence). cated to prevent late recurrence of Candida prosthetic valve en-
63. For patients who cannot undergo valve replacement, long- docarditis [360, 367, 368]. Because Candida endocarditis has a
term suppression with fluconazole, 400–800 mg (6–12 mg/ propensity to relapse months to years later, follow-up should be
kg) daily, if the isolate is susceptible, is recommended (strong maintained for several years after treatment [350, 351].
recommendation; low-quality evidence). What Is the Treatment for Candida Infection of Implantable
64. For prosthetic valve endocarditis, the same antifungal reg- Cardiac Devices?
imens suggested for native valve endocarditis are recom-
mended (strong recommendation; low-quality evidence). Recommendations
Chronic suppressive antifungal therapy with fluconazole, 65. For pacemaker and implantable cardiac defibrillator infec-
400–800 mg (6–12 mg/kg) daily, is recommended to prevent tions, the entire device should be removed (strong recommen-
recurrence (strong recommendation; low-quality evidence). dation; moderate-quality evidence).
66. Antifungal therapy is the same as that recommended for Evidence Summary
native valve endocarditis (strong recommendation; low- Most experience treating suppurative thrombophlebitis has
quality evidence). been with AmB deoxycholate. Fluconazole and caspofungin
67. For infections limited to generator pockets, 4 weeks of an- have also been successful in some cases [379–381], but other
tifungal therapy after removal of the device is recommended agents used for primary treatment of candidemia, including
(strong recommendation; low-quality evidence). echinocandins and voriconazole, should be effective [382].
68. For infections involving the wires, at least 6 weeks of anti- Higher-than-usual doses of echinocandins should be used, sim-
fungal therapy after wire removal is recommended (strong ilar to therapy for endocarditis.
recommendation; low-quality evidence). Surgical excision of the vein plays an important role in the
69. For ventricular assist devices that cannot be removed, the treatment of peripheral-vein Candida thrombophlebitis. When
antifungal regimen is the same as that recommended for na- a central vein is involved, surgery is usually not an option. In
tive valve endocarditis (strong recommendation; low-quality some cases, systemic anticoagulation or thrombolytic therapy
evidence). Chronic suppressive therapy with fluconazole, if has been used as adjunctive therapy, but there are insufficient
the isolate is susceptible, for as long as the device remains in data to recommend their use. Thrombolytic therapy, in con-
place is recommended (strong recommendation; low-quality junction with antifungal therapy, has been used successfully
evidence). in the management of an infected thrombus attached to a
CVC in a patient with persistent candidemia [381].
Evidence Summary

There are a few case reports and a single retrospective review of XI. What Is the Treatment for Candida Osteoarticular Infections?
Candida infections of pacemakers and cardiac defibrillators What Is the Treatment for Candida Osteomyelitis?
[369–374]. The entire device should be removed and antifungal
therapy given for 4–6 weeks depending on whether the infec- Recommendations
tion involves the wires in addition to the generator pocket 74. Fluconazole, 400 mg (6 mg/kg) daily, for 6–12 months OR
[369, 371–374]. Medical therapy alone has failed [370]. an echinocandin (caspofungin 50–70 mg daily, micafungin
There are isolated case reports and a few case series on Can- 100 mg daily, or anidulafungin 100 mg daily) for at least 2
dida infections of ventricular assist devices [375–378]. The Ex- weeks followed by fluconazole, 400 mg (6 mg/kg) daily, for
pert Panel believes that suppressive azole therapy after a full 6–12 months is recommended (strong recommendation;
course of initial antifungal therapy is warranted. Many of low-quality evidence).
these devices cannot be removed and suppression will be life- 75. Lipid formulation AmB, 3–5 mg/kg daily, for at least 2
long. The role of antifungal prophylaxis to prevent infection weeks followed by fluconazole, 400 mg (6 mg/kg) daily, for
in all patients receiving an assist device remains controversial 6–12 months is a less attractive alternative (weak recommen-
[378]. dation; low-quality evidence).
What Is the Treatment for Candida Suppurative 76. Surgical debridement is recommended in selected cases
Thrombophlebitis? (strong recommendation; low-quality evidence).
Recommendations Evidence Summary

70. Catheter removal and incision and drainage or resection of Most patients with osteomyelitis present with a subacute to
the vein, if feasible, is recommended (strong recommenda- chronic course [383, 384]. The most common mechanism of in-
tion; low-quality evidence). fection is hematogenous dissemination, but direct inoculation
71. Lipid formulation AmB, 3–5 mg/kg daily, OR fluconazole, and contiguous spread of infection also occur. Involvement of
400–800 mg (6–12 mg/kg) daily, OR an echinocandin (cas- 2 or more bones is common, and therefore, when a single focus
pofungin 150 mg daily, micafungin 150 mg daily, or anidu- of infection is identified, there should be a search for other sites
lafungin 200 mg daily) for at least 2 weeks after candidemia of involvement. The axial skeleton, especially the spine, is the
(if present) has cleared is recommended (strong recommen- most common site of involvement in adults; in children, the
dation; low-quality evidence). long bones are more commonly involved [228, 384–388]. Nei-
72. Step-down therapy to fluconazole, 400–800 mg (6–12 mg/ ther the clinical picture nor the findings on radiographic imag-
kg) daily, should be considered for patients who have initially ing are specific for Candida infection. Candida albicans remains
responded to AmB or an echinocandin, are clinically stable, the dominant pathogen. However, 2 retrospective reviews of a
and have a fluconazole-susceptible isolate (strong recommen- large number of cases found that non-albicans Candida were
dation; low-quality evidence). an increasingly frequent cause of Candida osteomyelitis and
73. Resolution of the thrombus can be used as evidence to dis- mixed infections with bacteria, especially Staphylococcus aure-
continue antifungal therapy if clinical and culture data are us, were not uncommon, underscoring the need for biopsy and
supportive (strong recommendation; low-quality evidence). culture [384, 389].

Treatment recommendations are based on case reports and Evidence Summary
case series. Historically, AmB deoxycholate has been the most Adequate drainage is critical to successful therapy of Candida ar-
commonly used agent [388]. Recent literature favors the use thritis. In particular, Candida arthritis of the hip requires open
of fluconazole or an echinocandin over AmB [228, 384–386]. surgical drainage. Case reports have documented cures with
Fluconazole has been used successfully as initial therapy AmB, fluconazole, and caspofungin therapy in combination
for patients who have susceptible isolates, but treatment with adequate drainage [400–402]. Administration of either
failures have also been reported [390–393]. There are case AmB or fluconazole produces substantial synovial fluid levels, so
reports of the successful treatment of osteomyelitis with that intra-articular injection of antifungal agents is not necessary.
itraconazole, voriconazole, posaconazole, and caspofungin Candida prosthetic joint infection generally requires resec-
[228, 229, 394–396]. tion arthroplasty, although success with medical therapy alone
Cure rates appear to be significantly higher when an antifun- has been described rarely [403, 404]. The combination of re-
gal agent is administered for at least 6 months [384, 385]. The moval and reimplantation of the prosthesis in 2 stages separated
addition of AmB deoxycholate or fluconazole to bone cement by 3–6 months and a prolonged period of antifungal therapy for
has been suggested to be of value as adjunctive therapy in com- at least 12 weeks after the resection arthroplasty and at least 6
plicated cases and appears to be safe, but this practice is contro- weeks after prosthesis implantation is suggested on the basis
versial [397, 398]. of limited data [405–407]. The efficacy of antifungal-loaded ce-
Surgical debridement is frequently performed in conjunction ment spacers is controversial [408]. If the prosthetic device can-
with antifungal therapy. Some reports have found surgical ther- not be removed, chronic suppression with an antifungal agent,

apy important for Candida vertebral osteomyelitis [387], but usually fluconazole, is necessary.
others have not found that to be the case [388]. Surgery is indi-
cated in patients who have neurological deficits, spinal instabil- XII. What Is the Treatment for Candida Endophthalmitis?
ity, large abscesses, or persistent or worsening symptoms during What Is the General Approach to Candida Endophthalmitis?
therapy [384].
Recommendations
On the basis of a small number of cases, Candida mediasti-
82. All patients with candidemia should have a dilated retinal
nitis and sternal osteomyelitis in patients who have undergone
examination, preferably performed by an ophthalmologist,
sternotomy can be treated successfully with surgical debride-
within the first week of therapy in nonneutropenic patients
ment followed by either AmB or fluconazole [391, 399]. Irriga-
to establish if endophthalmitis is present (strong recommen-
tion of the mediastinal space with AmB is not recommended,
dation; low-quality evidence). For neutropenic patients, it is
because it can cause irritation. Antifungal therapy of several
recommended to delay the examination until neutrophil re-
months’ duration, similar to that needed for osteomyelitis at
covery (strong recommendation; low-quality evidence).
other sites, is appropriate.
83. The extent of ocular infection (chorioretinitis with or with-
What Is the Treatment for Candida Septic Arthritis?
out macular involvement and with or without vitritis) should
be determined by an ophthalmologist (strong recommenda-
77. Fluconazole, 400 mg (6 mg/kg) daily, for 6 weeks OR an
tion; low-quality evidence).
echinocandin (caspofungin 50–70 mg daily, micafungin
84. Decisions regarding antifungal treatment and surgical in-
100 mg daily, or anidulafungin 100 mg daily) for 2 weeks
tervention should be made jointly by an ophthalmologist and
followed by fluconazole, 400 mg (6 mg/kg) daily, for at least
an infectious diseases physician (strong recommendation;
4 weeks is recommended (strong recommendation; low-
low-quality evidence).
quality evidence).
78. Lipid formulation AmB, 3–5 mg/kg daily, for 2 weeks, fol- Evidence Summary
lowed by fluconazole, 400 mg (6 mg/kg) daily, for at least 4 Endophthalmitis refers to infections within the eye, usually in-
weeks is a less attractive alternative (weak recommendation; volving the posterior chamber and sometimes also the anterior
low-quality evidence). chamber. Candida endophthalmitis can be exogenous, initially
79. Surgical drainage is indicated in all cases of septic arthritis affecting the anterior chamber and occurring following trauma
(strong recommendation; moderate-quality evidence). or a surgical procedure. More often, Candida species cause en-
80. For septic arthritis involving a prosthetic device, device re- dogenous infection in which the organism reaches the posterior
moval is recommended (strong recommendation; moderate- chamber of the eye via hematogenous spread. Endogenous in-
quality evidence). fections can be manifested as isolated chorioretinitis or as cho-
81. If the prosthetic device cannot be removed, chronic sup- rioretinitis with extension into the vitreous, leading to vitritis
pression with fluconazole, 400 mg (6 mg/kg) daily, if the iso- [409–412]. Candida albicans is the species most commonly re-
late is susceptible, is recommended (strong recommendation; sponsible for endogenous endophthalmitis, but all Candida
low-quality evidence). species that cause candidemia have been reported to cause
this complication [411–414]. Outcomes in terms of visual acuity (6–12 mg/kg) daily OR voriconazole, loading dose 400 mg
depend on the extent of visual loss at the time of presentation (6 mg/kg) intravenous twice daily for 2 doses, then 300 mg
and macular involvement [415]. (4 mg/kg) intravenous or oral twice daily is recommended
Several basic principles are important in the approach to treat- (strong recommendation; low-quality evidence).
ment of Candida infections of the eye. It should first be deter- 86. For fluconazole-/voriconazole-resistant isolates, liposomal
mined whether infection involves the anterior and/or posterior AmB, 3–5 mg/kg intravenous daily, with or without oral flu-
segment of the eye and whether the macula or vitreous are in- cytosine, 25 mg/kg 4 times daily is recommended (strong rec-
volved [70, 416–418]. Achieving adequate concentrations of the ommendation; low-quality evidence).
appropriate antifungal agent in the area of the eye that is infected 87. With macular involvement, antifungal agents as noted
is crucial to success [419, 420]. Infections involving the chorior- above PLUS intravitreal injection of either AmB deoxycho-
etinal layer are more easily treated because this area of the poste- late, 5–10 µg/0.1 mL sterile water, or voriconazole, 100 µg/
rior chamber is highly vascular; many systemic antifungal agents 0.1 mL sterile water or normal saline, to ensure a prompt
likely reach adequate concentrations within the choroid and the high level of antifungal activity is recommended (strong rec-
retina [420–422]. The antifungal susceptibilities of the infecting ommendation; low-quality evidence).
species are important. Species that are susceptible to fluconazole 88. The duration of treatment should be at least 4–6 weeks,
or voriconazole are more easily treated because these agents with the final duration depending on resolution of
achieve adequate concentrations in the posterior segment of the lesions as determined by repeated ophthalmological ex-
the eye, including the vitreous [419, 420, 422]. Treatment must aminations (strong recommendation; low-quality evidence).

be systemic to treat candidemia and other organ involvement,
if present, in addition to the ocular infection. Evidence Summary
Sight-threatening lesions near the macula or invasion into the The greatest clinical experience for treatment of Candida en-
vitreous usually necessitate intravitreal injection of antifungal dophthalmitis has been with intravenous AmB deoxycholate,
agents, usually AmB deoxycholate or voriconazole, with or with- only because it has been available for the longest time. However,
out vitrectomy, in addition to systemic antifungal agents [412, this agent does not achieve adequate concentrations in the pos-
419, 422–425]. The ophthalmologist plays a key role in following terior chamber [419, 420, 427, 428]. In animal experiments in
the course of endogenous Candida endophthalmitis, deciding inflamed eyes, liposomal AmB achieved higher concentrations
when and if to perform intravitreal injections and vitrectomy. in the eye than either AmB deoxycholate or AmB lipid complex
The approach to the patient who has candidemia has [427]. A few patients have been treated successfully with lipid
evolved over time, and standard practice now includes consul- formulations of AmB, but concentrations in the vitreous in hu-
tation with an ophthalmologist to do a dilated retinal exami- mans have not been reported [429].
nation. The basis for the recommendation to perform an Flucytosine provides adjunctive synergistic activity when
ophthalmological evaluation is not a result of randomized used with AmB; it should not be used as monotherapy because
controlled trials showing the benefits of such an assessment, of development of resistance and reports of decreased efficacy in
but rather clinical judgment that the result of missing and animal models [428]. It attains excellent levels in the ocular
not appropriately treating Candida endophthalmitis could compartments, including the vitreous [412, 430]. Toxicity is
be of great consequence to the patient. The issue of whether common, and flucytosine serum levels must be monitored
an ophthalmological examination of all candidemic patients weekly to prevent dose-related toxicity.
is cost-effective has been raised [183, 426]. The members of Fluconazole is frequently used for the treatment of Candida
the Expert Panel believe that the risk of missing Candida en- endophthalmitis. In experimental animals, this agent achieves
dophthalmitis outweighs the cost of obtaining an ophthalmo- excellent concentrations throughout the eye, including the vit-
logical examination. We are concerned about the greater risk reous [428]. In humans, concentrations in the vitreous are ap-
of loss of visual acuity in patients who are examined only after proximately 70% of those in the serum [57]. Clinical and
manifesting ocular symptoms [415], and note that other cen- microbiological response rates in animals with experimental in-
ters report higher rates of endophthalmitis than reports from fection are somewhat conflicting, with most reports showing ef-
the centers cited by those who question the routine use of oc- ficacy of fluconazole, but some noting better efficacy with AmB
ular examination [417, 418, 421]. than fluconazole [428, 431, 432]. Early reports in humans noted
What Is the Treatment for Candida Chorioretinitis Without the efficacy of fluconazole, but some patients had received intra-
Vitritis? vitreal injection of antifungal agents, as well as systemic flucon-
azole [433, 434]. Despite the fact that no large published series
Recommendations has defined the efficacy of fluconazole therapy, this agent is rou-
85. For fluconazole-/voriconazole-susceptible isolates, flucon- tinely used for the treatment of Candida endophthalmitis [410,
azole, loading dose, 800 mg (12 mg/kg), then 400–800 mg 411, 415, 421].

Voriconazole has played an increasing role in the treatment What Is the Treatment for Candida Chorioretinitis With
of endophthalmitis [419]. Concentrations in the vitreous in hu- Vitritis?
mans are approximately 40% of serum concentrations; the drug
Recommendations
is relatively safe, and, like fluconazole, can be given by the oral
89. Antifungal therapy as detailed above for chorioretinitis
or intravenous route [435–438]. It is more active than flucona-
without vitritis, PLUS intravitreal injection of either ampho-
zole against C. glabrata, although resistance is increasing and
tericin B deoxycholate, 5–10 µg/0.1 mL sterile water, or
may preclude its use for some patients; it is uniformly active
voriconazole, 100 µg/0.1 mL sterile water or normal saline,
against C. krusei. Efficacy of voriconazole in treating Candida
is recommended (strong recommendation; low-quality
endophthalmitis has been documented, but not compared
evidence).
with fluconazole [429, 436, 438]. Serum and ( presumably) intra-
90. Vitrectomy should be considered to decrease the burden of
ocular concentrations of voriconazole are quite variable, and
organisms and to allow the removal of fungal abscesses that
serum trough levels should be routinely monitored to achieve
are inaccessible to systemic antifungal agents (strong recom-
concentrations between 2 µg/mL and 5 µg/mL to enhance effi-
mendation; low-quality evidence).
cacy and avoid toxicity [118].
91. The duration of treatment should be at least 4–6 weeks,
There are few data regarding the use of posaconazole for
with the final duration dependent on resolution of the lesions
Candida endophthalmitis. Intraocular penetration is poor,
as determined by repeated ophthalmological examinations
this agent has been used in very few patients, and it is not ap-
(strong recommendation; low-quality evidence).
proved for the treatment of candidemia [419].

Echinocandins are first-line agents for the treatment of can- Evidence Summary
didemia. Whether they can effectively treat chorioretinitis with- Candida endophthalmitis that has extended into the vitreous
out vitreal involvement cannot be answered with the data results in worse visual outcomes than chorioretinitis without
available. Penetration of all echinocandins into the different vitritis [415]. This may be related to the inability of many anti-
chambers of the eye is poor, and is especially poor in the vitre- fungal agents to achieve adequate concentrations in the vitreous
ous [412, 419, 420]. When levels have been achieved in experi- body. Poor outcomes could also be due to an increased burden
mental animal models and in one study in humans with of organisms in the posterior chamber or the existence of an ab-
micafungin, the dosages needed have been higher than those scess that cannot be visualized through the vitreal haziness. Ad-
currently licensed for use [112, 439–443]. Only a few case re- ditionally, in cases of endophthalmitis in which fungemia is not
ports of the use of an echinocandin as monotherapy have documented and the organism is unknown, vitrectomy pro-
been published, and the results are contradictory [444, 445]. vides material for culture that is superior to needle aspiration
With the availability of other agents that achieve adequate con- and allows the proper antifungal agent to be used [422, 424].
centrations in the vitreous, there is little reason to recommend The treatment when vitritis is documented is similar to that
the use of echinocandins for Candida endophthalmitis. recommended for chorioretinitis without vitreal involvement,
Because involvement of the macula is sight-threatening and with the added recommendations to (1) inject either AmB de-
concentrations of antifungal agents in the posterior chamber do oxycholate or voriconazole into the vitreous to achieve high
not immediately reach therapeutic levels, many ophthalmologists drug concentrations in the posterior chamber and to (2) consid-
perform an intravitreal injection of either AmB deoxycholate or er performing a pars plana vitrectomy. Several small series have
voriconazole to quickly achieve high antifungal activity in the pos- noted success in patients in whom early pars plana vitrectomy
terior chamber. AmB is the agent that has been used most often was accomplished [415, 423, 424, 452]. Removal of the vitreous
for intravitreal injection [422, 423]. A dosage of 5–10 µg given in is usually accompanied by intravitreal injection of antifungal
0.1 mL sterile water is generally safe [419]. Intravitreal injection of agents, and as noted above, the half-life of injected antifungal
lipid formulations of AmB has been compared with AmB deoxy- agents is shortened with vitrectomy [450, 451]. The risk of ret-
cholate in rabbits; all formulations showed toxicity at higher doses, inal detachment, a severe late complication of endophthalmitis
but at 10 µg, the least toxic was liposomal AmB [446], confirming with vitreal involvement, is decreased with early vitrectomy
a prior study using a noncommercial liposomal formulation [447]. [412, 415]. To have the best outcomes, Candida endophthalmi-
Voriconazole is increasingly used for intravitreal injection for tis with vitritis must be managed with close cooperation be-
both Candida and mold endophthalmitis [438, 448]. It has been tween ophthalmologists and infectious diseases specialists.
shown to be safe in animal eyes at concentrations <250 µg/mL XIII. What Is the Treatment for Central Nervous System Candidiasis?
[449]. The usual dose given to humans is 100 µg in 0.1 mL ster- Recommendations
ile water or normal saline (achieving a final concentration of 25 92. For initial treatment, liposomal AmB, 5 mg/kg daily,
µg/mL) [419, 438]. In vitrectomized eyes, the half-life of both with or without oral flucytosine, 25 mg/kg 4 times daily,
AmB and voriconazole is shortened, and repeated injections is recommended (strong recommendation; low-quality
may be required [450, 451]. evidence).
93. For step-down therapy after the patient has responded to ini- failure have been noted, and for this reason it is not recom-
tial treatment, fluconazole, 400–800 mg (6–12 mg/kg) daily, is mended as first-line therapy [453, 454, 463–465]. Fluconazole
recommended (strong recommendation; low-quality evidence). combined with flucytosine has been reported to cure Candida
94. Therapy should continue until all signs and symptoms and meningitis in a few patients [459], and this is a possible regimen
CSF and radiological abnormalities have resolved (strong rec- for step-down therapy. There are no reports of the use of vori-
ommendation; low-quality evidence). conazole or posaconazole for CNS candidiasis. Voriconazole
95. Infected CNS devices, including ventriculostomy drains, achieves excellent levels in CSF, and should be considered
shunts, stimulators, prosthetic reconstructive devices, and bio- for the rare case of C. glabrata that is not voriconazole
polymer wafers that deliver chemotherapy, should be removed resistant or C. krusei meningitis after initial treatment with
if possible (strong recommendation; low-quality evidence). AmB with or without flucytosine. Posaconazole does not
96. For patients in whom a ventricular device cannot be re- reach adequate concentrations in the CSF, and this agent is
moved, AmB deoxycholate could be administered through not recommended.
the device into the ventricle at a dosage ranging from 0.01 Echinocandins have been used infrequently for CNS candidi-
mg to 0.5 mg in 2 mL 5% dextrose in water (weak recommen- asis. There are case reports noting success [466], but CNS break-
dation; low-quality evidence). through infections in patients receiving an echinocandin for
candidemia have been reported [467]. There are experimental
Evidence Summary animal data noting that anidulafungin and micafungin can suc-
CNS Candida infections can occur as a manifestation of dissem- cessfully treat C. albicans meningitis, but the doses required in

inated candidiasis, as a complication of a neurosurgical proce- humans are much higher than currently recommended for can-
dure, especially when an intracranial device is inserted, or rarely didemia [296, 299]. At present, echinocandins are not recom-
as an isolated chronic infection [453–462]. Meningitis is the mended for CNS candidiasis.
most common presentation, but multiple small abscesses Infected CNS devices should be removed to eradicate Candi-
throughout the brain parenchyma, large solitary brain abscess- da. Most experience has been with external ventricular drains
es, and epidural abscesses have been reported [462]. Low-birth- and ventriculoperitoneal shunts that have become infected
weight neonates are at high risk to have CNS infection as a com- with Candida species [460, 463]. In recent years, infected devic-
plication of candidemia; neonatal CNS candidiasis is dealt with es include deep brain stimulators and Gliadel biopolymer wa-
in the section on neonatal Candida infections. Most infections fers that have been placed into the site of a brain tumor to
are due to C. albicans, with few reports of C. glabrata and other deliver chemotherapy locally. Although difficult to remove, ex-
species causing infection [453–457, 459, 461, 462]. Treatment is perience has shown that these devices must be taken out for
based on the antifungal susceptibilities of the infecting species cure of the infection [456, 468, 469].
and the ability of the antifungal agent to achieve appropriate Intraventricular administration of antifungal agents is not usu-
concentrations in the CSF and brain. ally necessary for treatment of CNS Candida infections. In pa-
No randomized controlled trials have been performed to eval- tients in whom the removal of a ventricular shunt or external
uate the most appropriate treatment for these uncommon infec- ventriculostomy drain is too risky because of significantly elevated
tions. Single cases and small series are reported. Most experience intracranial pressure, or among patients who have not responded
has accrued with the use of AmB deoxycholate, with or without to systemic antifungal therapy, intraventricular AmB deoxycholate
flucytosine [453–455, 457, 459, 460, 462]. Liposomal AmB (Am- has proved useful [453, 454, 460, 463, 469]. The dose of intraven-
Bisome) has been found to attain higher levels in the brain than tricular AmB deoxycholate is not standardized, and recommenda-
amphotericin B lipid complex (ABLC) or AmB deoxycholate in a tions vary from 0.01 mg to 1 mg in 2 mL of 5% dextrose in water
rabbit model of Candida meningoencephalitis [44]. daily [455, 463, 466, 469]. Toxicity—mainly headache, nausea, and
The combination of AmB and flucytosine is recommended vomiting—is a limiting factor when administering AmB by this
because of the in vitro synergism noted with the combination route [454, 463].
and the excellent CSF concentrations achieved by flucytosine.
XIV. What Is the Treatment for Urinary Tract Infections Due to Candida
However, flucytosine’s toxic effects on bone marrow and liver
Species?
must be carefully monitored, preferably with frequent serum
What Is the Treatment for Asymptomatic Candiduria?
flucytosine levels. The optimal length of therapy with AmB
alone or in combination with flucytosine has not been studied. Recommendations
Several weeks of therapy are suggested before transitioning to 97. Elimination of predisposing factors, such as indwelling
oral azole therapy. bladder catheters, is recommended whenever feasible (strong
Fluconazole achieves excellent levels in CSF and brain tissue recommendation; low-quality evidence).
and has proved useful as step-down therapy [453, 454, 459]. Flu- 98. Treatment with antifungal agents is NOT recommended
conazole also has been used as monotherapy; both success and unless the patient belongs to a group at high risk for

dissemination; high-risk patients include neutropenic pa- 102. For fluconazole-resistant C. glabrata, AmB deoxycholate,
tients, very low-birth-weight infants (<1500 g), and patients 0.3–0.6 mg/kg daily for 1–7 days OR oral flucytosine, 25 mg/
who will undergo urologic manipulation (strong recommen- kg 4 times daily for 7–10 days is recommended (strong rec-
dation; low-quality evidence). ommendation; low-quality evidence).
99. Neutropenic patients and very low-birth-weight infants 103. For C. krusei, AmB deoxycholate, 0.3–0.6 mg/kg daily, for
should be treated as recommended for candidemia (see sec- 1–7 days is recommended (strong recommendation; low-
tions III and VII) (strong recommendation; low-quality quality evidence).
evidence). 104. Removal of an indwelling bladder catheter, if feasible, is
100. Patients undergoing urologic procedures should be treated strongly recommended (strong recommendation; low-quality
with oral fluconazole, 400 mg (6 mg/kg) daily, OR AmB deox- evidence).
ycholate, 0.3–0.6 mg/kg daily, for several days before and after 105. AmB deoxycholate bladder irrigation, 50 mg/L
the procedure (strong recommendation; low-quality evidence). sterile water daily for 5 days, may be useful for treatment
of cystitis due to fluconazole-resistant species, such as C.
Evidence Summary
glabrata and C. krusei (weak recommendation; low-quality
The presence of candiduria is the usual trigger for a physician to
evidence).
consider whether a patient has a urinary tract infection due to
Candida species. The patients at most risk for candiduria are What Is the Treatment for Symptomatic Ascending Candida
those who are elderly, female, diabetic, have indwelling urinary Pyelonephritis?

devices, are taking antibiotics, and have had prior surgical pro-
cedures [470–475]. In the asymptomatic patient, candiduria al- Recommendations
most always represents colonization, and elimination of 106. For fluconazole-susceptible organisms, oral fluconazole,
underlying risk factors, such as indwelling catheters, is often ad- 200–400 mg (3–6 mg/kg) daily for 2 weeks, is recommended
equate to eradicate candiduria [471]. (strong recommendation; low-quality evidence).
Multiple studies have noted that candiduria does not com- 107. For fluconazole-resistant C. glabrata, AmB deoxycholate,
monly lead to candidemia [471, 472, 476–480]. Several of 0.3–0.6 mg/kg daily for 1–7 days, with or without oral flucy-
these studies have shown that candiduria is a marker for greater tosine, 25 mg/kg 4 times daily, is recommended (strong rec-
mortality, but death is not related to Candida infection and ommendation; low-quality evidence).
treatment for Candida infection does not change mortality 108. For fluconazole-resistant C. glabrata, monotherapy with
rates [476, 480, 481]. A prospective study in renal transplant re- oral flucytosine, 25 mg/kg 4 times daily for 2 weeks, could
cipients found that although mortality was higher in patients be considered (weak recommendation; low-quality evidence).
who had candiduria, treatment did not improve outcomes, sug- 109. For C. krusei, AmB deoxycholate, 0.3–0.6 mg/kg daily, for
gesting again that candiduria is a marker for severity of under- 1–7 days is recommended (strong recommendation; low-
lying illness [482]. quality evidence).
Several conditions require an aggressive approach to candi- 110. Elimination of urinary tract obstruction is strongly rec-
duria in asymptomatic patients. These include neonates with ommended (strong recommendation; low-quality evidence).
very low birth weight, who are at risk for invasive candidiasis 111. For patients who have nephrostomy tubes or stents in
that often involves the urinary tract [281, 483]. Many physi- place, consider removal or replacement, if feasible (weak rec-
cians who care for neutropenic patients treat those who have ommendation; low-quality evidence).
fever and candiduria because the candiduria may indicate in-
Evidence Summary
vasive candidiasis. However, a recent study from a cancer hos-
Candida UTI can develop by 2 different routes [487]. Most
pital of a small number of patients, 25% of whom were
symptomatic UTIs evolve as an ascending infection beginning
neutropenic, found that these patients did not develop candi-
in the lower urinary tract, similar to the pathogenesis of bacte-
demia or other complications of candiduria [484]. Several re-
rial UTI. Patients with ascending infection can have symptoms
ports have documented a high rate of candidemia when
of cystitis or pyelonephritis. The other route of infection occurs
patients undergo urinary tract instrumentation [485, 486],
as a consequence of hematogenous spread to the kidneys in a
which has led to recommendations to treat with antifungal
patient who has candidemia. These patients usually have no uri-
agents periprocedure.
nary tract symptoms or signs, and are treated for candidemia.
What Is the Treatment for Symptomatic Candida Cystitis?
Diagnostic tests on urine often are not helpful in differenti-
Recommendations ating colonization from infection or in pinpointing the involved
101. For fluconazole-susceptible organisms, oral fluconazole, site within the urinary tract [488, 489]. For example, pyuria in a
200 mg (3 mg/kg) daily for 2 weeks is recommended (strong patient with an indwelling bladder catheter cannot differentiate
recommendation; moderate-quality evidence). Candida infection from colonization. Similarly, the colony
count in the urine, especially when a catheter is present, cannot Irrigation of the bladder with AmB deoxycholate resolves can-
be used to define infection [488, 489]. Imaging of the urinary diduria in 80%–90% of patients, as shown in several open-label
tract by ultrasound or CT scanning is helpful in defining struc- trials, but in those studies, recurrent candiduria within several
tural abnormalities, hydronephrosis, abscesses, emphysematous weeks was very common [503–505]. This approach is useful
pyelonephritis, and fungus ball formation [490–492]. Aggrega- only for bladder infections and generally is discouraged, especially
tion of mycelia and yeasts (fungus balls) in bladder or kidney in patients who would not require an indwelling catheter for any
leads to obstruction and precludes successful treatment of infec- other reason [94, 506, 507]. Cystitis due to C. glabrata or C. krusei
tion with antifungal agents alone [94]. Rarely, Candida species can sometimes be treated with amphotericin B bladder irrigation
cause localized infections in prostate, epididymis, or testicles and endoscopic removal of any obstructing lesions [94].
[491, 493–495]. What Is the Treatment for Candida Urinary Tract Infection
Several basic principles are important in the approach to Associated With Fungus Balls?
treatment of Candida UTI. The ability of the antifungal agent
to achieve adequate concentrations in the urine is as important Recommendations
as the antifungal susceptibilities of the infecting species [94]. 112. Surgical intervention is strongly recommended in adults
Candida albicans, the most common cause of fungal UTI, is rel- (strong recommendation; low-quality evidence).
atively easy to treat because it is susceptible to fluconazole, 113. Antifungal treatment as noted above for cystitis or pyelo-
which achieves high concentrations in the urine. In contrast, nephritis is recommended (strong recommendation; low-
UTIs due to fluconazole-resistant C. glabrata and C. krusei quality evidence).

can be extremely difficult to treat. 114. Irrigation through nephrostomy tubes, if present, with
Fluconazole is the drug of choice for treating Candida UTI. It AmB deoxycholate, 25–50 mg in 200–500 mL sterile water,
was shown to be effective in eradicating candiduria in the only is recommended (strong recommendation; low-quality
randomized, double-blind, placebo-controlled trial that has evidence).
been conducted in patients with candiduria [496]. It is impor- Evidence Summary
tant to note that the patients in this trial were asymptomatic or Fungus balls are an uncommon complication of Candida UTI
had minimal symptoms of cystitis. Fluconazole is available as an except in neonates, in whom fungus ball formation in the col-
oral formulation, is excreted into the urine in its active form, lecting system commonly occurs as a manifestation of dissem-
and easily achieves urine levels exceeding the MIC for most inated candidiasis [483]. In adults, surgical or endoscopic
Candida isolates [94]. removal of the obstructing mycelial mass is central to successful
Flucytosine demonstrates good activity against many Candi- treatment [94, 508, 509]. In neonates, some series documented
da species, with the exception of C. krusei, and is excreted as resolution of fungus balls with antifungal treatment alone [510],
active drug in the urine [94]. Treatment with flucytosine is lim- but others found that endoscopic removal was necessary [511,
ited by its toxicity and the development of resistance when it is 512]. There are anecdotal reports of a variety of techniques used
used as a single agent. to remove fungus balls from the renal pelvis; these include en-
AmB deoxycholate is active against most Candida species (al- doscopic removal via a percutaneous nephrostomy tube, infu-
though some C. krusei isolates are resistant) and achieves con- sion of streptokinase locally, and irrigation with antifungal
centrations in the urine that exceed the MICs for most isolates, agents through a nephrostomy tube [511–513]. Fungus balls
and even low doses have been shown to be effective in treating in the bladder and lower ureter usually can be removed endo-
Candida UTI [497]. The major drawbacks are the need for in- scopically [509].
travenous administration and toxicity. The lipid formulations of
AmB appear to not achieve urine concentrations that are ade- XV. What Is the Treatment for Vulvovaginal Candidiasis?
quate to treat UTI and should not be used [498]. Recommendations
All other antifungal drugs, including the other azole agents 115. For the treatment of uncomplicated Candida vulvovagini-
and echinocandins, have minimal excretion of active drug tis, topical antifungal agents, with no one agent superior to
into the urine and generally are ineffective in treating Candida another, are recommended (strong recommendation; high-
UTI [94]. However, there are several reports of patients in quality evidence).
whom echinocandins were used, primarily because of UTI 116. Alternatively, for the treatment of uncomplicated Candi-
due to fluconazole-resistant organisms, and both success and da vulvovaginitis, a single 150-mg oral dose of fluconazole is
failure were reported [499–502]. Infection localized to the kid- recommended (strong recommendation; high-quality
ney, as occurs with hematogenous spread, probably can be treat- evidence).
ed with echinocandins because tissue concentrations are 117. For severe acute Candida vulvovaginitis, fluconazole 150
adequate even though these agents do not achieve adequate mg, given every 72 hours for a total of 2 or 3 doses, is recom-
urine concentrations [499]. mended (strong recommendation; high-quality evidence).

118. For C. glabrata vulvovaginitis that is unresponsive to oral days or orally with fluconazole 150 mg every 72 hours for 3
azoles, topical intravaginal boric acid, administered in a gel- doses [54, 514]. Most Candida species, with the exception of
atin capsule, 600 mg daily, for 14 days is an alternative C. krusei and C. glabrata, respond to oral fluconazole. Candida
(strong recommendation; low-quality evidence). krusei responds to all topical antifungal agents. However, treat-
119. Another alternative agent for C. glabrata infection is nys- ment of C. glabrata vulvovaginal candidiasis is problematic
tatin intravaginal suppositories, 100 000 units daily for 14 [514, 516]. The most important decision to make is whether
days (strong recommendation; low-quality evidence). the presence of C. glabrata in vaginal cultures reflects coloniza-
120. A third option for C. glabrata infection is topical 17% flu- tion in a patient who has another disease, or whether it indicates
cytosine cream alone or in combination with 3% AmB cream true infection requiring treatment. Azole therapy, including
administered daily for 14 days (weak recommendation; low- voriconazole, is frequently unsuccessful [519]. A variety of
quality evidence). local regimens have sometimes proved effective. These include
121. For recurring vulvovaginal candidiasis, 10–14 days of boric acid contained in gelatin capsules and nystatin intravagi-
induction therapy with a topical agent or oral fluconazole, fol- nal suppositories [520]. Topical 17% flucytosine cream can be
lowed by fluconazole, 150 mg weekly for 6 months, is recom- used alone or in combination with 3% AmB cream in recalci-
mended (strong recommendation; high-quality evidence). trant cases [520, 521]. These topical formulations, as well as
boric acid gelatin capsules, must be compounded by a pharmacist
Evidence Summary for specific patient use. Azole-resistant C. albicans infections are
Vulvovaginal candidiasis can be classified as either uncompli- extremely rare. However, recent evidence has emerged docu-

cated, which is present in about 90% of cases, or complicated, menting fluconazole and azole class resistance in women follow-
which accounts for only about 10% of cases, on the basis of clin- ing prolonged azole exposure [522].
ical presentation, microbiological findings, host factors, and re- Recurrent vulvovaginal candidiasis, defined as ≥4 episodes of
sponse to therapy [514]. Complicated vulvovaginal candidiasis symptomatic infection within one year, is usually caused by
is defined as severe or recurrent disease, infection due to non- azole-susceptible C. albicans [514, 523]. Contributing factors,
albicans species, and/or infection in an abnormal host. Candida such as diabetes, are rarely found. Treatment should begin
albicans is the usual pathogen, but other Candida species can with induction therapy with a topical agent or oral fluconazole
also cause this infection. for 10–14 days, followed by a maintenance azole regimen for at
A diagnosis of vulvovaginal candidiasis can usually be made least 6 months [523–525]. The most convenient and well-
clinically when a woman presents with symptoms of pruritus, tolerated regimen is 150 mg fluconazole once weekly. This reg-
irritation, vaginal soreness, external dysuria, and dyspareunia, imen achieves control of symptoms in >90% of patients [523].
often accompanied by a change in vaginal discharge. Signs in- After cessation of maintenance therapy, a 40%–50% recurrence
clude vulvar edema, erythema, excoriation, fissures, and a white, rate can be anticipated. If fluconazole therapy is not feasible,
thick, curdlike vaginal discharge. Unfortunately, these symp- topical clotrimazole cream, 200 mg twice weekly, clotrimazole
toms and signs are nonspecific and can be the result of a variety vaginal suppository 500 mg once weekly, or other intermittent
of infectious and noninfectious etiologies. Before proceeding oral or topical antifungal treatment is recommended [526, 527].
with empiric antifungal therapy, the diagnosis should be con-
firmed by a wet-mount preparation with use of saline and XVI. What Is the Treatment for Oropharyngeal Candidiasis?
10% potassium hydroxide to demonstrate the presence of Recommendations
yeast or hyphae and a normal pH (4.0–4.5). For those with neg- 122. For mild disease, clotrimazole troches, 10 mg 5 times
ative findings, vaginal cultures for Candida should be obtained. daily, OR miconazole mucoadhesive buccal 50 mg tablet ap-
A variety of topical and systemic oral agents are available for plied to the mucosal surface over the canine fossa once daily
treatment of vulvovaginal candidiasis. No evidence exists to for 7–14 days, are recommended (strong recommendation;
show the superiority of any one topical regimen [515, 516], high-quality evidence).
and oral and topical antifungal formulations have been shown 123. Alternatives for mild disease include nystatin suspension
to achieve entirely equivalent results [517]. Uncomplicated in- (100 000 U/mL) 4–6 mL 4 times daily, OR 1–2 nystatin pas-
fection can be effectively treated with either single-dose flucon- tilles (200 000 U each) 4 times daily, for 7–14 days (strong
azole or short-course fluconazole for 3 days, both of which recommendation; moderate-quality evidence).
achieve >90% response [517, 518]. Treatment of vulvovaginal 124. For moderate to severe disease, oral fluconazole, 100–200
candidiasis should not differ on the basis of human immunode- mg daily, for 7–14 days is recommended (strong recommen-
ficiency virus (HIV) infection status; identical response rates are dation; high-quality evidence).
anticipated for HIV-positive and HIV-negative women. 125. For fluconazole-refractory disease, itraconazole solution,
Complicated vulvovaginal candidiasis requires that therapy 200 mg once daily OR posaconazole suspension, 400 mg
be administered intravaginally with topical agents for 5–7 twice daily for 3 days then 400 mg daily, for up to 28 days,
are recommended (strong recommendation; moderate-quality miconazole applied once daily to the mucosal surface over the
evidence). canine fossa were as effective as 10-mg clotrimazole troches
126. Alternatives for fluconazole-refractory disease include used 5 times daily [537].
voriconazole, 200 mg twice daily, OR AmB deoxycholate Fluconazole tablets and itraconazole solution are superior to
oral suspension, 100 mg/mL 4 times daily (strong recommen- ketoconazole and itraconazole capsules [538–540]. Local effects
dation; moderate-quality evidence). of oral solutions may be as important as the systemic effects.
127. Intravenous echinocandin (caspofungin: 70-mg loading Posaconazole suspension is also as efficacious as fluconazole
dose, then 50 mg daily; micafungin: 100 mg daily; or ani- in patients with AIDS [541]. Posaconazole, 100-mg delayed re-
dulafungin: 200-mg loading dose, then 100 mg daily) OR in- lease tablets, given as 300 mg daily as a single dose, are FDA ap-
travenous AmB deoxycholate, 0.3 mg/kg daily, are other proved for the prophylaxis of fungal infections in high-risk
alternatives for refractory disease (weak recommendation; patients. The tablets provide a stable bioavailability (approxi-
moderate-quality evidence). mately 55%), once-daily dosing, and the convenience of less
128. Chronic suppressive therapy is usually unnecessary. If re- stringent food requirements for absorption. This formulation
quired for patients who have recurrent infection, fluconazole, has not been fully evaluated for mucosal candidiasis, but, with
100 mg 3 times weekly, is recommended (strong recommen- further study, could replace the oral suspension for this purpose.
dation; high-quality evidence). Recurrent infections typically occur in patients who have per-
129. For HIV-infected patients, antiretroviral therapy is sistent immunosuppression, especially those who have AIDS
strongly recommended to reduce the incidence of recurrent and low CD4 cell counts (<50 cells/µL) [530–533]. Long-term

infections (strong recommendation; high-quality evidence). suppressive therapy with fluconazole has been shown to be ef-
130. For denture-related candidiasis, disinfection of the den- fective in the prevention of oropharyngeal candidiasis [53, 542,
ture, in addition to antifungal therapy, is recommended 543]. In a large multicenter study of HIV-infected patients,
(strong recommendation; moderate-quality evidence). long-term suppressive therapy with fluconazole was compared
with the episodic use of fluconazole in response to symptomatic
Evidence Summary disease. Continuous suppressive therapy reduced the relapse
Oropharyngeal and esophageal candidiasis occur in association rate more effectively than did intermittent therapy, but was as-
with HIV infection, diabetes, leukemia and other malignancies, sociated with increased in vitro resistance. The frequency of re-
steroid use, radiation therapy, antimicrobial therapy, and den- fractory disease was the same for both groups [53]. Oral AmB
ture use [528, 529], and their occurrence is recognized as an in- deoxycholate, nystatin solution, and itraconazole capsules are
dicator of immune dysfunction. In HIV-infected patients, less effective than fluconazole in preventing oropharyngeal can-
oropharyngeal candidiasis is most often observed in patients didiasis [544, 545].
with CD4 counts <200 cells/µL [528–530]. The advent of effec- Fluconazole-refractory infections should be treated initially
tive antiretroviral therapy has led to a dramatic decline in the with itraconazole solution; between 64% and 80% of patients
prevalence of oropharyngeal candidiasis and a marked diminu- will respond to this therapy [546, 547]. Posaconazole suspension
tion in cases of refractory disease [531]. is efficacious in approximately 75% of patients with refractory
Fluconazole or multiazole resistance is predominantly the oropharyngeal or esophageal candidiasis [548], and voriconazole
consequence of previous repeated and long-term exposure to also is efficacious for fluconazole-refractory infections [549]. In-
fluconazole or other azoles [530–533]. Especially in patients travenous caspofungin, micafungin, and anidulafungin have been
with advanced immunosuppression and low CD4 counts, C. al- shown to be effective alternatives to azole agents for refractory
bicans resistance has been described, as has gradual emergence candidiasis [24, 87, 88, 550]. Oral or intravenous AmB deoxycho-
of non-albicans Candida species, particularly C. glabrata, as a late is also effective in some patients; however, a pharmacist must
cause of refractory mucosal candidiasis [532, 533]. compound the oral formulation [551]. Immunomodulation with
Most cases of oropharyngeal candidiasis are caused by C. al- adjunctive granulocyte-macrophage colony-stimulating factor or
bicans, either alone or in mixed infections. Symptomatic infec- interferon-γ have been occasionally used in the management of
tions caused by C. glabrata, C. dubliniensis, and C. krusei alone refractory oral and esophageal candidiasis [552, 553].
have been described [532–534]. Multiple randomized prospec- Decreasing rates of oral carriage of Candida species and a re-
tive studies of oropharyngeal candidiasis have been performed duced frequency of symptomatic oropharyngeal candidiasis are
involving patients with AIDS and patients with cancer. Most seen among HIV-infected patients on effective antiretroviral
patients will respond initially to topical therapy [532, 535, therapy [554]. Thus, antiretroviral therapy should be used
536]. In HIV-infected patients, symptomatic relapses occur whenever possible for HIV-infected patients with oropharyn-
sooner and more frequently with topical therapy than with flu- geal or esophageal candidiasis.
conazole [535]. In a multicenter randomized study among HIV- Chronic mucocutaneous candidiasis is a rare condition that
infected individuals, 50-mg mucoadhesive buccal tablets of is characterized by chronic, persistent onychomycosis and/or

mucocutaneous lesions due to Candida species. Some patients 140. For HIV-infected patients, antiretroviral therapy is
have a thymoma or autoimmune polyendocrinopathy syn- strongly recommended to reduce the incidence of recurrent
drome type 1 [555]. Fluconazole should be used as initial ther- infections (strong recommendation; high-quality evidence).
apy for candidiasis in these patients. Response to antifungal
Evidence Summary
therapy may be delayed when there is extensive skin or nail in-
Esophageal candidiasis typically occurs at lower CD4 counts
volvement. Because of the intrinsic immunodeficiency, most
than oropharyngeal disease [528–530]. The advent of effective
patients require chronic suppressive antifungal therapy and fre-
antiretroviral therapy has led to a dramatic decline in the prev-
quently develop azole-refractory infections [556]. Patients with
alence of esophageal candidiasis and a marked diminution in
fluconazole-refractory Candida infections should be treated the
cases of refractory disease [531]. Most cases of esophageal
same as patients with AIDS who develop azole refractory infec-
candidiasis are caused by C. albicans. However, symptomatic
tions [528].
infections caused by C. glabrata, C. dubliniensis, and C. krusei
have been described [534].
XVII. What Is the Treatment for Esophageal Candidiasis?
The presence of oropharyngeal candidiasis and dysphagia or
Recommendations
odynophagia in an immunocompromised host is frequently
131. Systemic antifungal therapy is always required. A diag-
predictive of esophageal candidiasis, although esophageal can-
nostic trial of antifungal therapy is appropriate before
didiasis can present as odynophagia without concomitant oro-
performing an endoscopic examination (strong recommenda-
pharyngeal candidiasis. A therapeutic trial with fluconazole
tion; high-quality evidence).

for patients with presumed esophageal candidiasis is a cost-
132. Oral fluconazole, 200–400 mg (3–6 mg/kg) daily, for 14–
effective alternative to endoscopic examination. In general,
21 days is recommended (strong recommendation; high-
most patients with esophageal candidiasis will have improve-
quality evidence).
ment or resolution of their symptoms within 7 days after the
133. For patients who cannot tolerate oral therapy, intravenous
initiation of antifungal therapy [557].
fluconazole, 400 mg (6 mg/kg) daily, OR an echinocandin
Fluconazole is superior to ketoconazole, itraconazole cap-
(micafungin: 150 mg daily; caspofungin: 70-mg loading
sules, and flucytosine, and is comparable to itraconazole solu-
dose, then 50 mg daily; or anidulafungin: 200 mg daily) is
tion for the treatment of esophageal candidiasis [558, 559]; up
recommended (strong recommendation; high-quality
to 80% of patients with fluconazole-refractory infections will re-
evidence).
spond to itraconazole solution [547]. Voriconazole is as effica-
134. A less preferred alternative for those who cannot tolerate
cious as fluconazole and has shown success in the treatment of
oral therapy is AmB deoxycholate, 0.3–0.7 mg/kg daily
fluconazole-refractory mucosal candidiasis [63, 549].
(strong recommendation; moderate-quality evidence).
The echinocandins are as effective as fluconazole but are as-
135. Consider de-escalating to oral therapy with fluconazole
sociated with higher relapse rates than those observed with flu-
200–400 mg (3–6 mg/kg) daily once the patient is able to tol-
conazole [24, 87, 88, 550]. Thus, higher doses of echinocandins
erate oral intake (strong recommendation; moderate-quality
are recommended for use for esophageal disease than are used
evidence).
for candidemia to decrease relapses. Higher doses have been
136. For fluconazole-refractory disease, itraconazole solution,
studied for micafungin [560]. Fluconazole-refractory disease re-
200 mg daily, OR voriconazole, 200 mg (3 mg/kg) twice
sponds to caspofungin, and it is likely that micafungin and ani-
daily either intravenous or oral, for 14–21 days is recom-
dulafungin are as effective as caspofungin. In patients with
mended (strong recommendation; high-quality evidence).
advanced AIDS, recurrent infections are common, and long-
137. Alternatives for fluconazole-refractory disease include an
term suppressive therapy with fluconazole is effective in de-
echinocandin (micafungin: 150 mg daily; caspofungin: 70-
creasing the recurrence rates [53]. The use of effective antiretro-
mg loading dose, then 50 mg daily; or anidulafungin: 200
viral therapy has dramatically decreased the incidence of
mg daily) for 14–21 days, OR AmB deoxycholate, 0.3–0.7
esophageal candidiasis in HIV-infected patients.
mg/kg daily, for 21 days (strong recommendation; high-qual-
ity evidence).
138. Posaconazole suspension, 400 mg twice daily, or extend- Notes
ed-release tablets, 300 mg once daily, could be considered for Acknowledgments. The Expert Panel expresses its gratitude for
thoughtful reviews of an earlier version by Anna Thorner and Pranatharthi
fluconazole-refractory disease (weak recommendation; low-
Chandrasekar; and David van Duin as liaison of the IDSA Standards and
quality evidence). Practice Guidelines Committee (SPGC). The panel also greatly appreciates
139. For patients who have recurrent esophagitis, chronic sup- the work of Charles B. Wessels and Michele Klein Fedyshin of the Health
pressive therapy with fluconazole, 100–200 mg 3 times week- Sciences Library System of the University of Pittsburgh for the development
and execution of the systematic literature searches for this guideline.
ly, is recommended (strong recommendation; high-quality Financial support. Support for this guideline was provided by the In-
evidence). fectious Diseases Society of America.
Potential conflicts of interest. The following list is a reflection of what 5. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB.
has been reported to IDSA. To provide thorough transparency, IDSA re- Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases
quires full disclosure of all relationships, regardless of relevancy to the guide- from a prospective nationwide surveillance study. Clin Infect Dis 2004;
39:309–17.
line topic. Evaluation of such relationships as potential conflicts of interest
6. Gudlaugsson O, Gillespie S, Lee K, et al. Attributable mortality of nosocomial
(COI) is determined by a review process that includes assessment by the
candidemia, revisited. Clin Infect Dis 2003; 37:1172–7.
SPGC Chair, the SPGC liaison to the development panel, and the Board 7. Pappas PG, Rex JH, Lee J, et al. A prospective observational study of candidemia:
of Directors liaison to the SPGC and, if necessary, the COI Task Force of epidemiology, therapy, and influences on mortality in hospitalized adult and pe-
the Board. This assessment of disclosed relationships for possible COI diatric patients. Clin Infect Dis 2003; 37:634–43.
will be based on the relative weight of the financial relationship (ie, mone- 8. Pfaller M, Neofytos D, Diekema D, et al. Epidemiology and outcomes of candi-
tary amount) and the relevance of the relationship (ie, the degree to which demia in 3648 patients: data from the Prospective Antifungal Therapy (PATH
an association might reasonably be interpreted by an independent observer Alliance(R)) registry, 2004–2008. Diagn Microbiol Infect Dis 2012; 74:323–31.
as related to the topic or recommendation of consideration). The reader of 9. Diekema D, Arbefeville S, Boyken L, Kroeger J, Pfaller M. The changing epide-
miology of healthcare-associated candidemia over three decades. Diagn Micro-
these guidelines should be mindful of this when the list of disclosures is re-
biol Infect Dis 2012; 73:45–8.
viewed. For activities outside of the submitted work, P. G. P. served as a con-
10. Pfaller MA, Messer SA, Moet GJ, Jones RN, Castanheira M. Candida blood-
sultant to Merck, Astellas ( past), Gilead, T2 Biosystems, Scynexis, Viamet, stream infections: comparison of species distribution and resistance to echino-
IMMY Diagnostics, and Pfizer ( past) and has received research grants from candin and azole antifungal agents in intensive care unit (ICU) and non-ICU
T2 Biosystems, Gilead, Merck, Astellas, Scynexis, and IMMY. For activities settings in the SENTRY Antimicrobial Surveillance Program (2008–2009). Int
outside of the submitted work, C. A. K. has received research grants from VA J Antimicrob Agents 2011; 38:65–9.
Cooperative Studies, Merck, the Centers for Disease Control and Prevention 11. Pfaller MA, Moet GJ, Messer SA, Jones RN, Castanheira M. Candida blood-
(CDC) and The National Institute on Aging (all past), and has received roy- stream infections: comparison of species distributions and antifungal resistance
alties from UpToDate. For activities outside of the submitted work, patterns in community-onset and nosocomial isolates in the SENTRY Antimi-
crobial Surveillance Program, 2008–2009. Antimicrob Agents Chemother
D. A. has served a consultant to Merck, Astellas, Pfizer, Seachaid, Mayne,
2011; 55:561–6.
Roche, Theravance, Viamet, and Scynexis and has received research grants
12. Pfaller MA, Moet GJ, Messer SA, Jones RN, Castanheira M. Geographic variations

from Merck, Pfizer, MSG, Actellion, Theravance, Scynexis, and Astellas. For in species distribution and echinocandin and azole antifungal resistance rates
activities outside of the submitted work, C. J. C. has consulted for Merck, and among Candida bloodstream infection isolates: report from the SENTRY Antimi-
received research grants from Pfizer, Merck, Astellas, CSL Behring, and T2 crobial Surveillance Program (2008 to 2009). J Clin Microbiol 2011; 49:396–9.
Diagnostics. For activities outside of the submitted work, K. A. M. has re- 13. Morgan J, Meltzer MI, Plikaytis BD, et al. Excess mortality, hospital stay, and cost
ceived research grants from Pfizer, Astellas, Merck, and the National Insti- due to candidemia: a case-control study using data from population-based can-
tutes of Health (NIH) and served as a consultant for Astellas, Chimerix, didemia surveillance. Infect Control Hosp Epidemiol 2005; 26:540–7.
Cidara, Genentech, Merck, Revolution Medicines, and Theravance. She 14. Kollef M, Micek S, Hampton N, Doherty JA, Kumar A. Septic shock attributed to
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the submitted work, L. O.-Z. has served as a consultant to Viracor ( past),
15. Grim SA, Berger K, Teng C, et al. Timing of susceptibility-based antifungal drug
Novadigm ( past), Pfizer ( past), Astellas, Cidara, Scynexis, and Merck and administration in patients with Candida bloodstream infection: correlation with
has received research grants from Merck ( past), Astellas, Pfizer ( past), Im- outcomes. J Antimicrob Chemother 2012; 67:707–14.
munetics, Associates of Cape Cod ( past), and T2 Biosystems, and has been 16. Ostrosky-Zeichner L, Kullberg BJ, Bow EJ, et al. Early treatment of candidemia in
on the speakers’ bureau for Merck and Pfizer. For activities outside of the adults: a review. Med Mycol 2011; 49:113–20.
submitted work, A. C. R. has received research grants from Merck and T2 17. Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of Candida
Biosystems, and royalties from UpToDate. For activities outside of the sub- bloodstream infection until positive blood culture results are obtained: a potential
mitted work, J. A. V. has served as a consultant for Astellas, Forest, served on risk factor for hospital mortality. Antimicrob Agents Chemother 2005; 49:3640–5.
18. Garey KW, Rege M, Pai MP, et al. Time to initiation of fluconazole therapy im-
promotional speakers’ bureau for Astellas, Pfizer, Forest, and Astra Zeneca,
pacts mortality in patients with candidemia: a multi-institutional study. Clin In-
and has received research grants from Astellas, Pfizer, Merck, MSG, T2 Bio-
fect Dis 2006; 43:25–31.
systems, and NIH/National Institute of Dental and Craniofacial Research. 19. Andes DR, Safdar N, Baddley JW, et al. Impact of treatment strategy on
For activities outside of the submitted work, T. J. W. has served as a consul- outcomes in patients with candidemia and other forms of invasive candidiasis:
tant for Astellas, Drais ( past), Novartis, Pfizer, Methylgene, SigmaTau, a patient-level quantitative review of randomized trials. Clin Infect Dis 2012;
Merck, ContraFect Trius, and has received research grants from SOS Kids 54:1110–22.
Foundation, Sharpe Family Foundation, Astellas, Cubist, Theravance, Med- 20. Clancy CJ, Nguyen MH. Finding the “missing 50%” of invasive candidiasis: how
icines Company, Actavis, Pfizer, Merck, Novartis, ContraFect, and The nonculture diagnostics will improve understanding of disease spectrum and
Schueler Foundation. For activities outside of the submitted work, T. E. Z. transform patient care. Clin Infect Dis 2013; 56:1284–92.
21. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole
has served as a consultant for Astellas, Pfizer, Merck, and Cubist (all past)
with amphotericin B for the treatment of candidemia in patients without neutro-
and has received research grants from Merck ( past), Cubist ( past), Agency
penia. Candidemia Study Group and the National Institute. N Engl J Med 1994;
for Health Research and Quality, CDC, NIH, and the Thrasher Foundation. 331:1325–30.
All other authors report no potential conflicts. All authors have submitted 22. Rex JH, Pappas PG, Karchmer AW, et al. A randomized and blinded multicenter
the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin
that the editors consider relevant to the content of the manuscript have been B as therapy for candidemia and its consequences in nonneutropenic subjects.
disclosed. Clin Infect Dis 2003; 36:1221–8.
23. Kullberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole versus a regimen of ampho-
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Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by

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