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Invasive Candidiasis

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What is invasive candidiasis?

Invasive candidiasis is an infection caused by a yeast (a type of fungus) called Candida. Unlike Candida infections in the mouth and throat (also called "thrush") or vaginal "yeast infections," which are localized to one part of the body, invasive candidiasis is a serious infection that can affect the blood, heart, brain, eyes, bones, or other parts of the body.1

Candida normally lives inside the body (in places such as the mouth, throat, gut, and vagina) and on the skin without causing any problems.2 However, in certain patients who are at risk, Candida can enter the bloodstream or internal organs and cause an infection. A Candida bloodstream infection, also called candidemia, is the most common form of invasive candidiasis.1 In the United States, candidemia is one of the most common causes of bloodstream infections in hospitalized patients,3-4 and it often results in long hospital stays and death. It is also responsible for high medical costs.5

Antifungal medication can treat invasive candidiasis. Certain patients such as those with cancer or bone marrow or organ transplants might receive antifungal medication to prevent invasive candidiasis.6

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Invasive candidiasis is a fungal infection that can occur when Candida yeasts enter the bloodstream.

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Invasive candidiasis is an infection caused by yeast which is a type of fungus. Candida is the formal name but this infection is not like other candida infections. Most candida infections are located in the mouth or eyes while invasive candidiasis can affect more important parts of the body. This infection can have affects on the blood, heart, brain, eyes, and bones.

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Candida

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1.) Fever
2.) Chills
3.) If it gets worse it starts to affect the heart and joints

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People who develop invasive candidiasis are often already sick from other medical conditions, so it can be difficult to know which symptoms are related to a Candida infection. However, the most common symptoms of invasive candidiasis are fever and chills that don't improve after antibiotic treatment for suspected bacterial infections. Other symptoms can develop if the infection spreads to other parts of the body, such as the heart, brain, eyes, bones, or joints.

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Invasive candidiasis is a fungal infection that can occur when Candida yeasts enter the bloodstream.

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Invasive Candidiasis has a mortality rate of 40-55%. This causes it to be one of the most critical cared fungal infections that need to be taken care of in the United States. It can be caught in the early stages with tools like Candida colonisation index, clinical prediction rules, and fungal non-cultural based tests.
https://pubmed.ncbi.nlm.nih.gov/32990778/

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Prevention: Antifungal medication like echinocandin, also telling your doctor your symptoms and washing your hands
Treatment: Taking the antifungal medication through IV for a least two weeks after your symptoms have went away
More Info:

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Abstract

EXECUTIVE SUMMARY

Background

Invasive infection due to Candida species is largely a condition associated with medical progress, and is widely recognized as a major cause of morbidity and mortality in the healthcare environment. There are at least 15 distinct Candida species that cause human disease, but >90% of invasive disease is caused by the 5 most common pathogens, C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei. Each of these organisms has unique virulence potential, antifungal susceptibility, and epidemiology, but taken as a whole, significant infections due to these organisms are generally referred to as invasive candidiasis. Mucosal Candida infections-especially those involving the oropharynx, esophagus, and vagina-are not considered to be classically invasive disease, but they are included in these guidelines. Since the last iteration of these guidelines in 2009 [ 1], there have been new data pertaining to diagnosis, prevention, and treatment for proven or suspected invasive candidiasis, leading to significant modifications in our treatment recommendations.

I. What Is the Treatment for Candidemia in Nonneutropenic Patients?

Recommendations

1. An echinocandin (caspofungin: loading dose 70 mg, then 50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose 200 mg, then 100 mg daily) is recommended as initial therapy (strong recommendation; high-quality evidence).

3. Testing for azole susceptibility is recommended for all bloodstream and other clinically relevant Candida isolates. Testing for echinocandin susceptibility should be considered in patients who have had prior treatment with an echinocandin and among those who have infection with C. glabrata or C. parapsilosis (strong recommendation; low-quality evidence).

6. Lipid formulation amphotericin B (AmB) (3-5 mg/kg daily) is a reasonable alternative if there is intolerance, limited availability, or resistance to other antifungal agents (strong recommendation; high-quality evidence).

7. Transition from AmB to fluconazole is recommended after 5-7 days among patients who have isolates that are susceptible to fluconazole, who are clinically stable, and in whom repeat cultures on antifungal therapy are negative (strong recommendation; high-quality evidence).

10. All nonneutropenic patients with candidemia should have a dilated ophthalmological examination, preferably performed by an ophthalmologist, within the first week after diagnosis (strong recommendation; low-quality evidence).

11. Follow-up blood cultures should be performed every day or every other day to establish the time point at which candidemia has been cleared (strong recommendation; low-quality evidence).

II. Should Central Venous Catheters Be Removed in Nonneutropenic Patients With Candidemia?

Recommendation

III. What Is the Treatment for Candidemia in Neutropenic Patients?

Recommendations

IV. What Is the Treatment for Chronic Disseminated (Hepatosplenic) Candidiasis?

Recommendations

V. What Is the Role of Empiric Treatment for Suspected Invasive Candidiasis in Nonneutropenic Patients in the Intensive Care Unit?

Recommendations

29. Preferred empiric therapy for suspected candidiasis in nonneutropenic patients in the intensive care unit (ICU) is an echinocandin (caspofungin: loading dose of 70 mg, then 50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose of 200 mg, then 100 mg daily) (strong recommendation; moderate-quality evidence).

31. Lipid formulation AmB, 3-5 mg/kg daily, is an alternative if there is intolerance to other antifungal agents ( strong recommendation; low-quality evidence).

32. Recommended duration of empiric therapy for suspected invasive candidiasis in those patients who improve is 2 weeks, the same as for treatment of documented candidemia (weak recommendation; low-quality evidence).

33. For patients who have no clinical response to empiric antifungal therapy at 4-5 days and who do not have subsequent evidence of invasive candidiasis after the start of empiric therapy or have a negative non-culture-based diagnostic assay with a high negative predictive value, consideration should be given to stopping antifungal therapy (strong recommendation; low-quality evidence).

VI. Should Prophylaxis Be Used to Prevent Invasive Candidiasis in the Intensive Care Unit Setting?

Recommendations

VII. What Is the Treatment for Neonatal Candidiasis, Including Central Nervous System Infection?
What Is the Treatment for Invasive Candidiasis and Candidemia?
Recommendations
What Is the Treatment for Central Nervous System Infections in Neonates?
Recommendations
What Are the Recommendations for Prophylaxis in the Neonatal Intensive Care Unit Setting?
Recommendations

VIII. What Is the Treatment for Intra-abdominal Candidiasis?

Recommendations

IX. Does the Isolation of Candida Species From the Respiratory Tract Require Antifungal Therapy?

Recommendation

X. What Is the Treatment for Candida Intravascular Infections, Including Endocarditis and Infections of Implantable Cardiac Devices?

What Is the Treatment for Candida Endocarditis?

Recommendations

59. For native valve endocarditis, lipid formulation AmB, 3-5 mg/kg daily, with or without flucytosine, 25 mg/kg 4 times daily, OR high-dose echinocandin (caspofungin 150 mg daily, micafungin 150 mg daily, or anidulafungin 200 mg daily) is recommended for initial therapy (strong recommendation; low-quality evidence).

60. Step-down therapy to fluconazole, 400-800 mg (6-12 mg/kg) daily, is recommended for patients who have susceptible Candida isolates, have demonstrated clinical stability, and have cleared Candida from the bloodstream (strong recommendation; low-quality evidence).

61. Oral voriconazole, 200-300 mg (3-4 mg/kg) twice daily, or posaconazole tablets, 300 mg daily, can be used as step-down therapy for isolates that are susceptible to those agents but not susceptible to fluconazole (weak recommendation; very low-quality evidence).

62. Valve replacement is recommended; treatment should continue for at least 6 weeks after surgery and for a longer duration in patients with perivalvular abscesses and other complications (strong recommendation; low-quality evidence).

63. For patients who cannot undergo valve replacement, long-term suppression with fluconazole, 400-800 mg (6-12 mg/kg) daily, if the isolate is susceptible, is recommended (strong recommendation; low-quality evidence).

What Is the Treatment for Candida Infection of Implantable Cardiac Devices?

Recommendations

What Is the Treatment for Candida Suppurative Thrombophlebitis?

Recommendations

XI. What Is the Treatment for Candida Osteoarticular Infections?

What Is the Treatment for Candida Osteomyelitis?

Recommendations

What Is the Treatment for Candida Septic Arthritis?

XII. What Is the Treatment for Candida Endophthalmitis?

What Is the General Approach to Candida Endophthalmitis?

Recommendations

83. The extent of ocular infection (chorioretinitis with or without macular involvement and with or without vitritis) should be determined by an ophthalmologist (strong recommendation; low-quality evidence).

84. Decisions regarding antifungal treatment and surgical intervention should be made jointly by an ophthalmologist and an infectious diseases physician (strong recommendation; low-quality evidence).

What Is the Treatment for Candida Chorioretinitis Without Vitritis?

Recommendations

What Is the Treatment for Candida Chorioretinitis With Vitritis?

Recommendations

XIII. What Is the Treatment for Central Nervous System Candidiasis?

Recommendations

XIV. What Is the Treatment for Urinary Tract Infections Due to Candida Species?
What Is the Treatment for Asymptomatic Candiduria?
Recommendations

What Is the Treatment for Symptomatic Candida Cystitis?

Recommendations

What Is the Treatment for Symptomatic Ascending Candida Pyelonephritis?

Recommendations

What Is the Treatment for Candida Urinary Tract Infection Associated With Fungus Balls?

Recommendations

XV. What Is the Treatment for Vulvovaginal Candidiasis?

Recommendations

121. For recurring vulvovaginal candidiasis, 10-14 days of induction therapy with a topical agent or oral fluconazole, followed by fluconazole, 150 mg weekly for 6 months, is recommended (strong recommendation; high-quality evidence).

XVI. What Is the Treatment for Oropharyngeal Candidiasis?

Recommendations

XVII. What Is the Treatment for Esophageal Candidiasis?

Recommendations

INTRODUCTION

In the first section, the panel summarizes background information relevant to the topic. In the second section, the panel poses questions regarding the management of candidiasis, evaluates applicable clinical trial and observational data, and makes recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework [ 2]. The following 17 questions were answered:

I. What is the treatment for candidemia in nonneutropenic patients?

II. Should central venous catheters be removed in nonneutropenic patients with candidemia?

III. What is the treatment for candidemia in neutropenic patients?

IV. What is the treatment for chronic disseminated (hepatosplenic) candidiasis?

V. What is the role of empiric treatment for suspected invasive candidiasis in nonneutropenic patients in the intensive care unit?

VI. Should prophylaxis be used to prevent invasive candidiasis in the intensive care unit setting?

VII. What is the treatment for neonatal candidiasis, including central nervous system infection?

VIII. What is the treatment for intra-abdominal candidiasis?

IX. Does the isolation of Candida species from the respiratory tract require antifungal therapy?

X. What is the treatment for Candida intravascular infections, including endocarditis and infections of implantable cardiac devices?

XI. What is the treatment for Candida osteoarticular infections?

XII. What is the treatment for Candida endophthalmitis?

XIII. What is the treatment for central nervous system candidiasis?

XIV. What is the treatment for urinary tract infections due to Candida species?

XV. What is the treatment for vulvovaginal candidiasis?

XVI. What is the treatment for oropharyngeal candidiasis?

XVII. What is the treatment for esophageal candidiasis?

Infections due to Candida species are major causes of morbidity and mortality in humans, causing a diverse spectrum of clinical disease ranging from superficial and mucosal infections to invasive disease associated with candidemia and metastatic organ involvement. As an entity, candidemia is one of the most common healthcare-associated bloodstream infections in US hospitals, typically ranking as the third or fourth most common cause of healthcare-associated bloodstream infection. A recent multicenter point-prevalence survey identified Candida species as the most commonly isolated healthcare-associated bloodstream pathogen [ 4]. Among patients with candidemia and other forms of invasive candidiasis, non- albicans Candida species constitute approximately 50% of all relevant isolates, representing a steady trend in many regions throughout the world for more than a decade [ 5-12].

The continued reliance on blood cultures, which are notoriously insensitive as markers of disease, remains a significant obstacle to early intervention for this condition. The development of reliable nonculture assays is critical to providing the opportunity for earlier intervention and more targeted antifungal therapy among large numbers of patients in whom traditional blood cultures are insensitive or provide untimely results [ 20].

Species distribution is also a significant challenge for all forms of candidiasis, and there is considerable geographic, center-to-center, and even unit-to-unit variability in the prevalence of pathogenic Candida species [ 8-12]. Indeed, candidiasis is not one but rather several diseases, with each Candida species presenting its own unique characteristics with respect to tissue tropism, propensity to cause invasive disease, virulence, and antifungal susceptibility. A working knowledge of the local epidemiology and rates of antifungal resistance is critical in making informed therapeutic decisions while awaiting culture and susceptibility data.

The echinocandins have emerged as preferred agents for most episodes of candidemia and invasive candidiasis, with the exception of central nervous system (CNS), eye, and urinary tract infections due to these organisms. This preference is based on a strong safety profile, convenience, early fungicidal activity, a trend toward better outcomes based on data from individual studies and combined analyses of candidemia studies [ 19, 25], and the emergence of azole-resistant Candida species. The recent emergence of multidrug-resistant Candida species further complicates the selection of antifungal therapy for the immediate future [ 10, 12, 35-38] as there are no good prospective data to guide therapy.

There is an abundance of clinical data generated from large randomized clinical trials for candidemia, Candida esophagitis, oropharyngeal candidiasis, and prophylaxis studies in special populations, such as patients in intensive care units (ICUs), neonates, and selected transplant recipients, and these studies have led to important insights into optimal therapeutic approaches in these vulnerable populations. For those with less common manifestations of disease, such as osteomyelitis, endophthalmitis, and infective endocarditis, treatment recommendations are largely based on extrapolation from randomized studies of patients with other forms of disease, small retrospective series, and anecdotal reports. Thus, there is a critical need to assess these data in an ongoing manner to provide timely recommendations pertaining to the management of patients with these less common forms of candidiasis.

METHODS

Panel Composition

The most recent version of the Infectious Diseases Society of America (IDSA) guideline on the management of patients with candidiasis was published in 2009 [ 1]. For this update, the IDSA Standards and Practice Guidelines Committee (SPGC) convened a multidisciplinary panel of 12 experts in the management of patients with candidiasis. The panel consisted of 12 members of IDSA, and included 11 adult infectious diseases physicians and 1 pediatric infectious diseases physician. All panel members were selected on the basis of their expertise in clinical and/or laboratory mycology with a focus on candidiasis.

Literature Review and Analysis

Panel members were each assigned to review the recent literature for at least 1 topic, evaluate the evidence, determine the strength of recommendations, and develop written evidence in support of these recommendations. PubMed, which includes Medline (1946 to present), was searched to identify relevant studies for the Candida guideline PICO (population/patient, intervention/indicator, comparator/control, outcome) questions. Search strategies were developed and built by 2 independent health sciences librarians from the Health Sciences Library System, University of Pittsburgh. For each PICO question, the librarians developed the search strategies using PubMed's command language and appropriate search fields. Medical Subject Headings (MeSH) terms and keywords were used for the main search concepts of each PICO question. Articles in all languages and all publication years were included. Initial searches were created and confirmed with input from the guideline committee chairs and group leaders from August to November 2013. The searches were finalized and delivered between late November 2013 and January 2014. After the literature searches were performed, authors continued to review the literature and added relevant articles as needed.

Process Overview

The panel met face-to-face twice and conducted a series of conference calls over a 2-year period. The panel reviewed and discussed all recommendations, their strength, and the quality of evidence. Discrepancies were discussed and resolved, and all final recommendations represent a consensus opinion of the entire panel. For the final version of these guidelines, the panel as a group reviewed all individual sections.

Evidence Review: The GRADE Method

Guidelines and Conflicts of Interest

The expert panel complied with the IDSA policy on conflicts of interest, which requires disclosure of any financial or other interest that may be construed as constituting an actual, potential, or apparent conflict. Panel members were provided IDSA's conflicts of interest disclosure statement and were asked to identify ties to companies developing products that may be affected by promulgation of the guideline. Information was requested regarding employment, consultancies, stock ownership, honoraria, research funding, expert testimony, and membership on company advisory committees. Decisions were made on a case-by-case basis as to whether an individual's role should be limited as a result of a conflict. Potential conflicts of interests are listed in the Acknowledgments section.

Consensus Development Based on Evidence

The panel obtained feedback from 3 external peer reviewers. The guidelines were reviewed and endorsed by the MSG, the American Academy of Pediatrics (AAP) and the Pediatric Infectious Diseases Society (PIDS). The guideline was reviewed and approved by the IDSA SPGC and the IDSA Board of Directors prior to dissemination.

Revision Dates

At annual intervals, the panel chairs will be asked for their input on the need to update the guideline based on an examination of the current literature. The IDSA SPGC will consider this input and determine the necessity and timing of an update. If warranted, the entire panel or a subset thereof will be convened to discuss potential changes.

BACKGROUND

Antifungal Agents

Pharmacologic Considerations for Therapy for Candidiasis

Systemic antifungal agents shown to be effective for the treatment of invasive candidiasis comprise 4 major categories: the polyenes (amphotericin B [AmB] deoxycholate, liposomal AmB, AmB lipid complex [ABLC], and amphotericin B colloidal dispersion [ABCD, not available in the United States]), the triazoles (fluconazole, itraconazole, voriconazole, and posaconazole), the echinocandins (caspofungin, anidulafungin, and micafungin), and flucytosine. Data from a recently completed clinical trial comparing isavuconazole to an echinocandin for treatment of invasive candidiasis are unavailable at this time. Clinicians should become familiar with strategies to optimize efficacy through an understanding of relevant pharmacokinetic properties.

Amphotericin B

Most experience with AmB is with the deoxycholate preparation. Three lipid formulations of AmB have been developed and approved for use in humans: ABLC, ABCD, and liposomal AmB. These agents possess the same spectrum of activity as AmB deoxycholate, but daily dosing regimens and toxicity profiles differ for each agent. The 3 lipid formulation AmB agents have different pharmacological properties and rates of treatment-related adverse events and should not be interchanged without careful consideration. In this document, a reference to AmB, without a specific dose or other discussion of form, should be taken to be a reference to the general use of any of the AmB preparations. For most forms of invasive candidiasis, the typical intravenous dosage for AmB deoxycholate is 0.5-0.7 mg/kg daily, but dosages as high as 1 mg/kg daily should be considered for invasive Candida infections caused by less susceptible species, such as C. glabrata and C. krusei. The typical dosage for lipid formulation AmB is 3-5 mg/kg daily when used for invasive candidiasis. Nephrotoxicity is the most common serious adverse effect associated with AmB deoxycholate therapy, resulting in acute kidney injury in up to 50% of recipients and an electrolyte-wasting tubular acidosis in a majority of patients [ 40, 41]. Lipid formulations of AmB are more expensive than AmB deoxycholate, but all have considerably less nephrotoxicity [ 42, 43]. Most observers agree that lipid formulations, with the exception of ABCD, have fewer infusion-related reactions than AmB deoxycholate. The impact of the pharmacokinetics and differences in toxicity of lipid formulations of AmB have not been formally examined in clinical trials. We are not aware of any forms of candidiasis for which lipid formulations of AmB are superior to AmB deoxycholate in terms of clinical efficacy. In addition, we are not aware of any situation in which lipid formulations should not be used, with the exception of urinary tract infections, because of reduced renal excretion of these formulations. Animal model studies suggest a pharmacokinetic and therapeutic advantage for liposomal AmB in the CNS [ 44]. Data demonstrating that AmB deoxycholate-induced nephrotoxicity is associated with a 6.6-fold increase in mortality have led many clinicians to use lipid formulations of AmB in proven or suspected candidiasis, especially among patients in a high-risk environment, such as an ICU [ 45].

Triazoles

Fluconazole, itraconazole, voriconazole, posaconazole, and a new expanded-spectrum triazole, isavuconazole, demonstrate similar activity against most Candida species [ 46-51]. Each of the azoles has less activity against C. glabrata and C. krusei than against other Candida species. All of the azole antifungals inhibit cytochrome P450 enzymes to some degree [ 52]. Thus, clinicians must carefully consider the influence on a patient's drug regimen when adding or removing an azole. In large clinical trials, fluconazole demonstrated efficacy comparable to that of AmB deoxycholate for the treatment of candidemia [ 21, 22] and is also considered to be standard therapy for oropharyngeal, esophageal, and vaginal candidiasis, as well as urinary tract infections [ 53, 54]. Fluconazole is readily absorbed, with oral bioavailability resulting in concentrations equal to approximately 90% of those achieved by intravenous administration [ 55]. Absorption is not affected by food consumption, gastric pH, or disease state. Among the triazoles, fluconazole has the greatest penetration into the cerebrospinal fluid (CSF) and vitreous, achieving concentrations of >70% of those in serum [ 56-59]. For this reason, it is often used in the treatment of CNS and intraocular Candida infections. Fluconazole achieves urine concentrations that are 10-20 times the concentrations in serum and, thus, is the preferred treatment option for symptomatic cystitis [ 59]. For patients with invasive candidiasis, fluconazole should be administered with an average loading dose of 800 mg (12 mg/kg), followed by an average daily dose of 400 mg (6 mg/kg). The higher-dose level (800 mg daily, 12 mg/kg) is often recommended for therapy of susceptible C. glabrata infections, but this has not been validated in clinical trials. Fluconazole elimination is almost entirely renal; thus, a dose reduction is needed in patients with creatinine clearance <50 mL/minute.

Voriconazole has demonstrated effectiveness for both mucosal and invasive candidiasis [ 23, 63]. Its clinical use has been primarily for step-down oral therapy in patients with infection due to C. krusei and fluconazole-resistant, voriconazole-susceptible C. glabrata. CSF and vitreous concentrations are >50% of serum concentration, and voriconazole has been shown to be efficacious in case series for these infection sites [ 64-66]. Voriconazole does not accumulate in active form in the urine and thus should not be used for urinary candidiasis. The oral bioavailability of voriconazole is excellent and is not affected by gastric pH, but it decreases when the drug is administered with food [ 67, 68]. In adults, the recommended oral dosing regimen for candidiasis includes a loading dose of 400 mg (6 mg/kg) twice daily for 2 doses, followed by 200-300 mg (3-4 mg/kg) twice daily.

Common polymorphisms in the gene encoding the primary metabolic enzyme for voriconazole result in wide variability of serum levels [ 72]. Drug-drug interactions are common with voriconazole and should be considered when initiating and discontinuing treatment with this compound [ 52]. Voriconazole has not been studied systematically in fluconazole-resistant Candida species, and with the exception of C. krusei, use is currently discouraged. Each of the triazoles can be associated with uncommon side effects. However, several effects are unique to voriconazole or more commonly associated with higher voriconazole concentrations, including hepatic injury, visual side effects, photosensitivity, periostitis, and CNS side effects [ 73-75].

Posaconazole does not have an indication for primary candidiasis therapy. It demonstrates in vitro activity against Candida species that is similar to that of voriconazole, but clinical data are inadequate to make an evidence-based recommendation for treatment of candidiasis other than oropharyngeal candidiasis [ 76]. Posaconazole is currently available as an extended-release tablet, an oral suspension, and an intravenous solution. The tablet formulation, given as 300 mg twice daily for 2 doses, then 300 mg daily produces predictable serum concentrations and excellent drug exposure and requires only once-daily dosing [ 77, 78]. The oral suspension has unpredictable bioavailability [ 79-81]. Intravenous posaconazole is given as 300 mg twice daily for 2 doses, then 300 mg daily.

Isavuconazole is a recently approved expanded-spectrum triazole antifungal with excellent in vitro activity against Candida species. Preliminary analysis of the recently completed large international double-blind trial comparing isavuconazole to an echinocandin for invasive candidiasis suggests that isavuconazole did not meet criteria for noninferiority (personal communication, Astellas US).

Echinocandins

Caspofungin, anidulafungin, and micafungin are available only as parenteral preparations [ 82-84]. The minimum inhibitory concentrations (MICs) of the echinocandins are low for most Candida species, including C. glabrata and C. krusei [ 48-50]. However, recent case series have described treatment failure associated with resistant strains of C. glabrata [ 85, 86]. Candida parapsilosis demonstrates innately higher MICs to the echinocandins than do most other Candida species, which raises the concern that C. parapsilosis may be less responsive to the echinocandins.

Flucytosine

Flucytosine demonstrates broad antifungal activity against most Candida species, with the exception of C. krusei. The compound is available in the United States only as an oral formulation. The drug has a short half-life (2.4-4.8 hours) and is ordinarily administered at a dosage of 25 mg/kg 4 times daily for patients with normal renal function. Flucytosine demonstrates excellent absorption after oral administration (80%-90%), and most of the drug is excreted unchanged (microbiologically active) in the urine [ 89, 90]; dose adjustment is necessary for patients with renal dysfunction [ 91, 92].The compound exhibits high penetration into the CNS and eye. Concentration-dependent toxicity results in bone marrow suppression and hepatitis.

Flucytosine is usually given in combination with another antifungal agent due to a high rate of emergence of resistance during monotherapy [ 93]. The most common use of flucytosine in the setting of Candida infection is in combination with AmB for patients with more refractory infections, such as Candida endocarditis, meningitis, or endophthalmitis. Occasionally, it is used for the treatment of symptomatic urinary tract candidiasis due to fluconazole-resistant C. glabrata [ 94].

Pediatric Dosing

Flucytosine clearance is directly proportional to glomerular filtration rate, and infants with a very low birth weight may accumulate high plasma concentrations because of poor renal function due to immaturity [ 101]. Thus, the use of flucytosine without careful monitoring of serum drug levels is discouraged in this group of patients.

Caspofungin and micafungin are approved by the US Food and Drug Administration (FDA) for use in children. Caspofungin dosing is based on body surface area rather than weight. Dosing in children is a loading dose of 70 mg/m ², followed by 50 mg/m ²/day. Preliminary studies suggest an optimal dose of caspofungin in neonates of 25 mg/m ²/day. The current recommendation for micafungin for invasive candidiasis is 2 mg/kg/day, with the option to increase to 4 mg/kg/day in children <40 kg. The optimal dose of micafungin in neonates is unknown, but likely to be 10 mg/kg/day or greater [ 109]. Anidulafungin should be dosed at 1.5 mg/kg/day for neonates and children [ 110-112].

Considerations During Pregnancy

AmB is the treatment of choice for invasive candidiasis in pregnant women [ 113]. Fluconazole, itraconazole, posaconazole, and isavuconazole should be avoided in pregnant women, especially those in the first trimester, because of the possibility of birth defects associated with their use. Voriconazole is contraindicated during pregnancy because of fetal abnormalities observed in animals. There are few data concerning the echinocandins; thus, their use is cautioned during pregnancy. Flucytosine is contraindicated during pregnancy because of fetal abnormalities observed in animals.

Therapeutic Drug Monitoring

Therapeutic drug monitoring (TDM) for itraconazole, voriconazole, posaconazole, and flucytosine has been shown to be useful for optimizing efficacy and limiting toxicity in patients receiving therapy for a variety of invasive fungal infections, including mucosal and invasive candidiasis [ 114]. The basis for TDM is widely variable concentrations among patients and a strong relationship between concentration and efficacy and/or toxicity.

Antifungal Susceptibility Testing

Intensive efforts to develop standardized, reproducible, and relevant susceptibility testing methods for fungi have resulted in the development of the Clinical and Laboratory Standards Institute (CLSI) M27-A3 and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodologies for susceptibility testing of yeasts [ 120]. Interpretive breakpoints for susceptibility take into account the MIC, as well as pharmacokinetic/pharmacodynamic data and animal model data. They are reported for each species. Breakpoints have been established for most, but not all, drugs for the 5 most common Candida species [ 47, 50, 121, 122] (Table 1).

In many instances, clinical breakpoints have decreased from those used previously. For example, the prior Candida clinical breakpoint for susceptibility to fluconazole was ≤8 mg/L. With the new interpretation, the susceptible value has been reduced to ≤2 mg/L for C. albicans. For C. glabrata, there is no breakpoint established for susceptibility to fluconazole, itraconazole, posaconazole, or voriconazole (Table 1).

When there is no clinical breakpoint established, the epidemiologic cutoff value (ECV) based on an examination of the distribution of MICs within a species can be used. The ECV is defined as the MIC value that excludes non-wild type strains, 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.

The susceptibility of Candida to the currently available antifungal agents is generally predictable if the species of the infecting isolate is known. Currently, antifungal resistance in C. albicans is uncommon. However, individual isolates may not necessarily follow this general pattern [ 124]. Recent surveillance studies suggest that triazole resistance among C. glabrata isolates has increased to a degree that is it difficult to rely upon these agents for therapy in the absence of susceptibility testing [ 12, 125, 126]. A similar trend has begun to emerge for a smaller proportion of C. glabrata isolates and the echinocandins [ 35, 85, 125]. The value of susceptibility testing for other Candida species is less clear, although resistance among C. tropicalis and C. parapsilosis has been reported from tertiary care institutions that have extensive use of antifungal agents [ 127, 128]. Because of these trends, susceptibility testing is increasingly used to guide the management of candidemia and invasive candidiasis.

Diagnosis of Candidiasis

Cultures of blood or other samples collected under sterile conditions have long been considered diagnostic gold standards for invasive candidiasis. Nonculture diagnostic tests, such as antigen, antibody, or β-D-glucan detection assays, and polymerase chain reaction (PCR) are now entering clinical practice as adjuncts to cultures. If used and interpreted judiciously, these tests can identify more patients with invasive candidiasis and better direct antifungal therapy. To fully realize the benefits of combining culture and nonculture tests, however, clinicians must carefully consider the types of invasive candidiasis, understand the strengths and limitations of each assay, and interpret test results in the context of the clinical setting.

Use of Cultures in the Diagnosis of Invasive Candidiasis

The overall sensitivity of blood cultures for diagnosing invasive candidiasis is roughly 50% [ 20]. The limit of detection of blood cultures is ≤1 colony-forming unit/mL [ 130, 131]. The limit of detection for cultures is at or below that of PCR [ 132-135]. As such, blood cultures should be positive during the vast majority of active Candida bloodstream infections. They may be negative in cases of extremely low-level candidemia, intermittent candidemia, deep-seated candidiasis that persists after sterilization of the bloodstream, or deep-seated candidiasis resulting from direct inoculation of Candida in the absence of candidemia. Blood cultures are limited by slow turnaround times (median time to positivity of 2-3 days, ranging from 1 to ≥7 days), and the fact that they may become positive relatively late in the disease course [ 130, 136]. Cultures of tissues or fluid recovered from infected sites during deep-seated candidiasis also exhibit poor sensitivity (often <50%) and slow turnaround times, and require invasive sampling procedures that may be dangerous or contraindicated due to underlying medical conditions [ 137].

Antigen and Antibody Detection

Candida antigen and anti- Candida antibody detection has gained greater acceptance in Europe than the United States. In general, antigen detection is limited by rapid clearance from the bloodstream [ 138]. Concerns have been expressed about the reliability of antibody detection in immunosuppressed hosts, but assays have performed well in patients with neutropenia and cell-mediated immune defects (including hematopoietic cell and solid organ transplant recipients) [ 138, 139]. Serum immunoglobulin G (IgG) responses against specific antigens have typically performed better than immunoglobulin M (IgM) responses, suggesting that many patients mount amnestic responses or have ongoing, subclinical tissue invasion [ 139]. The best-studied test is a combined mannan/antimannan antibody assay, which is currently approved for use in Europe, but not the United States (Platelia Candida Ag and Ab; Bio-Rad). In a meta-analysis of 14 studies, the sensitivity/specificity for the diagnosis of invasive candidiasis of mannan and antimannan IgG individually were 58%/93% and 59%/83%, respectively [ 140]. Values for the combined assay were 83% and 86%, with best performances for C. albicans, C. glabrata, and C. tropicalis infections. In one study of candidemia, at least one test was positive before blood culture in 73% of patients [ 141]. In a study of hepatosplenic candidiasis, at least one test was positive before radiographic changes in 86% of patients [ 142]. This assay is not used widely in the United States, and its role in the diagnosis and management of invasive candidiasis is unclear.

β-D-Glucan detection

β-D-glucan is a cell wall constituent of Candida species, Aspergillus species, Pneumocystis jiroveci, and several other fungi. A serum β-D-glucan assay (Fungitell; Associates of Cape Cod, East Falmouth, Massachusetts) has been approved by the FDA as an adjunct to cultures for the diagnosis of invasive fungal infections. True-positive results are not specific for invasive candidiasis, but rather suggest the possibility of an invasive fungal infection. For this reason, among patient populations that are also at risk for invasive mold infections, such as hematopoietic cell transplant recipients, β-D-glucan offers a theoretical advantage over more narrow assays for candidiasis. β-D-glucan detection can identify cases of invasive candidiasis days to weeks prior to positive blood cultures, and shorten the time to initiation of antifungal therapy [ 143]. Prophylactic or empiric antifungal treatment is likely to impact test performance. On the one hand, antifungal agents may reduce diagnostic sensitivity [ 144-146], but decreasing β-D-glucan levels may also correlate with responses to antifungal therapy [ 147].

In meta-analyses of β-D-glucan studies, the pooled sensitivity and specificity for diagnosing invasive candidiasis were 75%-80% and 80%, respectively [ 144-146]. A number of issues complicate the interpretation of these data, including uncertainties about the best cutoff value for a positive result, number of positive tests required to establish a diagnosis, and optimal timing and frequency of testing among at-risk patients. There is marked heterogeneity among studies in how they address these issues, as well as in patient and control populations, range and type of fungal pathogens targeted, invasive candidiasis disease entities, distributions of Candida species, prior antifungal use, specific β-D-glucan assays employed, and other aspects of study design and statistical interpretation.

The role of β-D-glucan testing of samples other than serum in the diagnosis of invasive candidiasis is not established. Studies of β-D-glucan testing of CSF reported sensitivity and specificity of 100% and 95%-98%, respectively, for the diagnosis of non- Candida fungal CNS infections [ 156, 157]. β-D-glucan detection was highly sensitive and specific in a rabbit model of hematogenous C. albicans meningoencephalitis [ 158]. Limited data suggest that positive predictive values of β-D-glucan in bronchoalveolar lavage fluid are poor for diagnosing fungal pneumonia [ 159]. There are case reports for testing of samples collected from other sites of invasive Candida infection [ 160].

Polymerase Chain Reaction

Candida PCR shares many of the potential benefits and shortcomings of β-D-glucan detection. Compared to cultures, PCR assays of various blood fractions have been shown to shorten the time to diagnosis of invasive candidiasis and initiation of antifungal therapy [ 134, 135]. The pooled sensitivity and specificity of PCR for suspected invasive candidiasis in a recent meta-analysis were 95% and 92%, respectively [ 134]. In probable invasive candidiasis, sensitivity of PCR and blood cultures was 85% and 38%, respectively. The impact of antifungal agents on diagnostic sensitivity was unclear. Data among patients colonized with Candida were surprisingly limited, but there was a trend toward lower specificity.

A major limitation of PCR studies is the lack of standardized methodologies and multicenter validation of assay performance. A multicenter US study assessing the performance of a self-contained instrument that amplifies and detects Candida DNA by PCR and T2 magnetic resonance (T2 Biosystems, Lexington, Massachusetts), respectively, has been completed [ 163]. This assay is FDA approved, but its role in the early diagnosis and management of candidemia remains unclear until more data are available. PCR has potential advantages over β-D-glucan or antigen-antibody assays, including the capacity for species identification, detection of molecular markers for drug resistance, and multiplex formatting. In Europe, a whole-blood, multiplex real-time PCR assay (SeptiFast, Roche) that detects 19 bacteria and 6 fungi ( C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, and Aspergillus fumigatus) has been investigated in several studies of sepsis and neutropenic fever. Among patients with candidemia in one study, the sensitivity of the test was 94%; the only negative result was observed with C. famata candidemia [ 164]. The role of PCR in testing samples other than blood is not established.

Nonculture Diagnostic Testing for Blood Culture-Negative Invasive Candidiasis

The overwhelming majority of studies have examined nonculture diagnostics in the setting of candidemia. More limited data on deep-seated candidiasis demonstrate how these tests may identify cases that are currently missed by blood cultures. In a single-center study of prospectively enrolled patients, the sensitivities/specificities of the Fungitell β-D-glucan assay and a real-time quantitative PCR assay (ViraCor-IBT, Lee's Summit, Missouri) for invasive candidiasis were 56%/73% and 80%/70%, respectively [ 132]. More importantly, the sensitivities of contemporaneously collected blood cultures, β-D-glucan assay, and PCR samples among patients with deep-seated candidiasis (mostly intra-abdominal candidiasis) were 21%, 67%, and 88%, respectively. The combination of either a positive blood culture or positive β-D-glucan assay had sensitivity for invasive candidiasis of 79%; a positive blood culture or positive PCR sample was 98% sensitive. A second study investigated the serum β-D-glucan assay, Candida score (a predictive score for invasive candidiasis based on clinical parameters and burden of Candida colonization), and Candida colonization indices (predictive scores based on burden of colonization) among prospectively enrolled patients who were in surgical ICUs at 2 hospitals and who were at particularly high risk for intra-abdominal candidiasis [ 143]. The sensitivity/specificity of 2 consecutive positive β-D-glucan results was 65%/78%. In contrast, the sensitivity of blood cultures was only 7%. In addition to identifying cases missed by blood cultures, the β-D-glucan assay was positive a median of 5 and 6 days prior to positive intra-abdominal cultures and institution of antifungal therapy, respectively. The sensitivities of Candida scores and colonization indices were comparable to β-D-glucan, but specificities were poorer (≤43%).

The interpretation of specificity in these studies was complicated by the fact that negative controls were also at risk for invasive candidiasis. Therefore, it is unclear if positive test results for controls were false positives (as defined in the studies) or true positives that were missed due to the poor sensitivity of intra-abdominal and blood cultures. Indeed, this is a central challenge in assessing new diagnostics for invasive candidiasis: How can test performance be accurately measured when the gold standard is inadequate?

I. What Is the Treatment for Candidemia in Nonneutropenic Patients?

Recommendations

1. An echinocandin (caspofungin: loading dose 70 mg, then 50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose 200 mg, then 100 mg daily) is recommended as initial therapy (strong recommendation; high-quality evidence).

3. Testing for azole susceptibility is recommended for all bloodstream and other clinically relevant Candida isolates. Testing for echinocandin susceptibility should be considered in patients who have had prior treatment with an echinocandin and among those who have infection with C. glabrata or C. parapsilosis (strong recommendation; low-quality evidence).

6. Lipid formulation AmB (3-5 mg/kg daily) is a reasonable alternative if there is intolerance, limited availability, or resistance to other antifungal agents (strong recommendation; high-quality evidence).

7. Transition from AmB to fluconazole is recommended after 5-7 days among patients who have isolates that are susceptible to fluconazole, who are clinically stable, and in whom repeat cultures on antifungal therapy are negative (strong recommendation; high-quality evidence).

10. All nonneutropenic patients with candidemia should have a dilated ophthalmological examination, preferably performed by an ophthalmologist, within the first week after diagnosis (strong recommendation; low-quality evidence).

11. Follow-up blood cultures should be performed every day or every other day to establish the time point at which candidemia has been cleared (strong recommendation; low-quality evidence).

Evidence Summary

There are significant challenges in treating candidemia and invasive candidiasis. First, the infection is associated with high mortality. Earlier therapy is associated with better overall outcomes [ 14-18], but there remain significant limitations to early diagnosis. The development of rapid diagnostic assays has been slow; thus, clinicians continue to rely on cultures to establish a diagnosis [ 20]. Second, there is considerable geographic, center-to-center, and even unit-to-unit variability of species causing candidemia [ 12]; each Candida species presents its own unique challenges with respect to virulence, pathogenicity, and antifungal susceptibility. Third, despite the overall robust nature of the randomized controlled trials examining treatment of candidemia and other forms of invasive candidiasis, no single trial has demonstrated the clear superiority of one therapeutic agent over another [ 19, 21-34]. Fourth, the recent emergence of multidrug-resistant Candida species will complicate the selection of antifungal therapy in the immediate future [ 10, 12, 35-38].

The selection of any particular agent for the treatment of candidemia should take into account a history of recent azole or echinocandin exposure, a history of intolerance to an antifungal agent, the dominant Candida species and current susceptibility data in a particular clinical unit, severity of illness, relevant comorbidities, and evidence of involvement of the CNS, cardiac valves, and/or visceral organs. The risk of mortality among patients with candidemia ranges from 10% to 47% [ 6-8, 13], but the actual disease-associated mortality is more likely 10%-20%, with the risk of death being related to increasing age, higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, infecting Candida species, immunosuppressive agents, preexisting renal dysfunction, venous catheter retention, and antifungal selection [ 8, 19, 165-167]. Early initiation of effective antifungal therapy and source control is critical in the successful treatment of candidemia, as demonstrated by data suggesting significantly higher mortality rates among patients with candidemia in whom antifungal therapy was delayed or considered inadequate, and/or in whom source control was not promptly attained [ 14, 16-18, 168].

The echinocandins demonstrate significant fungicidal activity against most Candida species, and each of these agents has demonstrated success in approximately 70%-75% of patients in randomized, comparative clinical trials [ 24-28, 31, 32]. Despite the need for intravenous administration, their superb efficacy, favorable safety profile, limited drug interactions, and concerns about fluconazole resistance have led many experts to favor the echinocandins as initial therapy for most adult patients with candidemia. Few studies comparing different echinocandins have been performed [ 28, 169], but most experts agree that these agents are sufficiently similar to be considered interchangeable.

Only one study comparing an echinocandin to fluconazole has been performed, and the results from this study suggest a strong trend toward more favorable outcomes with anidulafungin compared with fluconazole as primary therapy for candidemia [ 27]. In a subanalysis of patients with C. albicans infections, there was a significant improvement in global response among those receiving anidulafungin [ 31]. In another subanalysis of critically ill patients from this trial, those receiving anidulafungin had significantly better responses at end of therapy compared with fluconazole-treated patients [ 170]. A combined analysis of 7 of the largest randomized clinical trials comparing treatment for candidemia and invasive candidiasis and involving almost 2000 patients found that initial therapy with an echinocandin was a significant predictor of survival [ 19]. This same analysis identified higher APACHE II score, older age, and infection with C. tropicalis to be associated with worse outcomes and higher mortality [ 19].

In many parts of the world, based on success rates reported from well-designed clinical trials, fluconazole remains standard therapy for patients with candidemia [ 21-23, 27]. However, in light of recent data on the efficacy of echinocandins and increasing resistance to fluconazole, the Expert Panel believes that fluconazole should be considered first-line therapy only in patients who are hemodynamically stable, who have had no previous exposure to azoles, and who do not belong in a group at high risk for C. glabrata infection, including those who are elderly, have underlying malignancy, or are diabetic.

In previous iterations of these guidelines, the Expert Panel favored fluconazole over an echinocandin for treatment of candidemia due to C. parapsilosis based on reports of decreased in vitro activity of echinocandins against this species and of echinocandin resistance among some isolates [ 11, 12, 172-175]. In spite of these laboratory observations, there have been no clinical studies that have demonstrated superiority of fluconazole over the echinocandins for the treatment of C. parapsilosis infections. Moreover, recent observational data from Spain among almost 200 patients with candidemia due to C. parapsilosis suggested no difference in outcome among patients who received initial treatment with an echinocandin compared with those who received other regimens [ 176]. Any recommendation supporting fluconazole over an echinocandin is generally based on theoretical concerns rather than on observed therapeutic failure of the echinocandins in these patients.

Voriconazole was shown to be as effective for candidemia and invasive candidiasis as the comparator regimen of sequential therapy with AmB for 4-7 days followed by fluconazole [ 23]. Voriconazole possesses activity against most Candida species, including C. krusei [ 177, 178], but the need for more frequent administration, less predictable pharmacokinetics, more drug interactions, and poor tolerance to the drug make it less attractive for initial therapy. Parenteral voriconazole appears to be safe when administered to those with baseline renal dysfunction, despite concerns based on possible nephrotoxicity of its vehicle (sulfobutylether β-cyclodextrin) [ 70]. Voriconazole does not provide predictable activity against fluconazole-resistant C. glabrata [ 47, 177-179]. It does, however, fill an important niche for patients who have fluconazole-resistant isolates of C. krusei, C. guilliermondii, or C. glabrata that are voriconazole susceptible and who are ready for transition from an echinocandin or AmB to oral therapy.

AmB has broad activity against all Candida species with the exception of C. lusitaniae, which is frequently resistant. Lipid formulations of AmB are preferred to AmB deoxycholate and should be considered when there is a history of intolerance to echinocandins and/or azoles, the infection is refractory to other therapy, the organism is resistant to other agents, or there is a suspicion of infection due to non- Candida yeasts, such as Cryptococcus neoformans or Histoplasma capsulatum. Liposomal AmB, 3 mg/kg daily, has been shown to be as effective as micafungin for treatment of candidemia [ 26].

The emergence of echinocandin-resistant and echinocandin-/azole-resistant Candida isolates, especially C. glabrata, clearly has been documented, and this finding appears to be associated with worse clinical outcomes [ 10, 12, 35-37, 181, 182]. Fluconazole resistance is a frequent finding among echinocandin-resistant isolates [ 9, 10], further complicating therapeutic choices. There are currently no prospective data to inform a decision, but the Expert Panel favors lipid formulation AmB for treatment of patients with candidemia due to proven or suspected fluconazole and echinocandin-resistant (multidrug resistant) strains until more data become available.

Follow-up blood cultures every day or every other day until demonstration of clearance of Candida from the bloodstream are helpful to establish the appropriate duration of antifungal therapy. If there are no metastatic complications of candidemia, the duration of therapy with systemic antifungal agents should be 14 days following documented clearance of Candida species from the bloodstream and resolution of signs and symptoms attributable to infection. This recommendation is based on the results of several prospective, randomized trials in which this rule has been universally and successfully applied, and it is generally associated with few complications and relapses [ 21-23, 26-28, 30, 32-34].

II. Should Central Venous Catheters Be Removed in Nonneutropenic Patients With Candidemia?

Recommendation

Evidence Summary

The Expert Panel members strongly believe that CVCs should be removed if this can be performed safely when candidemia is documented in the nonneutropenic patient. It is intuitive that each patient with candidemia must be managed individually with respect to CVC removal or retention, but on balance, the bulk of data supports an approach that leads to early removal among nonneutropenic patients in whom the catheter is a likely source of infection.

Among neutropenic patients, the role of the gastrointestinal tract as a source for disseminated candidiasis is evident from autopsy studies, but in an individual patient, it is difficult to determine the relative contributions of the gastrointestinal tract vs the CVC as the primary source of candidemia [ 195, 201]. An exception is made for candidemia due to C. parapsilosis, which is very frequently associated with CVCs [ 188, 189, 200, 202]. A recent retrospective analysis that included mostly nonneutropenic patients underscored the influence of early CVC removal, specifically among patients with C. parapsilosis bloodstream infection, on clinical outcome [ 176].

III. What Is the Treatment for Candidemia in Neutropenic Patients?

Recommendations

Evidence Summary

Candidemia that develops in neutropenic patients is a life-threatening infection associated with acute disseminated candidiasis, a sepsis-like syndrome, multiorgan failure, and death. Outcomes are particularly poor in people with protracted neutropenia, such as that which develops after induction therapy for hematologic malignancies [ 190, 203, 204]. Candidemia associated with C. tropicalis is associated with particularly poor outcomes in neutropenic hosts. Chronic disseminated candidiasis (hepatosplenic candidiasis) can ensue as a complication of candidemia in neutropenic patients, especially when patients with gastrointestinal tract mucositis do not receive antifungal prophylaxis. There are no adequately powered randomized controlled trials of treatment of candidemia in neutropenic patients. The data are largely derived from single-arm studies, small subsets of randomized controlled studies that have enrolled mostly nonneutropenic patients, and pooled outcomes from randomized trials [ 205, 206].

Historically, candidemia in neutropenic patients was treated with an AmB formulation. The availability of voriconazole and the echinocandins has led to greater use of these agents, but without compelling clinical data. The extensive use of fluconazole for prophylaxis to prevent invasive candidiasis in neutropenic patients and the lack of meaningful prospective data has led to a diminished therapeutic role for this agent among these patients, except for use as maintenance, or step-down therapy after organism species and susceptibilities are obtained in clinically stable patients [ 207].

IV. What Is the Treatment for Chronic Disseminated (Hepatosplenic) Candidiasis?

Recommendations

Evidence Summary

Chronic disseminated candidiasis is an uncommon syndrome seen almost entirely in patients who have hematologic malignancies and who have just recovered from neutropenia [ 217-219]. Candida albicans is the species most commonly isolated, but C. tropicalis, C. glabrata, C. krusei, and other Candida species also have been implicated. Fever, right upper quadrant discomfort, nausea, and elevation of liver enzymes occur following return of neutrophils and persist for months unless treatment is initiated. Contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography-CT (PET-CT), and sometimes ultrasound have all been shown to be useful for diagnosis and for follow-up [ 217, 218, 220, 221]. Biopsy of lesions may reveal budding yeasts and hyphae, but organisms may not be seen on biopsy specimens and often do not grow in culture, leading some to suggest that chronic disseminated candidiasis represents an immune reconstitution syndrome [ 219].

V. What Is the Role of Empiric Treatment for Suspected Invasive Candidiasis in Nonneutropenic Patients in the Intensive Care Unit?

Recommendations

29. Preferred empiric therapy for suspected candidiasis in nonneutropenic patients in the ICU is an echinocandin (caspofungin: loading dose of 70 mg, then 50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose of 200 mg, then 100 mg daily) (strong recommendation; moderate-quality evidence).

31. Lipid formulation AmB, 3-5 mg/kg daily, is an alternative if there is intolerance to other antifungal agents (strong recommendation; low-quality evidence).

32. Recommended duration of empiric therapy for suspected invasive candidiasis in those patients who improve is 2 weeks, the same as for treatment of documented candidemia (weak recommendation; low-quality evidence).

33. For patients who have no clinical response to empiric antifungal therapy at 4-5 days and who do not have subsequent evidence of invasive candidiasis after the start of empiric therapy or have a negative non-culture-based diagnostic assay with a high negative predictive value, consideration should be given to stopping antifungal therapy (strong recommendation; low-quality evidence).

Evidence Summary

Candida species are an increasing cause of invasive infection in nonneutropenic patients in the ICU; half to two-thirds of all episodes of candidemia occur in an ICU [ 5, 14, 167, 170, 234]. Candida bloodstream infections are associated with increased ICU and hospital stay [ 129, 235]. Most estimates of attributable mortality rates for invasive candidiasis in this setting are 30%-40% [ 167, 170]. In those patients who have septic shock due to Candida species and who do not have adequate source control or antifungal therapy begun within 24 hours, the mortality approaches 100% [ 14]. Prompt initiation of appropriate antifungal therapy has been associated with as much as a 50% reduction in mortality [ 14, 17, 18, 236]. Prompt and appropriate antifungal therapy is often delayed because of the relative insensitivity of blood cultures, the time needed for blood cultures to yield growth, the possibility of negative blood cultures with invasive abdominal candidiasis, and the lack of specific clinical signs and symptoms. Strategies for initiating empiric antifungal therapy include an evaluation of risk factors and use of surrogate markers.

Optimal utilization of risk factors and colonization status to derive clinical scoring systems and the interpretation of non-culture-based diagnostic tests to identify patients with invasive candidiasis to initiate early empiric antifungal therapy have been the subjects of many investigations. Retrospective and single-center studies have yielded conflicting results, depending on unique patient populations. Well-designed prospective clinical trials in this area have been difficult to perform, and many unanswered questions remain.

Risk factors for development of invasive candidiasis include Candida colonization, severity of illness, exposure to broad-spectrum antibiotics, recent major surgery, particularly abdominal surgery, necrotizing pancreatitis, dialysis, parenteral nutrition, corticosteroids, and the use of CVCs [ 237, 238]. Empiric therapy based solely on colonization with Candida species appears inadequate [ 16, 239]. Prospective studies evaluating the extent of Candida colonization with scores or indices have not been shown to change management, and they are labor intensive and expensive [ 234].

Surrogate markers that have been evaluated in the ICU setting include β-D-glucan, mannan-antimannan antibodies, and PCR testing. β-D-glucan appears to be more sensitive than Candida colonization scores or indices, but appears to have low positive predictive value [ 245-248]. False-positive results are a problem, as noted in the Background section. The optimal timing and number of samples is unknown. In a recent prophylaxis trial of high-risk ICU patients, β-D-glucan testing performed twice weekly identified 87% of patients with proven candidiasis [ 249]. Small studies basing preemptive therapy on β-D-glucan testing suggest that the high negative predictive value of this test could be useful in excluding invasive candidiasis in the ICU setting [ 151, 248, 250-252].

Combined mannan-antimannan testing has variable sensitivity and specificity [ 142, 253]. Real-time PCR appears to have similar sensitivity to β-D-glucan for the diagnosis of candidemia, but may be more sensitive for the diagnosis of other forms of invasive candidiasis [ 132]. Tests using magnetic biosensor technology for the rapid detection of Candida species from whole-blood samples (T2 Biosystems) are also promising [ 163]. Recommendations for the clinical use of these tests are challenging without robust data in the at-risk ICU population.

Limited clinical studies have evaluated the efficacy of empiric strategies. Retrospective studies indicate potential for higher survival when empiric antifungal therapy is given to high-risk patients [ 254]. Prospective clinical trials of empiric antifungal therapy in the ICU are difficult to conduct and have yielded conflicting results. Selected older studies, including those in specific patient populations, such as those with prior gastrointestinal surgery or bowel perforation, demonstrated potential benefit [ 255, 256]. In a randomized clinical trial of ICU patients at risk for invasive candidiasis and with unexplained fever, empiric fluconazole (800 mg daily for 14 days) was not associated with better outcomes when compared with placebo [ 257]. A recent study comparing caspofungin to placebo among ICU patients with signs of infection, Candida colonization, and clinical risk factors for invasive candidiasis was stopped prematurely due to poor patient accrual, confirming the difficulty in conducting these trials [ 249].

Widespread use of antifungal agents must be balanced against the cost, the risk of toxicity, and the emergence of resistance. None of the existing clinical trials have been adequately powered to assess the risk of the emergence of azole or echinocandin resistance. Empiric antifungal therapy should be considered in critically ill patients with risk factors for invasive candidiasis and no other known cause of fever. Preference should be given to an echinocandin in hemodynamically unstable patients, those previously exposed to an azole, and in those colonized with azole-resistant Candida species. Fluconazole may be considered in hemodynamically stable patients who are colonized with azole-susceptible Candida species or who have no prior exposure to azoles. There are no data guiding the appropriate duration of empiric antifungal therapy among patients who have a clinical response to therapy, but it is logical that it should not differ from the treatment of documented candidemia. Conversely, therapy can be stopped after several days in the absence of clinical response if cultures and surrogate markers are negative.

VI. Should Prophylaxis Be Used to Prevent Invasive Candidiasis in the ICU Setting?

Recommendations

Evidence Summary

For ICUs that show very high rates of invasive candidiasis, in excess of the expected rates of <5% of patients, antifungal prophylaxis may be warranted in selected patients who are at highest risk [ 260]. Two randomized, placebo-controlled trials have shown a reduction in the incidence of invasive candidiasis in single units or single hospitals when fluconazole prophylaxis was used broadly in the ICU; one study targeted all patients in a surgical ICU [ 262] and, in the other, all patients receiving mechanical ventilation [ 261]. In both studies, Candida urinary tract infections, as well as invasive candidiasis and candidemia, were included as endpoints.

Several meta-analyses have assessed the issue of fluconazole prophylaxis in ICU patients [ 265-268]. Not surprisingly, there were methodological differences among the studies, and there was variation among the study populations. All 4 meta-analyses showed that fluconazole prophylaxis was associated with a reduction in invasive candidiasis, but only 2 showed a reduction in candidemia [ 267, 268]. Importantly, only one analysis showed a reduction in mortality from invasive candidiasis [ 268]. None of the meta-analyses assessed the issues of adverse effects of antifungal agents, the emergence of resistance to fluconazole, or major ecological shifts in Candida species, topics of great importance in the ICU setting. A Cochrane analysis confirmed the importance of focusing prophylactic efforts on high-risk patients, noting that the number needed to treat to prevent one case of invasive candidiasis in the ICU setting varied from 9 in high-risk patients to 188 in low-risk patients [ 269].

Few data exist on risk factors for candidemia in pediatric intensive care unit (PICU) patients. A population-based, case-control study conducted in a large tertiary care pediatric center found an incidence of candidemia of 3.5 per 1000 PICU admissions [ 270]. The presence of a CVC, a diagnosis of malignancy, and receipt of either vancomycin or an antianaerobic antimicrobial agent for >3 days were independently associated with the development of candidemia. Children who had ≥3 of these risk factors in different combinations had a predicted probability of developing candidemia of between 10% and 46%.

Data are accruing on the use of skin decolonization with antiseptic agents in the ICU to decrease bloodstream infections, including those caused by Candida species [ 271-274]. Several multicenter randomized clinical trials have shown that daily bathing of ICU patients with chlorhexidine decreases the incidence of both catheter-associated and non-catheter-associated hospital-acquired bloodstream infections [ 271-273]. These studies were aimed primarily at evaluating the impact on multidrug-resistant bacterial infections and provide few data on Candida infections. However, at least one of these trials found a significant reduction in catheter associated Candida bloodstream infections [ 272]. A meta-analysis on the effects of daily chlorhexidine bathing included 10 studies performed in an ICU setting, only one of which was a randomized controlled trial. The conclusion was that chlorhexidine bathing reduced the incidence of bloodstream infections, including catheter-associated bacterial infections [ 274]. Although not proven to prevent candidemia, there is little risk to the use of chlorhexidine in ICU patients, and this practice may prove beneficial.

VII. What Is the Treatment for Neonatal Candidiasis, Including Central Nervous System Infection?
What Is the Treatment for Neonatal Invasive Candidiasis and Candidemia?
Recommendations

Evidence Summary

Neonatal candidiasis occurs predominately in the neonatal intensive care unit (NICU). Candida species are the third most common pathogen associated with bloodstream infection in NICUs in the United States [ 275]. However, the incidence of neonatal candidiasis has decreased dramatically over the past decade [ 276-278]. Neonatal candidiasis is associated with significant risk of death, neurodevelopmental impairment in extremely low-birth-weight infants who weigh ≤1000 g, and increased healthcare costs [ 279-284]. The primary risk factor for neonatal candidiasis is prematurity with those neonates who have an extremely low birth weight at greatest risk. These infants are at high risk to have CNS involvement as a complication of candidemia [ 285, 286]. Candida albicans and C. parapsilosis account for 80%-90% of neonatal invasive candidiasis [ 278, 287].

Neonatal candidiasis differs from invasive disease in older patients in that neonates are more likely to present with nonspecific or subtle signs and symptoms of infection. Candida species invade virtually all tissues, including the retina, brain, heart, lung, liver, spleen, and joints [ 288]. Endocarditis is an uncommon complication of candidiasis in neonates. Although meningitis is seen frequently in association with candidemia, approximately half of neonates with Candida meningitis do not have a positive blood culture [ 285]. CNS disease in the neonate typically manifests as meningoencephalitis and should be assumed to be present in the neonate who has candidemia and signs and symptoms suggesting meningoencephalitis, as CSF findings of Candida infection may be unreliable. Neurodevelopmental impairment is common in survivors; therefore, careful follow-up of neurodevelopmental parameters is important [ 279, 281, 282, 284].

Recent studies have highlighted the significance of candiduria in the absence of candidemia in this population [ 281]. Extremely low-birth-weight infants with candiduria are at a substantial risk of death or neurodevelopmental impairment. Candiduria in this population should prompt an evaluation (blood cultures, lumbar puncture, and abdominal ultrasound) for disseminated Candida infection and warrants treatment.
What Is the Treatment for Central Nervous System Infections in Neonates?
Recommendations

Evidence Summary

There are limited data to guide therapy for CNS Candida infections in the neonate. All AmB preparations, including the lipid formulations, penetrate the CNS and have fungicidal activity in the CNS [ 44]. AmB deoxycholate and liposomal AmB were found to have greater antifungal efficacy when studied in a rabbit model of Candida meningoencephalitis compared with the other formulations [ 44]. The clinician must weigh the benefits and drawbacks of using liposomal AmB with its good CSF penetration but poor urine levels vs using AmB deoxycholate with less good CSF levels but better urine levels.

The benefit of adding flucytosine for neonates with CNS candidiasis is uncertain. In the largest prospective study evaluating treatment outcomes of CNS candidiasis in neonates, the median time to clear CSF was longer for those who received flucytosine plus AmB deoxycholate (17.5 days; 6 infants), compared with those who received only AmB deoxycholate (6 days; 18 infants) [ 279]. In addition, flucytosine is poorly tolerated, and gastrointestinal side effects may hinder oral feeding in neonates. In general, flucytosine is used only in neonates who have not responded to AmB alone.
What Are the Recommendations for Prophylaxis in the Neonatal Intensive Care Unit Setting?
Recommendations

Evidence Summary

Numerous studies examining fluconazole prophylaxis for the prevention of invasive candidiasis in neonates have consistently demonstrated efficacy and possibly reduced mortality [ 300-310]. Fluconazole, 3 mg/kg or 6 mg/kg twice weekly, significantly reduced rates of invasive candidiasis in premature neonates weighing <1000 g in nurseries with a very high incidence of Candida infections [ 300, 302]. A 2007 Cochrane review of clinical trials of fluconazole prophylaxis demonstrated efficacy, with a typical relative risk of 0.23 and number needed to treat of 9. The number needed to treat varied substantially depending on the incidence of invasive candidiasis in a particular ICU. The majority of studies have demonstrated the safety of fluconazole prophylaxis and lack of emergence of resistance.

VIII. What Is the Treatment for Intra-abdominal Candidiasis?

Recommendations

Evidence Summary

Diagnosis is hampered by the lack of specific clinical signs and symptoms. Blood cultures are often negative [ 321]. A laboratory report of yeast isolated from an abdominal specimen must be evaluated to distinguish between contamination, colonization, and invasive infection. Swabs of superficial wounds and specimens taken from intra-abdominal catheters that have been in place for >24 hours do not provide useful information and should not be performed. In contrast, the presence of yeast obtained from normally sterile intra-abdominal specimens (operative room specimens, and/or drains that have been placed within 24 hours) in patients with clinical evidence for infection should be considered indicative of intra-abdominal candidiasis.

Source control with adequate drainage and/or debridement is an important part of therapy of intra-abdominal candidiasis [ 14]. The choice of antifungal agent should be guided by the Candida species isolated and knowledge of the local epidemiology, including antifungal susceptibility patterns. Duration of antifungal therapy should be guided by clinical response and the adequacy of source control.

IX. Does the Isolation of Candida Species From the Respiratory Tract Require Antifungal Therapy?

Recommendation

Evidence Summary

The isolation of Candida species from the respiratory tract is commonly encountered among patients who are in the ICU and are intubated or have a chronic tracheostomy. This almost always reflects colonization of the airways and not infection. Candida pneumonia and lung abscess are very uncommon [ 322, 323]. Only rarely after aspiration of oropharyngeal material has primary Candida pneumonia or abscess been documented [ 324, 325]. Pneumonia due to Candida species is generally limited to severely immunocompromised patients who develop infection following hematogenous spread to the lungs. CT scan of the thorax usually shows multiple pulmonary nodules. Isolation of Candida species from respiratory samples in a patient who is severely immunosuppressed should trigger a search for evidence of invasive candidiasis.

Although the diagnosis of Candida pneumonia is supported by isolation of the organism from a bronchoalveolar lavage (BAL) specimen, a firm diagnosis requires histopathological evidence of invasive disease. Multiple prospective and retrospective autopsy studies consistently demonstrate the poor predictive value of the growth of Candida from respiratory secretions, including BAL fluid [ 326-328]. In one prospective study, none of 77 patients who died in an ICU and who had clinical and radiologic evidence of pneumonia and a positive culture for Candida species from BAL or sputum demonstrated evidence of Candida pneumonia at autopsy [ 328]. Because of the rarity of Candida pneumonia, the extremely common finding of Candida in respiratory secretions, and the lack of specificity of this finding [ 329-331], a decision to initiate antifungal therapy should not be made on the basis of respiratory tract culture results alone.

Recent observations suggest that colonization of the airway with Candida species is associated with the development of bacterial colonization and pneumonia [ 332-336]. Candida airway colonization was also associated with worse clinical outcomes and higher mortality in these studies. However, it is not clear if Candida airway colonization has a causal relationship to poorer outcomes or is simply a marker of disease severity.

X. What Is the Treatment for Candida Intravascular Infections, Including Endocarditis and Infections of Implantable Cardiac Devices?

What Is the Treatment for Candida Endocarditis?

Recommendations

59. For native valve endocarditis, lipid formulation AmB, 3-5 mg/kg daily, with or without flucytosine, 25 mg/kg 4 times daily, OR high-dose echinocandin (caspofungin 150 mg daily, micafungin 150 mg daily, or anidulafungin 200 mg daily) is recommended for initial therapy (strong recommendation; low-quality evidence).

60. Step-down therapy to fluconazole, 400-800 mg (6-12 mg/kg) daily, is recommended for patients who have fluconazole-susceptible Candida isolates, have demonstrated clinical stability, and have cleared Candida from the bloodstream (strong recommendation; low-quality evidence).

61. Oral voriconazole, 200-300 mg (3-4 mg/kg) twice daily, or posaconazole tablets, 300 mg daily, can be used as step-down therapy for isolates that are susceptible to those agents but not susceptible to fluconazole (weak recommendation; very low-quality evidence).

62. Valve replacement is recommended; treatment should continue for at least 6 weeks after surgery and for a longer duration in patients with perivalvular abscesses and other complications (strong recommendation; low-quality evidence).

63. For patients who cannot undergo valve replacement, long-term suppression with fluconazole, 400-800 mg (6-12 mg/kg) daily, if the isolate is susceptible, is recommended (strong recommendation; low-quality evidence).

Evidence Summary

The incidence of Candida endocarditis has increased concurrent with the general increase in Candida infections [ 337]. Endocarditis should be suspected when blood cultures are persistently positive, when a patient with candidemia has persistent fever despite appropriate treatment, or when a new heart murmur, heart failure, or embolic phenomena occur in the setting of candidemia [ 338]. Most cases occur following cardiac valvular surgery, but other risk factors include injection drug use, cancer chemotherapy, prolonged presence of CVCs, and prior bacterial endocarditis. The signs, symptoms, and complications are generally similar to those of bacterial endocarditis, except for the frequent occurrence of large emboli to major vessels. Cases are fairly evenly divided between C. albicans and non- albicans Candida species [ 339].

AmB deoxycholate and azoles have decreased activity when compared with echinocandins against biofilms formed by Candida in vitro, and they penetrate poorly into vegetations. Echinocandins and lipid formulations of AmB demonstrate more potent activity against Candida biofilms [ 356]. A prospective, open-label clinical trial, cohort studies, and several case reports show a role for the echinocandins in the treatment of endocarditis [ 228, 346, 348, 357-365]. Higher dosages of the echinocandins are thought to be necessary to treat endocarditis [ 228, 365]. Caspofungin has been used as monotherapy and in combination with AmB, azoles, or flucytosine in single case reports, but data are limited for the other echinocandins [ 346, 360, 361, 363, 365, 366].

Lifelong suppressive therapy with fluconazole has been used successfully after a course of primary therapy in patients for whom cardiac surgery is contraindicated; it has also been advocated to prevent late recurrence of Candida prosthetic valve endocarditis [ 360, 367, 368]. Because Candida endocarditis has a propensity to relapse months to years later, follow-up should be maintained for several years after treatment [ 350, 351].

What Is the Treatment for Candida Infection of Implantable Cardiac Devices?

Recommendations

Evidence Summary

There are a few case reports and a single retrospective review of Candida infections of pacemakers and cardiac defibrillators [ 369-374]. The entire device should be removed and antifungal therapy given for 4-6 weeks depending on whether the infection involves the wires in addition to the generator pocket [ 369, 371-374]. Medical therapy alone has failed [ 370].

What Is the Treatment for Candida Suppurative Thrombophlebitis?

Recommendations

Evidence Summary

Surgical excision of the vein plays an important role in the treatment of peripheral-vein Candida thrombophlebitis. When a central vein is involved, surgery is usually not an option. In some cases, systemic anticoagulation or thrombolytic therapy has been used as adjunctive therapy, but there are insufficient data to recommend their use. Thrombolytic therapy, in conjunction with antifungal therapy, has been used successfully in the management of an infected thrombus attached to a CVC in a patient with persistent candidemia [ 381].

XI. What Is the Treatment for Candida Osteoarticular Infections?

What Is the Treatment for Candida Osteomyelitis?

Recommendations

Evidence Summary

Most patients with osteomyelitis present with a subacute to chronic course [ 383, 384]. The most common mechanism of infection is hematogenous dissemination, but direct inoculation and contiguous spread of infection also occur. Involvement of 2 or more bones is common, and therefore, when a single focus of infection is identified, there should be a search for other sites of involvement. The axial skeleton, especially the spine, is the most common site of involvement in adults; in children, the long bones are more commonly involved [ 228, 384-388]. Neither the clinical picture nor the findings on radiographic imaging are specific for Candida infection. Candida albicans remains the dominant pathogen. However, 2 retrospective reviews of a large number of cases found that non- albicans Candida were an increasingly frequent cause of Candida osteomyelitis and mixed infections with bacteria, especially Staphylococcus aureus, were not uncommon, underscoring the need for biopsy and culture [ 384, 389].

What Is the Treatment for Candida Septic Arthritis?

Evidence Summary

Candida prosthetic joint infection generally requires resection arthroplasty, although success with medical therapy alone has been described rarely [ 403, 404]. The combination of removal and reimplantation of the prosthesis in 2 stages separated by 3-6 months and a prolonged period of antifungal therapy for at least 12 weeks after the resection arthroplasty and at least 6 weeks after prosthesis implantation is suggested on the basis of limited data [ 405-407]. The efficacy of antifungal-loaded cement spacers is controversial [ 408]. If the prosthetic device cannot be removed, chronic suppression with an antifungal agent, usually fluconazole, is necessary.

XII. What Is the Treatment for Candida Endophthalmitis?

What Is the General Approach to Candida Endophthalmitis?

Recommendations

83. The extent of ocular infection (chorioretinitis with or without macular involvement and with or without vitritis) should be determined by an ophthalmologist (strong recommendation; low-quality evidence).

84. Decisions regarding antifungal treatment and surgical intervention should be made jointly by an ophthalmologist and an infectious diseases physician (strong recommendation; low-quality evidence).

Evidence Summary

Endophthalmitis refers to infections within the eye, usually involving the posterior chamber and sometimes also the anterior chamber. Candida endophthalmitis can be exogenous, initially affecting the anterior chamber and occurring following trauma or a surgical procedure. More often, Candida species cause endogenous infection in which the organism reaches the posterior chamber of the eye via hematogenous spread. Endogenous infections can be manifested as isolated chorioretinitis or as chorioretinitis with extension into the vitreous, leading to vitritis [ 409-412]. Candida albicans is the species most commonly responsible for endogenous endophthalmitis, but all Candida species that cause candidemia have been reported to cause this complication [ 411-414]. Outcomes in terms of visual acuity depend on the extent of visual loss at the time of presentation and macular involvement [ 415].

Sight-threatening lesions near the macula or invasion into the vitreous usually necessitate intravitreal injection of antifungal agents, usually AmB deoxycholate or voriconazole, with or without vitrectomy, in addition to systemic antifungal agents [ 412, 419, 422-425]. The ophthalmologist plays a key role in following the course of endogenous Candida endophthalmitis, deciding when and if to perform intravitreal injections and vitrectomy.

The approach to the patient who has candidemia has evolved over time, and standard practice now includes consultation with an ophthalmologist to do a dilated retinal examination. The basis for the recommendation to perform an ophthalmological evaluation is not a result of randomized controlled trials showing the benefits of such an assessment, but rather clinical judgment that the result of missing and not appropriately treating Candida endophthalmitis could be of great consequence to the patient. The issue of whether an ophthalmological examination of all candidemic patients is cost-effective has been raised [ 183, 426]. The members of the Expert Panel believe that the risk of missing Candida endophthalmitis outweighs the cost of obtaining an ophthalmological examination. We are concerned about the greater risk of loss of visual acuity in patients who are examined only after manifesting ocular symptoms [ 415], and note that other centers report higher rates of endophthalmitis than reports from the centers cited by those who question the routine use of ocular examination [ 417, 418, 421].

What Is the Treatment for Candida Chorioretinitis Without Vitritis?

Recommendations

Evidence Summary

The greatest clinical experience for treatment of Candida endophthalmitis has been with intravenous AmB deoxycholate, only because it has been available for the longest time. However, this agent does not achieve adequate concentrations in the posterior chamber [ 419, 420, 427, 428]. In animal experiments in inflamed eyes, liposomal AmB achieved higher concentrations in the eye than either AmB deoxycholate or AmB lipid complex [ 427]. A few patients have been treated successfully with lipid formulations of AmB, but concentrations in the vitreous in humans have not been reported [ 429].

Voriconazole has played an increasing role in the treatment of endophthalmitis [ 419]. Concentrations in the vitreous in humans are approximately 40% of serum concentrations; the drug is relatively safe, and, like fluconazole, can be given by the oral or intravenous route [ 435-438]. It is more active than fluconazole against C. glabrata, although resistance is increasing and may preclude its use for some patients; it is uniformly active against C. krusei. Efficacy of voriconazole in treating Candida endophthalmitis has been documented, but not compared with fluconazole [ 429, 436, 438]. Serum and (presumably) intraocular concentrations of voriconazole are quite variable, and serum trough levels should be routinely monitored to achieve concentrations between 2 µg/mL and 5 µg/mL to enhance efficacy and avoid toxicity [ 118].

There are few data regarding the use of posaconazole for Candida endophthalmitis. Intraocular penetration is poor, this agent has been used in very few patients, and it is not approved for the treatment of candidemia [ 419].

What Is the Treatment for Candida Chorioretinitis With Vitritis?

Recommendations

Evidence Summary

XIII. What Is the Treatment for Central Nervous System Candidiasis?

Recommendations

Evidence Summary

CNS Candida infections can occur as a manifestation of disseminated candidiasis, as a complication of a neurosurgical procedure, especially when an intracranial device is inserted, or rarely as an isolated chronic infection [ 453-462]. Meningitis is the most common presentation, but multiple small abscesses throughout the brain parenchyma, large solitary brain abscesses, and epidural abscesses have been reported [ 462]. Low-birth-weight neonates are at high risk to have CNS infection as a complication of candidemia; neonatal CNS candidiasis is dealt with in the section on neonatal Candida infections. Most infections are due to C. albicans, with few reports of C. glabrata and other species causing infection [ 453-457, 459, 461, 462]. Treatment is based on the antifungal susceptibilities of the infecting species and the ability of the antifungal agent to achieve appropriate concentrations in the CSF and brain.

No randomized controlled trials have been performed to evaluate the most appropriate treatment for these uncommon infections. Single cases and small series are reported. Most experience has accrued with the use of AmB deoxycholate, with or without flucytosine [ 453-455, 457, 459, 460, 462]. Liposomal AmB (AmBisome) has been found to attain higher levels in the brain than amphotericin B lipid complex (ABLC) or AmB deoxycholate in a rabbit model of Candida meningoencephalitis [ 44].

The combination of AmB and flucytosine is recommended because of the in vitro synergism noted with the combination and the excellent CSF concentrations achieved by flucytosine. However, flucytosine's toxic effects on bone marrow and liver must be carefully monitored, preferably with frequent serum flucytosine levels. The optimal length of therapy with AmB alone or in combination with flucytosine has not been studied. Several weeks of therapy are suggested before transitioning to oral azole therapy.

Fluconazole achieves excellent levels in CSF and brain tissue and has proved useful as step-down therapy [ 453, 454, 459]. Fluconazole also has been used as monotherapy; both success and failure have been noted, and for this reason it is not recommended as first-line therapy [ 453, 454, 463-465]. Fluconazole combined with flucytosine has been reported to cure Candida meningitis in a few patients [ 459], and this is a possible regimen for step-down therapy. There are no reports of the use of voriconazole or posaconazole for CNS candidiasis. Voriconazole achieves excellent levels in CSF, and should be considered for the rare case of C. glabrata that is not voriconazole resistant or C. krusei meningitis after initial treatment with AmB with or without flucytosine. Posaconazole does not reach adequate concentrations in the CSF, and this agent is not recommended.

Echinocandins have been used infrequently for CNS candidiasis. There are case reports noting success [ 466], but CNS breakthrough infections in patients receiving an echinocandin for candidemia have been reported [ 467]. There are experimental animal data noting that anidulafungin and micafungin can successfully treat C. albicans meningitis, but the doses required in humans are much higher than currently recommended for candidemia [ 296, 299]. At present, echinocandins are not recommended for CNS candidiasis.

Infected CNS devices should be removed to eradicate Candida. Most experience has been with external ventricular drains and ventriculoperitoneal shunts that have become infected with Candida species [ 460, 463]. In recent years, infected devices include deep brain stimulators and Gliadel biopolymer wafers that have been placed into the site of a brain tumor to deliver chemotherapy locally. Although difficult to remove, experience has shown that these devices must be taken out for cure of the infection [ 456, 468, 469].

XIV. What Is the Treatment for Urinary Tract Infections Due to Candida Species?
What Is the Treatment for Asymptomatic Candiduria?
Recommendations

Evidence Summary

Multiple studies have noted that candiduria does not commonly lead to candidemia [ 471, 472, 476-480]. Several of these studies have shown that candiduria is a marker for greater mortality, but death is not related to Candida infection and treatment for Candida infection does not change mortality rates [ 476, 480, 481]. A prospective study in renal transplant recipients found that although mortality was higher in patients who had candiduria, treatment did not improve outcomes, suggesting again that candiduria is a marker for severity of underlying illness [ 482].

What Is the Treatment for Symptomatic Candida Cystitis?

Recommendations

What Is the Treatment for Symptomatic Ascending Candida Pyelonephritis?

Recommendations

Evidence Summary

Candida UTI can develop by 2 different routes [ 487]. Most symptomatic UTIs evolve as an ascending infection beginning in the lower urinary tract, similar to the pathogenesis of bacterial UTI. Patients with ascending infection can have symptoms of cystitis or pyelonephritis. The other route of infection occurs as a consequence of hematogenous spread to the kidneys in a patient who has candidemia. These patients usually have no urinary tract symptoms or signs, and are treated for candidemia.

Diagnostic tests on urine often are not helpful in differentiating colonization from infection or in pinpointing the involved site within the urinary tract [ 488, 489]. For example, pyuria in a patient with an indwelling bladder catheter cannot differentiate Candida infection from colonization. Similarly, the colony count in the urine, especially when a catheter is present, cannot be used to define infection [ 488, 489]. Imaging of the urinary tract by ultrasound or CT scanning is helpful in defining structural abnormalities, hydronephrosis, abscesses, emphysematous pyelonephritis, and fungus ball formation [ 490-492]. Aggregation of mycelia and yeasts (fungus balls) in bladder or kidney leads to obstruction and precludes successful treatment of infection with antifungal agents alone [ 94]. Rarely, Candida species cause localized infections in prostate, epididymis, or testicles [ 491, 493-495].

Several basic principles are important in the approach to treatment of Candida UTI. The ability of the antifungal agent to achieve adequate concentrations in the urine is as important as the antifungal susceptibilities of the infecting species [ 94]. Candida albicans, the most common cause of fungal UTI, is relatively easy to treat because it is susceptible to fluconazole, which achieves high concentrations in the urine. In contrast, UTIs due to fluconazole-resistant C. glabrata and C. krusei can be extremely difficult to treat.

Fluconazole is the drug of choice for treating Candida UTI. It was shown to be effective in eradicating candiduria in the only randomized, double-blind, placebo-controlled trial that has been conducted in patients with candiduria [ 496]. It is important to note that the patients in this trial were asymptomatic or had minimal symptoms of cystitis. Fluconazole is available as an oral formulation, is excreted into the urine in its active form, and easily achieves urine levels exceeding the MIC for most Candida isolates [ 94].

AmB deoxycholate is active against most Candida species (although some C. krusei isolates are resistant) and achieves concentrations in the urine that exceed the MICs for most isolates, and even low doses have been shown to be effective in treating Candida UTI [ 497]. The major drawbacks are the need for intravenous administration and toxicity. The lipid formulations of AmB appear to not achieve urine concentrations that are adequate to treat UTI and should not be used [ 498].

Irrigation of the bladder with AmB deoxycholate resolves candiduria in 80%-90% of patients, as shown in several open-label trials, but in those studies, recurrent candiduria within several weeks was very common [ 503-505]. This approach is useful only for bladder infections and generally is discouraged, especially in patients who would not require an indwelling catheter for any other reason [ 94, 506, 507]. Cystitis due to C. glabrata or C. krusei can sometimes be treated with amphotericin B bladder irrigation and endoscopic removal of any obstructing lesions [ 94].

What Is the Treatment for Candida Urinary Tract Infection Associated With Fungus Balls?

Recommendations

Evidence Summary

XV. What Is the Treatment for Vulvovaginal Candidiasis?

Recommendations

121. For recurring vulvovaginal candidiasis, 10-14 days of induction therapy with a topical agent or oral fluconazole, followed by fluconazole, 150 mg weekly for 6 months, is recommended ( strong recommendation; high-quality evidence).

Evidence Summary

Vulvovaginal candidiasis can be classified as either uncomplicated, which is present in about 90% of cases, or complicated, which accounts for only about 10% of cases, on the basis of clinical presentation, microbiological findings, host factors, and response to therapy [ 514]. Complicated vulvovaginal candidiasis is defined as severe or recurrent disease, infection due to non- albicans species, and/or infection in an abnormal host. Candida albicans is the usual pathogen, but other Candida species can also cause this infection.

A diagnosis of vulvovaginal candidiasis can usually be made clinically when a woman presents with symptoms of pruritus, irritation, vaginal soreness, external dysuria, and dyspareunia, often accompanied by a change in vaginal discharge. Signs include vulvar edema, erythema, excoriation, fissures, and a white, thick, curdlike vaginal discharge. Unfortunately, these symptoms and signs are nonspecific and can be the result of a variety of infectious and noninfectious etiologies. Before proceeding with empiric antifungal therapy, the diagnosis should be confirmed by a wet-mount preparation with use of saline and 10% potassium hydroxide to demonstrate the presence of yeast or hyphae and a normal pH (4.0-4.5). For those with negative findings, vaginal cultures for Candida should be obtained.

Complicated vulvovaginal candidiasis requires that therapy be administered intravaginally with topical agents for 5-7 days or orally with fluconazole 150 mg every 72 hours for 3 doses [ 54, 514]. Most Candida species, with the exception of C. krusei and C. glabrata, respond to oral fluconazole. Candida krusei responds to all topical antifungal agents. However, treatment of C. glabrata vulvovaginal candidiasis is problematic [ 514, 516]. The most important decision to make is whether the presence of C. glabrata in vaginal cultures reflects colonization in a patient who has another disease, or whether it indicates true infection requiring treatment. Azole therapy, including voriconazole, is frequently unsuccessful [ 519]. A variety of local regimens have sometimes proved effective. These include boric acid contained in gelatin capsules and nystatin intravaginal suppositories [ 520]. Topical 17% flucytosine cream can be used alone or in combination with 3% AmB cream in recalcitrant cases [ 520, 521]. These topical formulations, as well as boric acid gelatin capsules, must be compounded by a pharmacist for specific patient use. Azole-resistant C. albicans infections are extremely rare. However, recent evidence has emerged documenting fluconazole and azole class resistance in women following prolonged azole exposure [ 522].

Recurrent vulvovaginal candidiasis, defined as ≥4 episodes of symptomatic infection within one year, is usually caused by azole-susceptible C. albicans [ 514, 523]. Contributing factors, such as diabetes, are rarely found. Treatment should begin with induction therapy with a topical agent or oral fluconazole for 10-14 days, followed by a maintenance azole regimen for at least 6 months [ 523-525]. The most convenient and well-tolerated regimen is 150 mg fluconazole once weekly. This regimen achieves control of symptoms in >90% of patients [ 523]. After cessation of maintenance therapy, a 40%-50% recurrence rate can be anticipated. If fluconazole therapy is not feasible, topical clotrimazole cream, 200 mg twice weekly, clotrimazole vaginal suppository 500 mg once weekly, or other intermittent oral or topical antifungal treatment is recommended [ 526, 527].

XVI. What Is the Treatment for Oropharyngeal Candidiasis?

Recommendations

Evidence Summary

Fluconazole or multiazole resistance is predominantly the consequence of previous repeated and long-term exposure to fluconazole or other azoles [ 530-533]. Especially in patients with advanced immunosuppression and low CD4 counts, C. albicans resistance has been described, as has gradual emergence of non- albicans Candida species, particularly C. glabrata, as a cause of refractory mucosal candidiasis [ 532, 533].

Most cases of oropharyngeal candidiasis are caused by C. albicans, either alone or in mixed infections. Symptomatic infections caused by C. glabrata, C. dubliniensis, and C. krusei alone have been described [ 532-534]. Multiple randomized prospective studies of oropharyngeal candidiasis have been performed involving patients with AIDS and patients with cancer. Most patients will respond initially to topical therapy [ 532, 535, 536]. In HIV-infected patients, symptomatic relapses occur sooner and more frequently with topical therapy than with fluconazole [ 535]. In a multicenter randomized study among HIV-infected individuals, 50-mg mucoadhesive buccal tablets of miconazole applied once daily to the mucosal surface over the canine fossa were as effective as 10-mg clotrimazole troches used 5 times daily [ 537].

Decreasing rates of oral carriage of Candida species and a reduced frequency of symptomatic oropharyngeal candidiasis are seen among HIV-infected patients on effective antiretroviral therapy [ 554]. Thus, antiretroviral therapy should be used whenever possible for HIV-infected patients with oropharyngeal or esophageal candidiasis.

Chronic mucocutaneous candidiasis is a rare condition that is characterized by chronic, persistent onychomycosis and/or mucocutaneous lesions due to Candida species. Some patients have a thymoma or autoimmune polyendocrinopathy syndrome type 1 [ 555]. Fluconazole should be used as initial therapy for candidiasis in these patients. Response to antifungal therapy may be delayed when there is extensive skin or nail involvement. Because of the intrinsic immunodeficiency, most patients require chronic suppressive antifungal therapy and frequently develop azole-refractory infections [ 556]. Patients with fluconazole-refractory Candida infections should be treated the same as patients with AIDS who develop azole refractory infections [ 528].

XVII. What Is the Treatment for Esophageal Candidiasis?

Recommendations

Evidence Summary

Esophageal candidiasis typically occurs at lower CD4 counts than oropharyngeal disease [ 528-530]. The advent of effective antiretroviral therapy has led to a dramatic decline in the prevalence of esophageal candidiasis and a marked diminution in cases of refractory disease [ 531]. Most cases of esophageal candidiasis are caused by C. albicans. However, symptomatic infections caused by C. glabrata, C. dubliniensis, and C. krusei have been described [ 534].

The presence of oropharyngeal candidiasis and dysphagia or odynophagia in an immunocompromised host is frequently predictive of esophageal candidiasis, although esophageal candidiasis can present as odynophagia without concomitant oropharyngeal candidiasis. A therapeutic trial with fluconazole for patients with presumed esophageal candidiasis is a cost-effective alternative to endoscopic examination. In general, most patients with esophageal candidiasis will have improvement or resolution of their symptoms within 7 days after the initiation of antifungal therapy [ 557].

Notes

Acknowledgments. The Expert Panel expresses its gratitude for thoughtful reviews of an earlier version by Anna Thorner and Pranatharthi Chandrasekar; and David van Duin as liaison of the IDSA Standards and Practice Guidelines Committee (SPGC). The panel also greatly appreciates the work of Charles B. Wessels and Michele Klein Fedyshin of the Health Sciences Library System of the University of Pittsburgh for the development and execution of the systematic literature searches for this guideline.

Financial support. Support for this guideline was provided by the Infectious Diseases Society of America.

Potential conflicts of interest. The following list is a reﬂection of what has been reported to IDSA. To provide thorough transparency, IDSA requires full disclosure of all relationships, regardless of relevancy to the guideline topic. Evaluation of such relationships as potential conﬂicts of interest (COI) is determined by a review process that includes assessment by the SPGC Chair, the SPGC liaison to the development panel, and the Board of Directors liaison to the SPGC and, if necessary, the COI Task Force of the Board. This assessment of disclosed relationships for possible COI will be based on the relative weight of the ﬁnancial relationship (ie, monetary amount) and the relevance of the relationship (ie, the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The reader of these guidelines should be mindful of this when the list of disclosures is reviewed. For activities outside of the submitted work, P. G. P. served as a consultant to Merck, Astellas (past), Gilead, T2 Biosystems, Scynexis, Viamet, IMMY Diagnostics, and Pfizer (past) and has received research grants from T2 Biosystems, Gilead, Merck, Astellas, Scynexis, and IMMY. For activities outside of the submitted work, C. A. K. has received research grants from VA Cooperative Studies, Merck, the Centers for Disease Control and Prevention (CDC) and The National Institute on Aging (all past), and has received royalties from UpToDate. For activities outside of the submitted work, D. A. has served a consultant to Merck, Astellas, Pfizer, Seachaid, Mayne, Roche, Theravance, Viamet, and Scynexis and has received research grants from Merck, Pfizer, MSG, Actellion, Theravance, Scynexis, and Astellas. For activities outside of the submitted work, C. J. C. has consulted for Merck, and received research grants from Pfizer, Merck, Astellas, CSL Behring, and T2 Diagnostics. For activities outside of the submitted work, K. A. M. has received research grants from Pfizer, Astellas, Merck, and the National Institutes of Health (NIH) and served as a consultant for Astellas, Chimerix, Cidara, Genentech, Merck, Revolution Medicines, and Theravance. She has a licensed patent to MycoMed Technologies. For activities outside of the submitted work, L. O.-Z. has served as a consultant to Viracor (past), Novadigm (past), Pfizer (past), Astellas, Cidara, Scynexis, and Merck and has received research grants from Merck (past), Astellas, Pfizer (past), Immunetics, Associates of Cape Cod (past), and T2 Biosystems, and has been on the speakers' bureau for Merck and Pfizer. For activities outside of the submitted work, A. C. R. has received research grants from Merck and T2 Biosystems, and royalties from UpToDate. For activities outside of the submitted work, J. A. V. has served as a consultant for Astellas, Forest, served on promotional speakers' bureau for Astellas, Pfizer, Forest, and Astra Zeneca, and has received research grants from Astellas, Pfizer, Merck, MSG, T2 Biosystems, and NIH/National Institute of Dental and Craniofacial Research. For activities outside of the submitted work, T. J. W. has served as a consultant for Astellas, Drais (past), Novartis, Pfizer, Methylgene, SigmaTau, Merck, ContraFect Trius, and has received research grants from SOS Kids Foundation, Sharpe Family Foundation, Astellas, Cubist, Theravance, Medicines Company, Actavis, Pfizer, Merck, Novartis, ContraFect, and The Schueler Foundation. For activities outside of the submitted work, T. E. Z. has served as a consultant for Astellas, Pfizer, Merck, and Cubist (all past) and has received research grants from Merck (past), Cubist (past), Agency for Health Research and Quality, CDC, NIH, and the Thrasher Foundation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

# data[].attributes.attachment_link.title
Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America

# data[].attributes.attachment_link.description
Background Invasive infection due to Candida species is largely a condition associated with medical progress, and is widely recognized as a major cause of morbidity and mortality in the healthcare environment. There are at least 15 distinct Candida species that cause human disease, but >90% of invasive disease is caused by the 5 most common pathogens, C.

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A main way to be diagnosed is for doctors to look at the patient's medical history, symptoms, and physical examinations. There can also be laboratory tests that can be done. The test is done by taking a blood sample or a sample of where there is an infection. It will take a couple days for the test results to come back.

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https://www.cidara.com/think-fungus/

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Peter G. Pappas, MD; University of Alabama