This slide set is meant to be used as an adjunct resource to the Medscape program titled “Managing Invasive Candidiasis: A Systematic Approach” by Thomas M. File, JR, MD, Professor of Internal Medicine; Master Teacher, Head, Infectious Diseases Section, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio; Chief, Infectious Disease Section; and Director, HIV Research, Summa Health System, Akron, Ohio. This slide set is not intended as a comprehensive review of invasive candidiasis.

Invasive fungal infections are increasingly common in hospitalized patients, especially among the critically ill, in part due to medical advances that allow patients with severe, complex illnesses to survive, but at the expense of leaving them vulnerable to a wide range of opportunistic infections. Candida spp are the fourth most common cause of nosocomial bloodstream infections in North America, the most common cause of invasive fungal disease, and the most common fungal pathogen among ICU patients. Mortality associated with candidemia is high, with crude rates ranging from 30% to 61%. In addition, a shift in the epidemiology of Candida infections is occurring; C non-albicans spp are an increasingly common cause of bloodstream infections.

In general, the diagnosis of invasive candidiasis is dependent on recovery of Candida spp from a sterile body site, such as the bloodstream, pleural fluid, intra-abdominal fluid, or abscess material.

According to the EORTC/MSG Consensus Group, a "proven" invasive fungal infection is defined as a positive fungal culture or histologic analysis of a tissue specimen taken from a disease site, or the identification or appearance of fungal or hyphal elements in a biopsy from a sterile site. "Probable" and "possible" invasive fungal infections are further defined on the basis of specific host factors (eg, neutropenia, transplantation, immunosuppressive therapy), clinical features of fungal infection, and mycologic evidence from culture and microscopic analysis and indirect tests, such as antigen detection. While the primary purpose of these consensus-derived definitions is to provide standardization of groups of patients for clinical and epidemiologic research, they also serve as a useful model to define patients at risk for such infections.

Treatment Recommendations* Nonneutroenic Patients Fluconazole (loading dose of 800 mg [12 mg/kg], then 400 mg [6 mg/kg] daily) or an echinocandin (caspofungin: loading dose of 70 mg, then 50 mg/d; micafungin: 100 mg/d; anidulafungin: loading dose of 200 mg, then 100 mg/d) is recommended as initial therapy for most adult patients. The Expert Panel favors an echinocandin for patients with moderately severe to severe illness or for patients who have had recent azole exposure. Fluconazole is recommended for patients who are less critically ill and who have had no recent azole exposure. The same therapeutic approach is advised for children, with attention to differences in dosing regimens. Neutropenic Patients An echinocandin (caspofungin: loading dose of 70 mg, then 50 mg/d; micafungin: 100 mg/d; anidulafungin: loading dose of 200 mg/d, then 100 mg/d) or LFAmB (3 to 5 mg/kg/d) is recommended for most patients. Neonatal Candidiasis AmB-d (1 mg/kg/d) is recommended for neonates with disseminated candidiasis. If urinary tract involvement is excluded, LFAmB (3 to 5 mg/kg/d) can be used. Fluconazole (12 mg/kg/d) is a reasonable alternative. The recommended length of therapy is 3 weeks. SOT Recipients For SOT recipients, fluconazole (200 to 400 mg [3 to 6 mg/kg]/d) or L-AmB (1 to 2 mg/kg/d for 7 to 14 days) is recommended as postoperative antifungal prophylaxis for liver, pancreas, and small bowel transplant recipients at high risk for candidiasis. For patients hospitalized in the ICU, fluconazole (400 mg [6 mg/kg]/d) is recommended for high-risk patients in adult units that have a high incidence of invasive candidiasis. *Refer to the guideline for levels of evidence and full treatment recommendations.

SOT recipients are at increased risk for invasive fungal infections; OLT recipients are especially at risk because of their general baseline health status, technical complications associated with the transplant surgery, and side effects of immunosuppressants taken to prevent allograft rejection. Fungal infections in transplant recipients are most frequently caused by Candida spp. The clinical syndromes range from minimal mucosal colonization with mild infection (oral candidiasis, which can lead to Candida esophagitis) to serious invasive infection and disease, such as candidemia with or without visceral involvement or disseminated candidiasis (infection of several deep-seated organs or an organ and the blood). Several terms are used to describe fungal infections in general, and Candida infections in particular; some terms overlap and are used interchangeably.

The risk for fungal infection is generally highest at 1 to 6 months after transplantation, but fungal infections can occur earlier, particularly when the net state of immunosuppression is high.

Despite the known risks, antifungal prophylaxis is not universally recommended for OLT recipients for several reasons. As a universal strategy, the benefits are limited with no effect on overall mortality or the number of patients given definitive treatment. Prophylaxis has also been linked to increased incidence of C non-albicans infections. In addition, this strategy exposes all patients to potential drug-drug interactions and drug-associated toxicities, and unnecessary expense.

Selection of antifungal agents is largely based on knowledge of the most likely causative species. According to data from TRANSNET consortium of 23 US transplant centers, the most frequent causes of invasive fungal infection among SOT recipients are Candida spp (C albicans, C glabrata, C parapsilosis, C tropicalis, C krusei, and C lusitaniae, in order of frequency), Aspergillis, and Cryptococcus, though epidemiology varies according to geographic region and patient care setting and local and/or institutional epidemiology should be taken into consideration when selecting a treatment. Independent of a patient's prior azole exposure, when the local incidence of C non-albicans blood isolates exceeds 10%, therapy with an echinocandin or amphotericin B should be considered because of the increased risk for azole resistance.[Evans, 2010] Reference Evans SE. Coping with Candida infections. Proc Am Thorac Soc. 2010;7:197-203.

A blood culture positive for Candida should always prompt aggressive treatment because the clinical course of candidemia is difficult to predict and is often associated with a poor outcome.[Evans, 2010] Several studies have documented high mortality rates in patients with candidemia; rates were highest in patients who did not receive antifungal drug therapy.[Nguyen, 1995; Nucci, 1998] The Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the IDSA recommend treatment within 24 hours of a positive blood culture.   Delayed treatment of candidemia is an independent predictor of in-hospital mortality. A retrospective cohort study of all patients with candidemia from 4 medical centers found that significant delay of initiation of fluconazole therapy was associated with increased mortality; mortality rates were lowest in patients who began therapy on the day that the positive blood culture was reported and highest in those who received treatment on the third day or later after the report (P = .0009 for trend).[Garey, 2006]  In another study evaluating the timing of effective antifungal therapy for candidemia, patients who received ≥ 24 hours of effective antifungal therapy showed significant mortality benefit to receiving antifungal treatment within 72 hours of a positive blood culture being drawn; the 30-day mortality for early treatment was 27% vs 40%.[Grim, 2011] References Evans SE. Coping with Candida infections. Proc Am Thorac Soc. 2010;7:197-203. Garey KW, Rege M, Pai MP, et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis. 2006;43:25-31. Grim SA, Berger K, Teng C, et al. Timing of susceptibility-based antifungal drug administration in patients with Candida bloodstream infection: correlation with outcomes. J Antimicrob Chemother. Published online: December 18, 2011. doi: 10.1093/jac/dkr511. Nguyen MH, Peacock JE Jr, Tanner DC, et al. Therapeutic approaches in patients with candidemia. Evaluation in a multicenter, prospective, observational study. Arch Intern Med. 1995;155:2429-2435. Nucci M, Colombo AL, Silveira F, et al. Infect Control Hosp Epidemiol. 1998;19:846-850.

Candida endophthalmitis is relatively common following candidemia; abdominal surgery is a risk factor. A dilated ophthalmologic evaluation is recommended for all patients with candidemia. Characteristic ophthalmologic findings include whitish "cotton ball" or "string of pearls" opacities. If there is ocular involvement, outcome is favorable if treatment is administered before the onset of retinal complications. Recommended treatment for endopthalmitis includes: vitrectomy, and intravitreal and systemic antifungal therapy for 4 to 6 weeks, AmB-d combined with flucytosine for lesions that are advancing or threatening the macula, and fluconazole for less severe infections in patients with no known resistance to fluconazole. Reference Pappas PG, Kauffman CA, Andes D, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503-535.

When 1 or more of these factors are present, corrective management (eg, changing or removal of indwelling urinary catheter) often clears the candiduria and eliminates the need for antifungal therapy. Antibiotics should be discontinued if no longer needed as they allow selective colonization of yeast in general and Candida spp specifically. If these and other factors are corrected and candiduria persists, deep-seated invasive or disseminated candidiasis should be suspected. In particular, candiduria in critically ill patients should be considered a potential marker for invasive candidiasis, regardless of whether symptoms are present.

When Candida is found in urine, whether observed microscopically or as growth in culture, the primary question the clinician should ask is whether it represents a significant UTI vs colonization or contamination. The presence of yeast in the urine is common; most patients with candiduria do not have a clinically significant Candida UTI. Pyuria is a helpful sign of Candida UTI, but in patients with indwelling catheters, it loses both sensitivity and specificity. Most patients with urinary catheters have WBCs in the urine as a nonspecific finding. The presence of Candida should be confirmed with a second, carefully performed, clean-voided or catheter-obtained urine culture. The second culture is often negative; if it is positive, a UTI clinically significant should be considered. The patient's history and other factors known to predispose to UTI, including diabetes and admission to an ICU, should be considered when making the diagnosis and determining the plan of care. The absence of these factors in otherwise healthy, immunocompetent individuals usually means no treatment is necessary; for most, candiduria will resolve on its own.