Nystatin and amphotericin B are natural antifungals discovered in the 1950s and obtained from aerobic bacteria (Streptomyces noursey and Streptomyces nodosus, respectively) that have broad-spectrum antifungal activities. In Candida infections, nystatin is reserved for superficial infections due to its topical action. Amphotericin B is indicated for severe forms of invasive candidiasis. The primary mechanism of action is the interaction with steroid components of the cell membranes of eukaryotic cells, leading to rupture. Other mechanisms have been suggested, such as the production of oxygen free radicals by phagocytes in the host. There are different formulations of amphotericin B for intravenous infusion: a deoxycholic acid formulation (amphotericin B deoxycholate or conventional) and lipid formulations (colloidal dispersion, lipid complex and liposomal). The safest lipid formulations in clinical use are amphotericin B lipid complex and liposomal formulation; the latter has lower toxicity and greater tolerability compared to the former formulation.61

Conventional amphotericin B is primarily associated with acute infusion events, including fever, chills, nausea, vomiting, bronchospasm and rash. Fewer side effects are experienced with the lipid complex formulation (two-hour infusion) and particularly with the liposomal formulation (one-hour infusion). The most serious adverse effects are related to the nephrotoxicity of conventional amphotericin B, including the deterioration of renal, cardiac and hematopoietic functions. Of these, renal failure is the most common, occurring in 12–80%, depending on the criteria adopted for renal failure and the population evaluated.62 Among the various alternatives to reduce nephrotoxicity, hydration with 500mL of isotonic saline solution produces better results without compromising effectiveness, but it can be limited in critically ill patients.63 Among the lipid formulations of amphotericin B, the liposomal formulation causes a lower incidence of nephrotoxicity.64,65

Amphotericin B is fungicidal and is active against various Candida species. Secondary resistance is rare. There are data suggesting that amphotericin B MICs for C. glabrata and C. krusei are higher, requiring the use of higher doses of polienic. There is evidence that primary and/or secondary resistance to amphotericin B can occur with clinical isolates of C. lusitaniae.66,67

The azoles are a therapeutic class of great clinical utility because of their broad spectrums of action (especially voriconazole and posaconazole), their safety and the availability of oral and intravenous formulations (fluconazole and voriconazole). This therapeutic class can be divided into two groups: the imidazoles and triazoles. The first imidazole with topical action, clotrimazole, was launched in 1960, and it is still being used for superficial candidiasis. In turn, the triazole compounds are subdivided into first-generation (itraconazole and fluconazole) and second-generation (voriconazole and posaconazole) compounds. Isavuconazole, a new second-generation triazole, is still under clinical investigation.68

The azole derivatives are characterized by their selective inhibition of the production of ergosterol, a steroid found in the fungal cell membrane. Their mode of action is the inhibition of fungal 14-α-demethylase, a cytochrome p450-dependent enzyme. Its catalyzing process is essential for the conversion of lanosterol into ergosterol, other actions that can contribute to the antifungal activity have been described, such as inhibition of the yeast transformation into mycelium, the decrease in fungal cell adhesion and the accumulation of steroids that are potentially toxic to fungal cells once the conversion of lanosterol into ergosterol is blocked.69,70 Mechanisms of resistance related to drug efflux, as described with C. glabrata, invariably lead to cross-resistance. Mutations in the gene ERG-11 and changes in the target enzyme 14-α-demethylase, as described with C. krusei and fluconazole, may not cause cross-resistance, as the second-generation triazoles (voriconazole and posaconazole) have higher avidity for the target enzyme.71 Recently, there has been discussion regarding harmonization of the breakpoints of susceptibility to fluconazole, and the MIC value limit for susceptible strains was decreased to 2μg/mL for C. albicans, C. parapsilosis and C. tropicalis.72 Based on this change, higher rates of resistance to fluconazole are expected.73

Because the triazoles are cleared via the hepatic metabolism, many drug interactions are possible.

Ketoconazole was the first imidazole developed for oral therapy of fungal infections. It has a wide spectrum of action against agents of dermatomycoses, endemic mycoses (including paracoccidioidomycosis and histoplasmosis) and isolates of Candida spp. Given its limited efficacy in systemic fungal infections in immunocompromised hosts and its toxicity (hepatotoxicity and depression of steroidogenesis), this drug was replaced by fluconazole and itraconazole in most indications (first-generation triazole).69

Itraconazole is a soluble triazole that is available in capsule form. Its intravenous formulation and oral solution, both in cyclodextrin, are not currently available in Brazil. Although it can be used for infections caused by Candida, the primary indication is for mild to moderate endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, coccidioidomycosis, blastomycosis, chromoblastomycosis, phaeohyphomycosis and sporotrichosis, in addition to dermatomycosis.74,75 Because it is well tolerated in long-term use, and considering its excellent availability in keratinized and subcutaneous tissues, itraconazole can be used in chronic mucocutaneous candidiasis and onychomycosis. It is considered as an alternative drug in cases of oral and vaginal candidiasis. Considering that only the capsule formulation is available in Brazil, itraconazole is not indicated for treatment of hematogenous candidiasis and other invasive forms of mycosis.76

Fluconazole is a water-soluble triazole for parenteral (200mg) and oral use (100mg and 150mg) that has antifungal activity against dermatophytes, Cryptococcus neoformans and most Candida spp., except for C. krusei, which has primary resistance, and C. glabrata, which has a lower susceptibility to fluconazole, particularly when isolated from patients with prior exposure to this antifungal. Fluconazole has an excellent safety profile, good absorption in the gastrointestinal tract and distribution in different compartments of the body, including the central nervous system and the eyes. Fluconazole is effective in the treatment of superficial and deep infections by Candida spp., including cases of oroesophageal candidiasis, hematogenous candidiasis and candiduria and its complications.77 Most cases of toxicity to fluconazole are related to drug-induced hepatitis and are often asymptomatic. GI intolerance is not frequent, and leukopenia and thrombocytopenia are rare. Unlike ketoconazole, there is no blockage in hormonal synthesis with fluconazole. The dose should be reduced patients with creatinine clearance <50mL/min.78

Voriconazole is a triazole available in tablets of 50mg and 200mg and vials of 200mg for intravenous administration whose carrier is cyclodextrin. It has a broader spectrum of action than fluconazole, and it is active against Candida species that include C. glabrata and C. krusei, C. neoformans, Trichosporon sp., Aspergillus spp., Fusarium spp., Scedosporium apiospermum, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis and Paracoccidioides brasiliensis. It is not active against Scedosporium prolificans and agents of mucormycosis. The oral formulation has good bioavailability and allows for safe sequential therapy and therapeutic levels in different tissues, including the central nervous system. Dose adjustments are needed in cases of moderate hepatic impairment, and the risks-benefits should be measured in severe forms of liver failure. Renal elimination of the active form is minimal, with no need for dose adjustment when using the oral formulation. However, the use of the intravenous form must be evaluated on a case-by-case basis in patients with creatinine clearance under 50mL/min, as the excipient (cyclodextrin) can be accumulated in patients with renal failure. Regarding safety, the main adverse effects are transient visual disturbances (up to 30% of patients) reversible with discontinuation of the drug, elevations of transaminases and bilirubin, skin reactions and photosensitivity (up to 25%); with use, it is recommended to avoid sun exposure and/or to use sunscreen.79

In the treatment of esophageal candidiasis, voriconazole has clinical efficacy similar to fluconazole. Although its use is most important in invasive aspergillosis, in a study with non-neutropenic patients with candidemia or invasive candidiasis, voriconazole exhibited similar efficacy and less renal toxicity compared to conventional amphotericin B followed by fluconazole.80,81

Posaconazole is a triazole whose chemical structure has been modified from the itraconazole molecule. This azole has a broad antifungal spectrum that acts in vitro and in vivo against isolates of Candida spp., including C. krusei and some isolates of C. glabrata resistant to fluconazole, Aspergillus spp., Fusarium spp., dematiaceous fungi and some agents of mucormycosis. To date, posaconazole is only available in an oral solution that is administered three to four times per day. The absorption can decrease in certain conditions, such as when the patient is receiving a proton pump inhibitor. An oral formulation in tablet form with a single daily administration and improved absorption and an intravenous formulation are under development. While the main indication is prophylaxis of fungal infections in patients with acute myelogenous leukemia and myelodysplastic syndrome receiving remission-inducing therapy as well as transplant recipients of allogeneic hematopoietic stem cells with chronic graft-versus-host disease, the triazole treatment is also indicated as a rescue treatment in several fungal infections, including oropharyngeal candidiasis. However, its unique availability in an oral suspension formulation may be a limitation for patients who are clinically unstable and/or with problems swallowing and absorbing drugs that require oral treatment.82 This drug is not yet available for clinical use in Brazil.

Echinocandins are a new class of antifungal exclusively for parenteral use that are classified as inhibitors of the enzyme complex 1,3-β-d-glucan synthase, which synthesizes 1,3-β-d-glucan, an essential polysaccharide component of the fungal cell wall. The echinocandins are rapidly fungicidal for Candida species and fungistatic for Aspergillus species.83 Currently, three drugs represent this therapeutic class: caspofungin, micafungin and anidulafungin.

By acting on an exclusive structure of fungal cells (the cell wall), the echinocandins are currently among the most safe and well-tolerated drugs. When present, the adverse effects are mild, such as fever, phlebitis at the infusion site and transient elevation of liver enzymes. In addition to fever, other symptoms mediated by histamine release may rarely occur, including rash, facial swelling, pruritus, sensation of warmth and bronchospasm. Given the small hepatic metabolism of these drugs, few (caspofungin and micafungin) or no drug interactions (anidulafungin) occur with the use of these drugs.83

Caspofungin has been available for clinical use in Brazil for almost a decade. Its formulation is available in vials of 50mg and 70mg. The dose needed for invasive candidiasis is 70mg, followed by 50mg daily. The elimination of the drug occurs by spontaneous hydrolysis and acetylation in the liver; it does not undergo oxidative metabolism by the cytochrome complex P450-dependent enzyme, which explains its low interference with other drugs metabolized in the liver. This antifungal has no renal elimination; therefore, dose adjustment in patients with renal failure is not indicated. In cases of moderate hepatic failure, it is recommended to use a low dosage (35mg/day in adults). There are no clinical data regarding its use in patients with severe hepatic impairment. It has good distribution in different body fluids and tissues, and its concentration is limited in the cerebrospinal fluid, urine and eyes.84 Caspofungin has a large plasma protein binding capacity. This drug should not be used in pregnant women, and there is little clinical information regarding pediatric indications; however, case series suggest that it is an effective and safe choice even in this group.85 Caspofungin has been evaluated in patients with candidemia and/or invasive candidiasis in a randomized trial comparing conventional amphotericin B, which had the same success rate and lower toxicity.30

This echinocandin is available in vials of 100mg. Among the few randomized clinical trials available for this drug, two studies have validated its clinical use in esophageal candidiasis and invasive candidiasis/candidemia, both in comparison to fluconazole. In the candidemia/invasive candidiasis study, anidulafungin was one of the few antifungal drugs that yielded the best therapeutic result versus the comparator (fluconazole) in a clinical study involving patients with candidemia.32 Experiences with anidulafungin in the pediatric population, in which the safety and efficacy of caspofungin and micafungin have been demonstrated, are very limited.86,87 This echinocandin has less hepatic metabolism and may be indicated for patients with moderate or severe hepatic impairment without any need for dose adjustment.88

This drug has been sold in vials of 100mg for several years in Japan and has recently begun being sold in the U.S. and Brazil. Among the echinocandins, micafungin is the drug involved in the largest number of phase II and III studies involving patients with candidiasis. In candidemia and invasive candidiasis, studies were compared to liposomal amphotericin B and caspofungina.31,89 Unlike other echinocandins, micafungin does not require a loading dose for treatment initiation.90

Tables 1 and 2 show the pharmacological aspects and antifungal dosages for systemic use.

Below, we discuss the treatment of major infections caused by Candida. The recommendations for therapy are indicated for adult patients and were based on levels of evidence according to the strength of the recommendation and the quality of evidence from the American Society of Infectious Diseases, adapted from the Canadian Ministry of Health,91 as shown in Table 3.

Each topography was discussed with regard to epidemiological, clinical and laboratory diagnostic and therapeutic recommendations. The therapeutic options for treating candidiasis are summarized in Table 4.

Oral candidiasis is considered superficial candidiasis that affects patients with changes in local or systemic immunity, either due to age (premature neonates and the elderly), prosthesis use, exposure to immunosuppressive drugs (chemotherapy, corticosteroids), antibiotics or the presence of diseases such as cancer, diabetes, sarcoidosis, cirrhosis, malnutrition, xerostomy and AIDS.92 In clinical practice, most cases of candidiasis are observed in pediatric patients, who exhibit immaturity of the defense mechanisms of the mucosa, and the elderly, whose defense mechanisms are senescent or even because of the use of dental prostheses.93 The pathological conditions most commonly associated with oral candidiasis in adult patients are AIDS, diabetes and exposure to antibiotics and/or corticosteroids for different conditions. Therefore, all adult patients presenting with oral candidiasis without obvious cause should be investigated for HIV infection.94

C. albicans accounts for approximately 90% of the isolates causing oroesophageal candidiasis, but C. tropicalis, C. krusei, C. glabrata, C. parapsilosis and C. dubliniensis can also be detected.95 In AIDS patients unresponsive to antiretroviral therapy, episodes of oropharyngeal candidiasis become recurrent, requiring prolonged use or repeated cycles of therapy with triazoles. In this scenario, there is an increase in episodes of candidiasis by Candida non-albicans isolates resistant to fluconazole or even in the risk of selecting resistant strains of C. albicans to this drug.96

Clinical manifestations are varied and depend on the host's immune status and the extent of oral candidiasis. The largest clinical experience of infectious disease is in the form of pseudomembranous candidiasis. The most common symptoms are oral discomfort, burning pain and the presence of removable white plaque under erythematous mucosa. These conditions make feeding difficult, and they can compromise the regularity of oral drug treatments.97 However, other clinical presentations are known. Erythematous candidiasis presents itself as erythematous infiltrate with reduced papillae when present on the tongue. Patients using dental prostheses with oral candidiasis have chronic erythema and discomfort in the region of the prosthesis. Angular cheilitis caused by Candida spp. manifests as discomfort, erythema, and fissures in the angular region of the lips.98

The clinical presentation is usually very characteristic of this condition, particularly when it is pseudomembranous. However, clinical diagnosis should be confirmed by laboratory investigation as follows: (a) by direct mycological examination, with scrapes of lesions in KOH preparations or by Gram staining, where the specimen is analyzed by the presence of fungal elements consistent with Candida spp. and/or (b) by culturing in selective fungal medium (preferably chromogenic medium to identify different species), where the yeast is isolated and the agent is forwarded to complete identification.99

Culture is particularly important in cases of recurrent candidiasis in patients with AIDS, in cases of poor response to conventional therapy or when an injury that is suggestive of candidiasis arises in patients receiving any antifungal drug. In these situations, the identification of the agent species and testing for susceptibility to antifungal agents are necessary recommendations for optimizing a new therapeutic indication in view of the possibility of infection by strains of Candida spp. resistant to one or all triazoles.100,101

The goal of treatment is to eliminate the signs and symptoms of the disease, reduce or eliminate colonization and prevent recurrence.92 Topical therapy is recommended for patients without HIV/AIDS (B-I) and for the initial episodes of cryptococcosis in patients with HIV/AIDS (A-I).

Esophageal candidiasis is considered a form of semi-invasive candidiasis that primarily affects patients with AIDS, cancer, diabetes, previous esophageal diseases, malnutrition and alcoholism, along with those in therapies using corticosteroids, antibiotics, H2 receptor antagonists and proton-pump inhibitors.92 In clinical practice, most cases of esophageal candidiasis occur in AIDS patients, followed by lower frequencies of diabetics and critically ill patients exposed to multiple antibiotic cycles.99

Candida esophagitis can be oligosymptomatic, but its main clinical manifestations include dysphagia, odynophagia and retroesternal burning. In children, nausea, vomiting and dehydration are the main signs. Although the presence of concomitant oral and esophageal candidiasis is common, particularly in AIDS patients, the absence of oral candidiasis does not exclude esophagitis diagnosis. Complications include bleeding, perforation and stenosis.101

In AIDS patients, the diagnosis is usually made based only on clinical data and treatment response. However, taking into account many other opportunistic diseases that affect the esophagus in immunocompromised patients (e.g., herpes and cytomegalovirus), laboratory investigation is mandatory for a definitive diagnosis.94 Endoscopy reports often reveal white plaques that may or may not be accompanied by ulcerated lesions. Apart from the morphological findings, it is recommended to perform a scrap (brush) to obtain a sample for microscopic examination and culturing, in addition to a mucosal biopsy.99

The microscopic examination of fungal elements is performed with a sample obtained by scraping on a slide with KOH or by Gram stain. The culture is performed with a sample obtained by scraping or biopsy. A biopsy should be processed with hematoxylin–eosin staining and silver methenamine (Grocott).99

The definitive diagnosis of esophageal candidiasis is made when, in addition to the clinical and morphological endoscopic findings, we identify fungal elements on microscopic examination and/or observe the presence of fungal elements in tissue, confirming invasion by the pathogen. From an academic point of view, the isolated identification of Candida in culture but no fungal elements by microscopic examination and biopsy may represent colonization of the gastrointestinal tract and not infection.101

Systemic therapy is recommended for cases of esophageal candidiasis (B-II). This starts with empirical systemic therapy (A-I) with fluconazole 200mg PO or IV in the first day, followed by 100mg QD for 14–21 days (A-I). When endoscopy is not performed at the time of diagnosis, it should be performed if no improvement occurs within 3–5 days.95

In patients with esophageal candidiasis refractory to fluconazole, the options are as follows:

• •

  Voriconazole 200mg BID for 14–21 days. This drug was validated in a comparative clinical trial with fluconazole in patients with esophageal candidiasis (A-I).105 Its use in the treatment of esophageal candidiasis refractory to fluconazole may have a compromised result due to eventual cross-resistance; however, it is a good indication for susceptibility tests, if available (B-II).

• •

  Itraconazole 200mg PO BID with food for 14–21 days (A-II).103,104 Given that there is no oral formulation in Brazil and cross-resistance is commonly observed across triazoles, treatment with capsules presents problems with absorption and lesser exposure of the drug to the saliva. These factors can compromise treatment success.

• •

  Posaconazole 200mg PO on the first day followed by 100mg PO QD for 13 days for primary therapy (A-I), or 400mg BID for 3 days followed by 400mg QD for 25 days for refractory cases (B-II). This drug was validated for this indication in two clinical trials: one controlled and randomized with fluconazole and another open-label for refractory cases.106,107 Its use for esophageal candidiasis refractory to fluconazole may be compromised by an eventual cross-resistance; however, it is a good indication for susceptibility tests, if available (B-II). This drug is not available in Brazil.

• •

  Amphotericin B deoxycholate 0.3–0.5mg/kg/day IV for 7–14 days (B-II).108

• •

  Caspofungin 50mg/day IV or anidulafungin 200mg/day IV or micafungin 150mg/day IV for 7–14 days. These drugs were validated in comparative clinical trials with fluconazole in patients with esophageal candidiasis (A-I).109–111

Vaginal candidiasis is highly prevalent in women during their childbearing life; approximately 75% have at least one episode lifelong, and 5–10% can develop a recurrence (defined as at least four episodes of vaginitis by Candida spp. within one year).112

The most frequent predisposing factors for vaginal candidiasis include exposure to high levels of estrogens (birth control, pregnancy and hormone replacement), uncontrolled diabetes mellitus, use of topical and systemic antibiotics and inadequate hygiene habits. Most women with recurrent vaginal candidiasis do not have underlying diseases associated with systemic immunosuppression, and recurrence may be secondary to a deficiency in the local immune response to the agent.113

Vulvovaginal candidiasis is usually classified as complicated or uncomplicated, pending on the severity of the clinical presentation and basic conditions of the host. Uncomplicated forms of vaginitis account for more than 90% of cases and have an excellent response to short oral or topical therapy. Patients with more complicated vaginitis require a prolonged antimycotic therapy.114

C. albicans is the most frequent cause of vaginitis, accounting for approximately 74–95% of cases, followed by C. glabrata in approximately 14.5% of cases. The non-albicans species are more common in recurrent forms and may be found in 10–20% of these patients. C. glabrata is the species most frequently identified in these cases.115,116

Considering that 30% of women may have Candida colonization and there is a wide differential diagnosis for infectious leukorrhea, the diagnosis of C. vulvovaginitis should be based on clinical and laboratory findings.117

Candidiasis involves the vulva and the vaginal lumen, causing intense itching, burning, local discomfort, dysuria, vaginal discharge and dyspareunia. Clinical examination revealed swelling and redness of the vulva and/or vagina, vaginal discharge that looks like milk and, eventually, vulvar carved cracks.118

Clinical diagnosis must be performed by the following tests:117

• •

  Direct microscopic examination with the addition of KOH (10%) or Gram stain to search for fungal elements, complemented by evaluation of the vaginal pH (infection usually occurs with a pH between 4 and 4.5);

• •

  Culture in specific material. To decrease costs, some authors recommend prompt culture only for complicated or recurrent vulvovaginal candidiasis.

The term candiduria refers to the growth of Candida spp. in urine cultures collected by appropriate techniques; this finding is not necessarily accompanied by signs and/or symptoms of urinary tract infection (UTI). Candiduria is very frequent among patients exposed to risk factors; up to 20% of hospitalized patients may have candiduria during their hospitalization, particularly intensive care unit (ICU) patients.126,127 This laboratory finding fosters dilemmas regarding its interpretation, as it can represent a simple contamination of the urine collection, candiduria asymptomatic cystitis or pyelonephritis, primary renal candidiasis, ureteropelvic fungus ball or disseminated candidiasis with renal manifestations.

Among hospitalized patients, the factors most often related to the development of candiduria are advanced age, female gender, broad-spectrum antibiotics, the use of corticosteroids and immunosuppressive drugs, the presence of urinary tract abnormalities, diabetes, delayed vesical catheterization, postoperative of major surgery and malignancies.127,128

Series of cases from Brazil confirm that the three most prevalent species isolated from urine in hospitalized patients are C. albicans, C. tropicalis and C. glabrata. These studies measure prevalences ranging from 35.5 to 70% for C. albicans, 4.6–52.5% for C. tropicalis and 7–8.8% for C. glabrata.129–132

In outpatients not exposed to the risk factors mentioned, in most cases, the identification of Candida in urine reflects inadequate collection or processing of the sample and consequent contamination of the culture. In patients exposed to risk factors for UTI by Candida, the finding of candiduria may signify colonization or infection. In these patients, the counting of colonies is highly variable and directly dependent on the methodology used to collect material. Thus, the isolation of Candida in the urine may occur even in the absence of disease, and there is considerable controversy regarding the value of colony counts obtained in culture, a procedure with low specificity and sensitivity in differentiating between patients colonized and infected by this agent.12

Some authors suggest that there is a greater relationship between candiduria and UTI when the colony count in the urine culture reaches values of approximately 10,000–100,000CFU/mL.133,134 However, scores below that can be measured in patients with Candida UTI, particularly in cases of pyelonephritis acquired by the hematogenous route due to systemic candidiasis, in which the kidneys function as filters and may reflect low counts in the urine. In this sense, there is no consensus among authors on the specific cutoff value for the interpretation of quantitative urine cultures for the recognition of patients with infection of the lower UTI or pyelonephritis.135

• •

  The best therapeutic approach for patients with candiduria should be defined on individual basis, considering clinical and epidemiological data to classify each patient into one of the following conditions: (1) no prior risk factors for candiduria, (2) exposure to risk factors but unlikely to be a case of disseminated candidiasis, or (3) exposure to risk factors for candiduria with septicemia without defining etiology and possible/probable systemic dissemination.102,12

• •

  The therapeutic approach suggested for these three different scenarios are the following. (1) No prior risk factors for candiduria: in this category, we have patients without underlying diseases who did not undergo catheterization and who have no history of previous use of corticosteroids and antibiotics. They should not receive systemic antifungal agents. It is recommended to request a new collection of material and, if yeasts are found, to investigate the possibility of fungal genital mucositis in the vagina or the glans (C-III).136 (2) Predisposed to candiduria, but unlikely to be disseminated candidiasis: this category includes asymptomatic outpatients or inpatients who underwent catheterization and/or other predisposing factors for candiduria. In these patients, the initial approach is the removal of the predisposing factors with subsequent clinical and laboratory follow-up (C-III). In the vast majority of patients, candiduria resolves after the introduction of these measures. Patients with symptoms of cystitis and with positive urine for yeasts should be treated with antifungal agents (B-III).102,136 (3) Predisposed to candiduria with probable systemic dissemination: critically ill patients with risk factors for systemic fungal infection and who evolve with candiduria and signs of sepsis should be investigated for invasive candidiasis (blood) and should begin the use of systemic antifungal drugs. This means that the patient is not merely colonized (C-III).102

• •

  If there are indications for treatment, treatment regimens include the following:

  • –

    Fluconazole, oral or intravenous dose of 200mg/day for 7–14 days (A-I).137

  • –

    Amphotericin B, systemic dose of 0.3mg/kg to 1mg/kg/day for 1–7 days (B-II) or amphotericin B, bladder irrigation, 50mg/day for 48–72h with continuous infusion in a two-way tube (B-II). These schemes are reserved for cases refractory infections or those intolerant to fluconazole, along with yeasts resistant to this azole.102,138

  • –

    In case of suspicion of systemic candidiasis, the patient should be treated according to the recommendations for hematogenous candidiasis.102

  • –

    Clinical experience with candiduria and echinocandins or voriconazole is restricted; pharmacological data suggest that the urinary concentrations of both antifungals are reduced.139

  • –

    In the clinical management of patients with candiduria, it is important to consider the removal of the catheterization system, taking into account that this measure may resolves approximately 40% of cases, besides reducing the recurrence of infection (B-I).139 If it is not possible to remove the system, it is at least recommended to change it.140

Peritoneal dialysis is a modality of renal replacement therapy that currently accounts for only 10–20% of dialysis modalities. It can be performed continuously with an oriented procedure performed at home or intermittently, which has been completely abandoned. Among the complications of peritoneal dialysis, infection ranks second place after cardiovascular events, and fungal infections account for 2–14% of peritonitis cases.141 The overall mortality in most series ranges from 10 to 25% of cases, and there are a few reports of up to 50% deaths.142 Among the fungal peritonitis diseases, 80–90% are caused by Candida, particularly isolates of C. albicans, C. parapsilosis and C. tropicalis.143 The risk factors for the occurrence of fungal peritonitis in patients on peritoneal dialysis are not completely known.144 The basic conditions most commonly reported in patients with fungal peritonitis include diabetes, the prior occurrence of peritonitis by other agents and the previous use of antibiotics.145

Diagnosis is made through clinical signs and symptoms of peritonitis, which are represented by abdominal pain, distention, and fever associated with clouding of the dialysis fluid, whose cell count increases due to the neutrophil count (>100leukocytes/mm3). Etiologic evidence is obtained by identification of yeasts in bacterioscopic examination of the peritoneal fluid, with growth of Candida spp. in culture.141,145

The guidelines for the treatment of fungal peritonitis are based on case reports and open-label studies of limited groups of patients. Among the key recommendations for the treatment of this complication, the authors suggest that the early removal of the dialysis catheter is essential to the success of the therapy (B-II).146

The largest experience in the treatment of fungal peritonitis is with fluconazole or amphotericin B (B-II). Many authors recommend starting with amphotericin and completing treatment with fluconazole after clinical improvement (B-II).146

Some authors suggest the use of intraperitoneal fluconazole concomitantly with the systemic use of amphotericin B (C-III).147 The treatment period is usually four to six weeks. It is essential to monitor the patient by abdominal ultrasound to rule out collections and to guide the treatment time (B-III).146

There is little reliable information regarding doses of antifungal agents, but the authors suggest the use of 0.7mg/kg to 1mg/kg/day of amphotericin B and 400mg/day of fluconazole.148

If implantation of a new peritoneal catheter is an option, this procedure should be performed with a minimum interval of four to six weeks after the initiation of treatment (C-III). According to recent studies, at least 40% of patients with fungal peritonitis cannot continue with peritoneal dialysis. Another modality for renal replacement therapy is needed.148

Among the new drugs, caspofungin has experienced the most success. It may be considered for patients with poor responses to conventional treatment and can be used at 50–100mg/day with good tolerability (B-II).149 However, in view of the pharmacological similarities and therapeutic success of echinocandins, it is believed that all echinocandins can be used with these conditions (C-III).

Postoperative peritonitis caused by Candida species occurs with significant frequency in the hospital. The majority of cases are related to episodes of secondary or tertiary peritonitis, when cases of acute abdomen perforated by bacterial peritonitis are subsequently followed by fungal peritonitis. The perforation of the upper digestive tract is more frequently associated with contamination of the peritoneal cavity by Candida compared to the ileum and appendix, occurring in 5–64% of the perforated cases.150

The pathological significance of Candida spp. isolation in the peritoneal fluid and drains of patients undergoing surgery involving manipulation of the gastrointestinal tract is uncertain. The disruption of the anatomical barrier of the gastrointestinal tract can lead to the isolation of transitional agents in the abdominal cavity or contamination of cultures without evolution of the process to properly fungal peritonitis.151 Moreover, a case–control study has isolated Candida spp. in the peritonea of patients who developed perforation of the gastrointestinal tract that caused increased mortality.152

In this context, the interpretation of the identification of Candida in peritoneal fluid should be evaluated on an individual basis, considering the patient's clinical conditions. When Candida is identified in the peritoneal fluid of patients with complicated postoperative recoveries, along with persistent fever and other evidence of peritonitis (for which sepsis is likely from an abdominal source), fungal etiology should be strongly considered. However, in most cases when Candida is isolated in the intraperitoneal fluid cultures of young patients without comorbidities and who have no evidence of systemic infection in postoperative uncomplicated appendicitis, the laboratory finding is generally transitory with no pathological meaning.153

Although the isolation of Candida in the abdominal cavity is associated with an increase in postoperative complications and mortality, the clinical and laboratory data that should trigger the use of antifungal agents are still a matter of controversy. If there is suspicion of invasive candidiasis, the patient should be treated according to the appropriate therapy for hematogenous candidiasis.153

The most experience in the treatment of peritonitis caused by Candida involves the use of amphotericin B (0.7–1mg/kg/day) or fluconazole (400–800mg/day) (B-II).154 However, the toxicity of amphotericin B and the limited spectrum of fluconazole limit their use in many clinical scenarios.

Taking into account the high rate of success of treating hematogenous candidiasis observed in patients with echinocandins and the large sample of surgical patients in these studies, it is believed that all echinocandins constitute good alternatives in this condition (B-I).149,154

Despite the controversies, there is a general concept in the literature that Candida pneumonia is an unusual event, particularly among non-neutropenic patients admitted to ICUs. The highest incidences of C. pneumonia are documented among neutropenic patients with hematologic malignancies or patients undergoing lung transplantation.155

In most cases, C. pneumonia is secondary to a hematogenous invasion. In patients undergoing lung transplantation, bronchial anastomosis has been identified as an anatomical site that is potentially more susceptible to colonization and invasion by opportunistic fungi, partly due to the relative ischemia of this region after transplantation. These infections may be complicated by anastomotic dehiscence and subsequent bleeding.156

In ICU patients, especially those undergoing mechanical ventilation, airway colonization by Candida is found with relative frequency, but with no pathological significance. Tracheobronchial colonization by Candida in ICU patients is the result of impairment of local defense mechanisms, the presence of an endotracheal tube, the use of antacids and the exposure to antibiotics, conditions that lead to substantial changes in the microbiota of the oropharynx and the gastrointestinal and respiratory tracts.157

The isolation of Candida in the respiratory tract of critically ill patients, even if obtained by bronchoalveolar lavage, does not allow for the diagnosis of pulmonary candidiasis. In most cases, this finding refers to the colonization and/or contamination of the sample during the procedure. Diagnosis by quantitative culture is not reliable for differentiating colonized patients from those with pneumonia caused by Candida. Thus, the final diagnosis is dependent on lung biopsy with demonstration of the presence of fungal elements in the intima of the parenchyma and supplemented by a culture of tissue fragments with growth of Candida spp.157 In practice, this is rarely a definitive diagnosis.

In general, the identification of positive cultures for Candida spp. in respiratory tract samples should be considered evidence of local colonization whose risk of progression to pneumonia is usually small (B-II).158

Special attention is recommended in the investigation of neutropenic patients, patients with cancer or hematologic malignancies, along with patients undergoing HSCT or lung transplantation (B-II).159–161 When a definitive diagnosis of pneumonia is reached, the antifungal should be chosen as discussed in the section involving acute disseminated candidiasis; there may be a choice between echinocandins, fluconazole or amphotericin B formulations (B-II).149,162

Hematogenous candidiasis encompasses a wide spectrum of clinical episodes, including isolates of Candida or cases in which the fungus is present in the bloodstream and spreads to one or more organs of the infected host.1 Considering that most of the data available for hematogenous Candida infection refer to candidemia, this is the term that will be used in these guidelines.

It is believed that the majority of cases of candidemia are acquired via the endogenous route due to the translocation of the pathogen through the gastrointestinal tract, where there is rich colonization by Candida spp. in up to 70% of the general population. Most candidemia events are preceded by colonization by the same species of yeast, which is considered as an independent risk factor for its development. Genotyping methods reveal the similarities between colonizing and infecting strains, confirming the probable endogenous origin of most of the infections caused by these pathogens.163

Any variables causing injury or imbalance in the microbiota of the gastrointestinal mucosa can be facilitators of translocation of Candida spp. to the mesenteric capillaries. Thus, factors that increase intestinal colonization by Candida (i.e., antibiotics, corticosteroids, ileus or intestinal obstruction) or that determine atrophy or intestinal mucosal damage (i.e., prolonged fasting, total parenteral nutrition, hypotension, surgical procedure, mucositis secondary to chemotherapy or radiotherapy) may potentiate the phenomenon of translocation in the gastrointestinal tract.164

Hematogenous infections by Candida spp. can also be acquired exogenously, either by contamination of invasive medical procedures, prostheses or contaminated infusion solutions, such as the colonization of vascular catheters in central positions.24

Case–control studies conducted during the 1980s and 1990s identified numerous risk factors associated with the occurrence of candidemia in hospitalized patients, including: the use of antibiotics, colonization by Candida spp. at different sites, dialysis, major surgery, the use of a CVC in place, chemotherapy, neutropenia, steroid use and parenteral nutrition.165,166

There is a wide geographical variation in the documented etiology patterns of candidemia in different medical centers. In different studies in tertiary hospitals in the public system in Brazil, C. tropicalis and C. parapsilosis are prevalent.42,167 Epidemiology can vary between different institutions; a recent study noted higher incidences of C. glabrata in private hospitals of São Paulo, Rio de Janeiro, Salvador, Belo Horizonte and Curitiba, where the use of fluconazole started in the 1990s. Confirming these data, other series published after 2008 reported rates of candidemia due to C. glabrata and/or C. krusei above 10% in our setting.43,168 These data reinforce the importance of implementing programs for microbiological surveillance of bloodstream infections for the optimization of control strategies and the treatment of these infectious complications.

Hematogenous candidiasis is an infectious complication that should always be investigated in patients with sepsis after a long period of hospitalization and exposure to risk factors of candidemia, particularly exposure to broad-spectrum antibiotic therapy, invasive medical procedures, immunosuppressive therapy and parenteral nutrition. Brazilian data suggest that 40–50% of these patients are in the ICU at the time of diagnosis. A substantial number of cases have antecedents involving major surgery, particularly with manipulation of gastrointestinal tract.9,42

The study of the natural history of patients with candidemia shows that some episodes of fungemia must be transient and self-limited, particularly in non-neutropenic hosts. However, there are no clinical or laboratory data that allow the clinician to identify with certainty which episodes are only transitory and which will lead to cases of disseminated hematogenous candidiasis with tissue invasion and severe sepsis at the moment of the fungemia diagnosis. Another important aspect to consider is that in some patients, infectious complications documented in the viscera appear weeks or months after a candidemia episode, as occurs in some cases of retinitis, meningitis, or osteomyelitis caused by Candida spp.169,170

These guidelines will discuss in detail the clinical management of three different scenarios of hematogenous candidiasis:

• 1.

  Candidemia: isolation of Candida spp. in the bloodstreams of patients without clinical and laboratory evidence of infectious foci in the viscera. In clinical practice, there are few cases for which there is documentation of the involvement of different organs during the episode of candidemia. The most frequent clinical pattern of presentation of candidemia in adults is only in the presence of fever that is unresponsive to antibiotics in patients at risk. The fever may have an insidious onset, without significant involvement of the general condition, or may be accompanied by chills, myalgia, hypotension and tachycardia. Eventually, some patients develop hypothermia and other evidence of sepsis.2

• 2.

  Acute disseminated candidiasis: documentation of the presence of concomitant fungemia infection in other organs. When present, the acute spread of candidemia to the organ involves the skin and eye. However, the spread of infection to multiple organs may occur, including cases of pyelonephritis, endocarditis, osteoarticular involvement and involvement of the central nervous system, among others. The appearance of skin lesions can be the first clinical manifestation of invasive disease and is a marker of disease spread. Skin lesions may affect approximately 8% of cases, presenting typically as small nodules or erythematous or purpuric maculopapules, but other morphological features of lesions are described. Systemic candidiasis with skin lesions is particularly frequent in neutropenic patients with candidemia due to C. tropicalis.171 In more recent studies, systematic evaluation of fundoscopy performed by an ophthalmologist suggests that ocular involvement occurs in up to 16% of patients with candidemia, being 2–9% of cases of chorioretinitis and 1% of cases of endophthalmitis.172,173 Symptoms include blurred vision, bulbar scotomas and pain. The ophthalmologic abnormalities are characterized by cotton wool lesions in the retina and vitreous humor, multiple retinal hemorrhages, Roth spots, and uveitis. However, all ocular structures may be affected. When endophthalmitis occurs, therapy is difficult, and the incidence of sequelae is high. The recognition of ocular involvement in patients with candidemia is crucial because the treatment should be administered for a longer period and may eventually require surgery to control the process. The diagnosis should be made early, before the involvement of the vitreous.174 In adults, Candida meningitis usually results from the contamination of a neurosurgical procedure and is rarely documented as a complication of candidemia. However, according to data from autopsy series (which may not represent the general population), patients with sepsis who develop Candida fungal lesions in the central nervous system have died in up to 20% of cases.175 Endocarditis caused by Candida usually occurs as a post-surgical complication of valve replacement surgery and in intravenous drug users, particularly those who use heroin. Endocarditis is rarely reported as a single candidemia complication in a patient who did not undergo cardiac surgery.175 Osteoarticular involvement of candidemia is quite rare but may arise as a late complication (more than one year after the alleged episode of fungemia). Bone involvement is recognized by local pain, fever and radiological findings consistent with osteomyelitis.175

  The diagnosis of hematogenous candidiasis in at-risk patients requires careful clinical examination to identify skin lesions and ocular changes consistent with candidemia, in addition to blood cultures.

  Blood cultures are a mandatory procedure in any patient with clinical suspicion of systemic infection by Candida, and some care must be taken to optimize the recovery of the agent:

  • •

    Follow appropriate antisepsis at the puncture site, and remember that the antiseptic must be allowed to act for a few minutes before performing the collection.

  • •

    It is desirable that blood cultures be performed before use of antimicrobials, or if this is not possible, blood should be harvested in the period preceding the administration of daily doses of drugs.

  • •

    Blood volume and number of samples are crucial for a good yield of blood cultures; it is recommended that at least two samples per episode of sepsis be collected and that each sample contain at least 20mL of blood (divided into two blood culture bottles per sample).176

  • •

    Conventional aerobic bottles for automated blood cultures allow the growth of Candida species. However, the performance of aerobic vials may vary between different products. Bactec system vials have lower sensitivity and a longer time for fungal growth than bottles from the BacTAlert system. There are no appreciable differences between these products when using bottles with selective media for fungi.177

  • •

    It is essential that blood cultures be processed by automated systems, which have better sensitivity and allow for quicker isolation of the agent.

  It is important to remember that there is a direct relationship between mortality and the time to onset of treatment of candidemia. Accordingly, every effort should be made for early recognition of patients with hematogenous candidiasis.102

  Given the low frequency of the occurrence of visceral lesions in the majority of adult patients with candidemia, the investigation of fungal endocarditis (echocardiography) and lesions in other organs (abdominal imaging) should be reserved for patients who persist with isolation of Candida in blood cultures despite appropriate antifungal therapy or who show signs of clinical deterioration and signs/symptoms suggestive of infection in the abdominal cavity and/or endocarditis. In turn, fundoscopic examination should be performed in all patients with candidemia and visual symptoms. In patients with candidemia but no visual symptoms, it is recommended to perform fundoscopy one week after the initiation of therapy to increase the sensitivity of eye lesion detection.102,174

• 3.

  Chronic disseminated candidiasis (CDC): complication documented in patients with neutropenia that develop suppurative lesions predominantly localized in the liver and spleen (but may occur in other organs, particularly the kidney) that manifest after the recovery of neutrophils and capacity of the host inflammatory response. High fever is the most important symptom and occurs in almost all patients; it is associated with anorexia, weight loss, pain in the right hypochondrium, nausea and vomiting. Hepatosplenomegaly is identified in half of the cases. A significant increase in serum alkaline phosphatase, which can be up to ten times the baseline, is the most important laboratory finding for CDC diagnosis in suspected patients with persistent fever after neutrophil recovery.175

A diagnosis can be confirmed with ultrasound, computerized tomography, magnetic resonance imaging or positron emission tomography (PET-CT) of the abdomen, along with findings of swelling of the affected organs and the presence of multiple abscesses in the liver, spleen and/or kidneys. Blood cultures are usually negative, and if a directed biopsy is conducted, necrotic cellular elements can be identified, and fungal elements are absent. In this context, microbiological confirmation of the process is rarely obtained. In most cases, the patient is treated according to the epidemiological and clinical findings, together with the laboratory evidence of CDC represented by abscesses in abdominal imaging and high levels of alkaline phosphatase.175,178 It is important to remember that this situation can occur in infections by other fungi, including yeast (e.g., Trichosporon) and molds (Fusarium, Scedosporium, etc.).

The definition of the best therapeutic strategy to be adopted for patients with hematogenous candidiasis should consider the aspects described below:179

• •

  Presence of infectious complications in organs: the occurrence of endophthalmitis, osteomyelitis, endocarditis and CDC are examples of clinical conditions for which antifungal therapy should be extended for periods of four weeks to six months. If prolonged therapy is needed, oral drugs should be chosen.

• •

  Severity of the clinical presentation of the case: this issue is controversial, but patients with organ failure are usually treated initially with fast-acting antifungal drugs; fluconazole is generally saved for a second event when there is an initial clinical response and identification of the Candida species.

• •

  Determination of Candida species: non-albicans species may exhibit lower susceptibility to fluconazole, requiring dose adjustment or a change in medication.

• •

  Risk of renal toxicity while using conventional amphotericin B: the occurrence of acute renal failure in patients in ICUs with renal dysfunction, elderly patients and those receiving other nephrotoxic drugs.

• •

  Previous exposure to antifungal prophylaxis regimens and/or empirical therapy: facing a breakthrough infection in a patient exposed to an antifungal agent, a change of therapeutic class is indicated until the involved Candida species and the susceptibility profile of the agent are confirmed.

• •

  Presence of an intravascular catheter in a central position: the clinical management of this aspect will be discussed in another section.

• •

  The need for surgical removal of the infectious focus: cases of osteomyelitis and endocarditis are examples of clinical situations in which surgical cleaning (or valve replacement) should be considered in the therapeutic management of patients.

We currently have the following drugs available for the treatment of invasive candidiasis: amphotericin B and its formulations, fluconazole, voriconazole and echinocandins.

Amphotericin B deoxycholate should not be used because these patients often have other risk factors for nephrotoxicity, including the underlying disease (e.g., multiple myeloma), its treatment (i.e., anticancer drugs, tumor lysis syndrome) and the use of other nephrotoxic agents (i.e., diuretics, antibiotics) (A-II).183

Patients who are receiving prophylactic fluconazole, do not have gastrointestinal mucositis and who are not at risk of infection by filamentous fungi may not receive empirical antifungal therapy (C-III).219

Patients who are not receiving fluconazole and who are not at risk of infection by filamentous fungus should receive fluconazole (B-I).219 Patients who are receiving fluconazole prophylaxis, yet the clinician considers the possibility of invasive candidiasis, should receive empirical therapy with an agent from another therapeutic class (i.e., a lipid preparation of amphotericin B or an echinocandin – caspofungin or micafungin) (B-II).219

Physicians should consider the use of empirical antifungal therapy in critically ill patients with risk factors for candidemia and clinical manifestations of infection that are not responding to treatment for bacterial infections (C-III).

The choice of antifungal drug for empirical therapy should be based on the same criteria for the selection of appropriate antifungal treatment for candidemia (see specific section).

To support the clinician in the task of selecting patients for empirical antifungal therapy, as experts, it is our opinion that this therapeutic strategy has a greater chance of success when used in ICU patients with sepsis that is unresponsive to antibiotics (excluding other causes of FOI) who have been exposed to three or more risk factors for candidemia for at least 4–7 days of intensive care, particularly those with Candida colonization in non-sterile sites and a history of major surgery in the last two weeks (C-III).

Renal transplantation is the most frequent solid organ transplantation and the least technically complex from the surgical point of view because it is an extraperitoneal surgery of short duration.

Renal transplantation is the solid organ transplantation with the lowest rate of invasive Candida infections and the one in which the clinical repercussion is least significant. Approximately 50% of yeast infections are caused by Candida species. Of these, over 70–80% represent urogenital infections (especially candiduria, which occurred in 11% of patients in a retrospective study) or esophagogastric infections. Only 0.5–5% of the infections occur in the form of candidemia or disseminated candidiasis.244

The most prevalent infections (i.e., UTI and esophagitis) are associated with low morbidity and are infections of secondary importance in the spectrum of fungal infections in kidney transplants.

Due to the benign nature of Candida infections in this group and the low rate of candidemia, there is no formal recommendation for chemoprophylaxis.

Exceptions are made for situations in which there is a UTI in the donor at the time of transplantation because there are anecdotal reports of transmission to the donor with serious consequences (i.e., loss of graft anastomosis). Prophylaxis depends on exact timing, and single-agent treatment is not established (C-III).245

Liver transplantation, the second most frequent solid organ transplantation, is related to high rates of fungal infections (30–40%) mainly due to the complexity of the surgical procedure, which requires an approach through the abdominal cavity and often the bowel, factors known to be related to the occurrence of Candida infections.

Among fungal infections, Candida infections represent 80% of the total events, and candidemia (40%), peritonitis and intracavitary abscesses are the most common manifestations. Most events occur before the sixth post-transplant month, and there has been a reduction in the frequency of Candida over the past years, which has been attributed to improved practices and surgical results.246

Risk factors that distinguish patients at higher risk for invasive candidiasis are retransplantation, dialysis and kidney failure, the need for large volumes of blood products during surgery, antibiotic therapy before transplantation and biliary-enteric anastomosis.246

Contrary to what is observed following kidney transplants, invasive Candida infections are associated with reduced patient survival and considerable morbidity.

In this patient population, randomized, placebo-controlled trials have attempted to reduce invasive candidiasis, reflecting the importance of the event. At least six randomized trials (using fluconazole, itraconazole or liposomal amphotericin) and a meta-analysis of these combined studies are available in the medical literature.247

The results of this meta-analysis, which involved total transplanted groups (with no selection criteria for special groups or subgroups), show total reduction of fungal infections, particularly invasive fungal infections (without specific reference to reducing candidemia), consistent with the results of each individual study and regardless of the antifungal agent used. However, a reduction in mortality is not demonstrated. There is a need for treatment of 11.8 patients to prevent one invasive fungal infection.247

Some authors, having identified heterogeneity in patients and the presence of specific risk factors that identify high-risk populations, advocate focusing on this population as a target for prophylactic therapy.248 However, these recommendations are based on observational and uncontrolled studies, decreasing the strength of the recommendation.

The focus on higher-risk patients is bolstered by the demonstration (from controlled studies) that prophylaxis can lead to side effects, such as the selection of non-albicans strains with greater potential for resistance to azoles.

With the above data available, it is the opinion of this consensus group that antifungal prophylaxis is recommended in liver transplant recipients at greatest risk, recognizing its clinical importance, frequency and the difficulty of establishing the diagnosis in advance. According to the criteria of cost, toxicity and acceptance, we also recommend the use of fluconazole as the drug of choice.249

Find below the specific recommendations.

• •

  Patients at risk for whom prophylaxis should be recommended in the first month after transplantation: the existence of at least two of the following risk factors in the first month after transplantation: retransplantation, the need for dialysis, the use of antibiotics and wide biliary-enteric anastomosis (B-II).

• •

  Prophylactic scheme: fluconazole 200mg (minimum dose) IV with the possibility of using orally for up to three months, individualized according to the patient's clinical condition (i.e., state of immunosuppression, presence in ICU and persistence of risk factors) (B-II).

• •

  Using this strategy, monitor the levels of calcineurin inhibitors (tendency to increase in serum) and check for interactions with other azoles (A-II).

This transplantation modality is also frequently associated with fungal infections because it is performed in diabetic patients and also because of the complexity of the surgery, which involves handling of the intestinal tract.

Over 90% of events are caused by Candida species in the form of intra-abdominal infections with or without concomitant candidemia. As is the case with liver transplantation, invasive Candida infections are associated with both reduced grafts and patient mortality.250

Although the frequency and clinical impact of Candida infections are very similar with respect to what occurs in liver transplantation, there are no randomized studies evaluating the effectiveness of prophylactic antifungal drugs. There are also no studies reporting specific risk factors for the occurrence of fungal infections in this group of transplant recipients. There is only one controlled observational study with historical groups showing lower rates of Candida infections with fluconazole 400mg/day for seven days. The practice is widespread in groups that perform pancreatic transplantation, and there is currently little room for the proposition of controlled studies with placebo.251

It is the opinion of this consensus that prophylaxis should be restricted, recognizing the importance of the event and to curb the excessive use of prophylaxis. Fluconazole can be used in a similar scheme to that used for liver transplantation (C-II).

In this group of patients, infections occur in 2.2% of patients undergoing heart transplantation and in 9% of patients undergoing lung or heart/lung transplantation. However, unlike what happens with other types of solid organ transplantations, there is a high prevalence of infections by filamentous fungi with high mortality. Candida infections occur in 30% of fungal infections, mainly in the form of hematogenous candidiasis.252

The low incidence of serious fungal infections in heart transplant does not indicate the use of specific prophylaxis in this population.

With respect to lung transplantation, the focus is to prevent the occurrence of filamentous fungi; preventing Candida infection is a less-important goal. Thus, this consensus does not suggest prophylaxis for Candida in this group of patients but reinforces the importance of anti-Aspergillus prophylaxis, which has been adopted by 75% of lung transplantation centers.253

Intestinal transplants are performed infrequently but are associated with high rates of Candida infections by extensive manipulation of the intestinal tract.

Data are scarce regarding prophylaxis in this group; treatment with fluconazole should be considered in high-risk patients.

There is no indication for routine prophylaxis against Candida in renal transplant patients (B-II). There is evidence for the use of prophylaxis for Candida in liver transplantation with reduction in invasive events but not in mortality (B-II).

Liver transplant patients should receive prophylaxis with fluconazole for one to three months (B-II).

The same level of evidence exists for the use of fluconazole in kidney/pancreas or intestinal transplants, but the use of fluconazole is suggested for high-risk patients (C-III).

There is no indication for routine prophylaxis against Candida in transplanted heart and/or lung patients (B-II).