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Disclosures: Carol A Kauffman, MD Nothing to disclose. Kieren A Marr, MD Grant/Research/Clinical Trial Support: Astellas; Merck; Pfizer [Antifungals (Liposomal amphotericin B, isavuconazole, micafungin, caspofungin, posaconazole, voriconazole)]. Consultant/Advisory Boards: Astellas; Merck; Pfizer [Antifungals (Liposomal amphotericin B, isavuconazole, micafungin, caspofungin, posaconazole, voriconazole)]. Anna R Thorner, MD Employee of UpToDate, Inc.

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Literature review current through: Oct 2014. | This topic last updated: Sep 23, 2014.

INTRODUCTION — The term candidemia describes the presence of Candida species in the blood. Candidemia is the most common manifestations of invasive candidiasis. Candida in a blood culture should never be viewed as a contaminant and should always prompt a search for the source of the bloodstream infection. For many patients, candidemia is a manifestation of invasive candidiasis that could have originated in a variety of organs, whereas for others, candidemia originated from an infected indwelling intravenous catheter [1].

The treatment of candidemia in adults will be reviewed here. The epidemiology, pathogenesis, clinical manifestations, and diagnosis of candidemia are discussed separately; an overview of Candida infections and the management of other forms of invasive candidiasis are also presented elsewhere. (See "Epidemiology and pathogenesis of candidemia in adults" and "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Overview of Candida infections" and "Candida endocarditis" and "Chronic disseminated candidiasis (hepatosplenic candidiasis)" and "Candida infections of the central nervous system" and "Candida osteoarticular infections".)

The treatment of candidemia in neonates and children is discussed in detail separately. (See "Treatment of Candida infection in neonates" and "Candidemia in children: Treatment".)

Antifungal susceptibility testing is also reviewed separately. (See "Antifungal susceptibility testing".)

EPIDEMIOLOGY — C. albicans is the most common cause of candidemia, but there has been increased isolation of non-albicans species of Candida in recent years. Most prominent have been C. glabrata and C. parapsilosis, followed by C. tropicalis and C. krusei. This is important because some C. glabrata isolates are resistant to fluconazole, and all C. krusei isolates are resistant to fluconazole (table 1). In addition, the minimal inhibitory concentrations for C. parapsilosis with all the echinocandins are higher than for other Candida species. Risk factors for infection with fluconazole-resistant Candida species include neutropenia, recent azole use, and others. The epidemiology of candidemia is discussed in detail separately. (See "Epidemiology and pathogenesis of candidemia in adults", section on 'Prevalence of Candida species'.)

ANTIFUNGAL AGENTS — Therapeutic antifungal classes for the treatment of candidiasis include the polyenes, azoles, and echinocandins. The relative advantages and disadvantages of available agents are discussed in this section. Efficacy is discussed below. (See 'Azoles' below and 'Echinocandins' below and 'Amphotericin B' below.)

Azoles — Fluconazole has been widely used for the treatment of candidiasis since its approval by the US Food and Drug Administration (FDA) in 1990. The azoles work primarily by inhibiting the cytochrome P450-dependent enzyme lanosterol 14-alpha-demethylase [2]. This enzyme is necessary for the conversion of lanosterol to ergosterol, a vital component of the cellular membrane of fungi. General susceptibility patterns of Candida species to fluconazole and other antifungal agents are shown in the Table (table 1).

Fluconazole has an excellent safety profile and is available in intravenous and oral formulations and is also inexpensive, since it is now generic. Fluconazole is highly bioavailable, making oral dosing appropriate for most patients. Most trials evaluating the efficacy of fluconazole for candidemia have used 400 or 800 mg [3-6]. For candidemia, we recommend that fluconazole be dosed as follows: 800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) orally daily [7].

Other available azoles include voriconazole, posaconazole, and itraconazole:

The activity of voriconazole against Candida species is superior to that of fluconazole, with minimal inhibitory concentrations (MICs) that are a log or more less than fluconazole [8]. However, cross-resistance between fluconazole and voriconazole is seen frequently, especially with C. glabrata. Voriconazole has significantly greater in vitro activity against C. krusei isolates compared with fluconazole because of more effective binding of its cytochrome P450 isoenzyme [9]. (See "Antifungal susceptibility testing", section on 'Azoles' and "Antifungal susceptibility testing", section on 'Azoles'.)

Posaconazole is available only as an oral suspension. It is approved for use as a prophylactic agent for fungal infections in allogeneic hematopoietic cell transplant recipients with graft-versus-host disease and in patients with prolonged neutropenia due to chemotherapy for hematologic malignancies. It is also approved for oropharyngeal candidiasis but not for systemic candidiasis. (See "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients" and "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Treatment of oropharyngeal and esophageal candidiasis".)

Itraconazole is sometimes used for mucosal candidiasis but is not used for systemic infections.

Azoles interact with multiple different cytochrome P450 enzymes; alternative antifungal agents, such as echinocandins, may be preferred if patients are taking other medications that utilize P450 pathways. (See "Pharmacology of azoles", section on 'Drug interactions'.)

The pharmacology of the azoles is discussed in detail elsewhere. (See "Pharmacology of azoles".)

Echinocandins — The echinocandins include caspofungin, anidulafungin, and micafungin. Echinocandins are noncompetitive inhibitors of the synthesis of 1,3-beta-D-glucan, which is an integral component of the fungal cell wall [10]. They have excellent activity against most Candida species, have favorable toxicity profiles, and are approved for the treatment of candidemia and other forms of invasive candidiasis. The echinocandins are preferred over azoles for the initial treatment of candidemia if C. glabrata or C. krusei is identified or suspected [11].

Due to their broad-spectrum activity against Candida species, the echinocandins are used extensively for candidemia and invasive candidiasis. The highest echinocandin MICs are found for C. parapsilosis and C. guilliermondii. Resistance to echinocandins has been noted in only a few individual cases until recently. However, acquired resistance has been increasingly reported, especially in C. glabrata. The mechanism of echinocandin resistance is similar in all species and involves mutations in the FKS 1 or FKS 2 genes that control the enzyme targeted by the echinocandins.

The echinocandins are administered intravenously as follows:

Caspofungin is given at an initial dose of 70 mg on the first day of treatment, followed by 50 mg daily; dose reduction is required with hepatic dysfunction.

Anidulafungin is given at an initial dose of 200 mg on the first day, followed by 100 mg daily.

Micafungin is given at a dose of 100 mg daily for candidemia; no loading dose is needed.

Adverse effects of all echinocandins are generally mild and include fever, thrombophlebitis, headache, and elevated aminotransferases [11]. The pharmacology of the echinocandins is discussed in detail separately. (See "Pharmacology of echinocandins".)

Amphotericin B — Amphotericin B is a polyene antifungal agent that disrupts fungal cell wall synthesis because of its ability to bind to sterols, primarily ergosterol, which leads to the formation of pores that allow leakage of cellular components. Amphotericin B deoxycholate, which was the standard drug for the treatment of candidiasis for decades, demonstrates rapidly cidal in vitro activity against most species of Candida. It is also associated with significant nephrotoxicity. This has led to the development of various lipid-based derivatives, including liposomal amphotericin B and amphotericin B lipid complex (ABLC). A third formulation, amphotericin B colloidal dispersion (ABCD) is used infrequently, in part because it causes more infusion-related reactions than amphotericin B deoxycholate. These lipid-based compounds have much less toxicity than amphotericin deoxycholate but are significantly more expensive. (See "Pharmacology of amphotericin B" and "Amphotericin B nephrotoxicity".)

The recommended doses for candidemia follow [7]:

Lipid formulations of amphotericin B – 3 to 5 mg/kg intravenously daily

Amphotericin B deoxycholate – 0.5 to 1 mg/kg intravenously daily

SUSCEPTIBILITY PATTERNS — Susceptibility testing for Candida species is becoming more readily available and widely used. General susceptibility patterns are shown in the Table (table 1), and general patterns for each class of antifungal agent are discussed above. (See 'Amphotericin B' above and 'Azoles' above and 'Echinocandins' above.)

Specific drug resistance information for the various Candida species is found below. Antifungal susceptibility testing is discussed in greater detail separately. (See "Antifungal susceptibility testing".)

C. albicans — The incidence of C. albicans resistance is extremely low. An analysis of in vitro susceptibilities of approximately 90,000 isolates of C. albicans collected from 40 countries from 1997 to 2005 demonstrated that only 1.5 percent were resistant to fluconazole [12]. Individual cases and small series of non-mucosal infection with fluconazole-resistant C. albicans have been reported from several tertiary care centers and usually occur in immunosuppressed patients who are taking fluconazole chronically for prophylaxis [13-15].

Most C. albicans isolates are susceptible to the echinocandins, although resistance has been reported [16,17]. The vast majority of C. albicans isolates are susceptible to amphotericin B.

C. krusei — C. krusei is intrinsically resistant to fluconazole due to an altered cytochrome P450 isoenzyme [18]. This resistance cannot be overcome with use of higher drug doses. Voriconazole binds more effectively to the cytochrome P450 isoenzyme in C. krusei than fluconazole, resulting in higher rates of susceptibility [19].

There are geographic differences in the incidence of voriconazole resistance. In an international surveillance study that included nearly 3500 bloodstream isolates of C. krusei, 83 percent of isolates were susceptible to voriconazole, ranging from 75 percent in Latin America to 92 percent in North America [20]. C. krusei isolates are usually susceptible to posaconazole [21].

In the large surveillance study described above, all C. krusei isolates were susceptible to the echinocandins (caspofungin, micafungin, and anidulafungin) [20]. However, individual cases of resistance to the echinocandins have been reported [22-24].

C. krusei demonstrates decreased susceptibility to amphotericin B, requiring higher doses (1 mg/kg daily of amphotericin B deoxycholate or 5 mg/kg daily of lipid-based formulations) to be used for treatment. C. krusei is usually resistant to flucytosine.

C. glabrata — Many C. glabrata isolates are resistant to the azoles, mostly due to changes in drug efflux [7,25]. This type of resistance can sometimes be overcome by using higher doses of fluconazole. Cross-resistance among the azoles is common with C. glabrata. Among the Candida species, the MICs for voriconazole are highest with C. glabrata. Isolates that are resistant to fluconazole are generally resistant to voriconazole as well [26,27].

The echinocandins have generally retained excellent activity against C. glabrata, although isolated cases of resistance have been reported [28-32].

Of note, there is increasing concern that some C. glabrata bloodstream isolates with resistance to fluconazole and voriconazole can also become resistant to the echinocandins. In a surveillance study of the in vitro susceptibility of 1669 C. glabrata bloodstream isolates collected in the United States between 2006 and 2010, 162 isolates (9.7 percent) were resistant to fluconazole, of which 98.8 percent were also not susceptible to voriconazole and 9.3, 9.3, and 8.0 percent were resistant to anidulafungin, caspofungin, and micafungin, respectively [27]. The mechanisms of fluconazole and voriconazole resistance are similar and largely mediated by efflux pumps that can export all azoles [33]. In addition, it was noted that of 162 isolates that were resistant to fluconazole, 18 (11.1 percent) were also resistant to one or more of the echinocandins, with associated mutations in FKS1 or FKS2 genes [27]. In comparison, there were no echinocandin-resistant strains detected among 110 fluconazole-resistant C. glabrata isolates tested between 2001 and 2004, years in which echinocandins were used sparingly. It is not clear what impact these findings will have on treatment regimens for candidemia.

A 10-year study of C. glabrata bloodstream infections at a single medical center in the United States showed an increase in echinocandin resistance from 4.9 percent in 2001 to 12.3 percent in 2010 [34]. This resistance was confirmed by the presence of FKS mutations; strains categorized as susceptible did not possess acquired mutations. On multivariate analysis, echinocandin resistance was associated with prior exposure to an echinocandin. Among 78 fluconazole-resistant isolates, 11 (14.1 percent) were resistant to one or more echinocandins and 8 (10.3 percent) were resistant to all echinocandins.

Amphotericin B has delayed killing kinetics against C. glabrata in vitro [35]; higher doses of amphotericin B are recommended when treating known C. glabrata infection (1 mg/kg daily of amphotericin B deoxycholate or 5 mg/kg daily of lipid-based formulations).

C. parapsilosis — C. parapsilosis is highly susceptible to most antifungal agents. An international surveillance study of 9371 C. parapsilosis isolates collected between 2001 and 2005 found high rates of susceptibility to fluconazole (91 to 96 percent) and voriconazole (95 to 98 percent) in all geographic regions except Africa and the Middle East (79 and 86 percent susceptible to fluconazole and voriconazole, respectively) [36].

The minimal inhibitory concentrations for C. parapsilosis with all the echinocandins are higher than for other Candida species [25]. The clinical implications of these in vitro data are unclear. In an analysis of five trials of caspofungin use in patients with invasive candidiasis, the overall (clinical and microbiologic) success rate among patients with C. parapsilosis (74 percent) was similar to patients with invasive candidiasis caused by other Candida species [37]. A multicenter prospective observational study of candidemia due to C. parapsilosis in Spain found no differences in outcomes of patients who were treated with an echinocandin compared with those who were treated with an azole [38]. These results should be interpreted with caution because this was not a randomized trial; it is unlikely that such a study will be performed [39].

C. tropicalis — C. tropicalis is usually susceptible to the azoles, amphotericin B, and the echinocandins. However, breakthrough C. tropicalis bloodstream infections with resistance to caspofungin have been reported rarely in patients with hematologic malignancies [17,40,41].

C. lusitaniae — C. lusitaniae is unique among Candida species in that it is often resistant to or quickly becomes resistant to amphotericin B; however, it is usually susceptible to the azoles and echinocandins [42].

C. guilliermondii — C. guilliermondii is an uncommon Candida species that in some studies has appeared to cause infections more often in patients who have hematologic malignancies [43]. Treatment can be problematic because some isolates have reduced susceptibility to fluconazole and many have reduced susceptibility to echinocandins [44]. However, C. guilliermondii is usually susceptible to amphotericin B.

C. dubliniensis — C. dubliniensis shares many phenotypic traits with C. albicans, and many isolates were previously misidentified as C. albicans. Special techniques must be undertaken in the microbiology laboratory to differentiate between these two species [45]. C. dubliniensis rose to importance in the mid-1990s when it was found primarily in AIDS patients and most of the isolates were fluconazole resistant. It has subsequently been shown that this species causes disease in other populations as well, and the susceptibilities are similar to those of C. albicans. Most C. dubliniensis isolates are azole susceptible and can therefore be treated with fluconazole; they are also susceptible to echinocandins and amphotericin B.

APPROACH TO ANTIFUNGAL THERAPY — The most common antifungal agents used currently for the treatment of candidemia are fluconazole and the echinocandins (caspofungin, micafungin, anidulafungin). Formulations of amphotericin B are given less often due to the risk of toxicity. Both the echinocandins and the azoles are better tolerated than amphotericin B formulations [46].

In all cases, candidemia requires treatment with an antifungal agent [7]; it should never be assumed that removal of a catheter alone is adequate therapy for candidemia. Several studies have noted the high mortality rates associated with candidemia [47-49] and have shown that mortality is highest in those patients who were not treated with an antifungal drug [48,49]. Furthermore, prompt initiation of therapy is crucial. (See 'Catheter removal' below and 'Outcomes' below.)

Choice of initial agent — When choosing an antifungal agent in patients with suspected candidemia, the following factors should be considered [7]:

History of recent azole exposure

Prevalence of different Candida species and current antifungal susceptibility data in the clinical unit and medical center

Severity of illness

Relevant comorbidities that increase the risk of fluconazole-resistant Candida species (eg, neutropenia) (see "Epidemiology and pathogenesis of candidemia in adults")

Evidence of involvement of the central nervous system, cardiac valves, eyes, and/or visceral organs

History of intolerance to an antifungal agent

It is particularly important to determine the risk of fluconazole-resistant Candida isolates, such as C. glabrata and C. krusei (see 'C. glabrata and C. krusei' below).

Nonneutropenic patients — In nonneutropenic patients with candidemia who are clinically stable, who have not been exposed to recent azole therapy, and who are in clinical units or medical centers in which C. glabrata or C. krusei are uncommonly isolated (<15 percent of all species causing candidemia), we suggest initial therapy with fluconazole rather than an echinocandin (table 2) [7]. (See 'Azoles' below.)

In nonneutropenic patients with moderately severe or severe infections and/or who are at increased risk of C. glabrata or C. krusei infection, we favor an echinocandin (caspofungin, micafungin, or anidulafungin) and we would not use fluconazole as initial therapy, prior to the identification of the causative species [7]. However, in patients who have documented C. glabrata infection, who are already improving clinically on fluconazole or voriconazole, and whose follow-up blood cultures are negative, continuing with the azole is reasonable. (See 'C. glabrata and C. krusei' below and 'Echinocandins' above.)

Neutropenic patients — In patients who are neutropenic, there are several important considerations in choosing appropriate therapy for candidemia [7]:

Most neutropenic patients with candidemia should be treated with an echinocandin or an amphotericin B formulation. Azole drugs have not been studied extensively for treatment of candidemia in this population. Also, neutropenic patients who are heavily pretreated with azole drugs as part of prophylactic regimens are at increased risk for fluconazole-resistant Candida spp, such as C. glabrata and C. krusei (table 2). If amphotericin B is used, a lipid formulation is preferred. (See 'C. glabrata and C. krusei' below and 'Echinocandins' above and 'Amphotericin B' above.)

Fluconazole should be restricted to clinically stable patients who have not received recent azole prophylaxis. (See 'Amphotericin B' above and 'Azoles' above and 'Echinocandins' above.)

C. parapsilosis — Patients with candidemia caused by C. parapsilosis should be treated with fluconazole rather than an echinocandin [7]. However, for patients with C. parapsilosis who are already improving clinically on an echinocandin and whose follow-up blood cultures are negative, continuing with the echinocandin is reasonable. (See 'C. parapsilosis' above.)

C. glabrata and C. krusei — A difficult issue is which antifungal agent to use when C. glabrata is isolated from the blood [7]. Because many C. glabrata strains are resistant to fluconazole, the most conservative approach is to treat fungemia due to this species with an agent other than fluconazole. However, several studies that used fluconazole found no differences in outcome related to the species causing candidemia [3,50,51]. In a study in cancer patients, C. glabrata bloodstream infection responded less well to therapy than C. albicans, but neither the initial regimen nor the species of Candida was an independent predictor of poor outcome [52]. Nevertheless, based on in vitro data, it is prudent to avoid use of fluconazole for the initial treatment of C. glabrata. (See 'C. glabrata' above.)

Since C. krusei is intrinsically resistant to fluconazole, this agent is avoided when C. krusei is suspected. (See 'C. krusei' above.)

Because of its safety profile, an echinocandin is generally preferred over amphotericin B for treatment of candidemia due to C. glabrata and C. krusei. Voriconazole is also approved for this indication, but there is likely to be cross-resistance between fluconazole and voriconazole among C. glabrata isolates. This cross-resistance does not occur with C. krusei. In clinical units or medical centers in which C. glabrata or C. krusei are commonly isolated (defined as >15 percent of all species causing candidemia), we suggest using an echinocandin rather than fluconazole for empiric therapy until the species is known. There are few differences among the echinocandins, and any of the three approved agents (caspofungin, micafungin, anidulafungin) can be used when indicated. (See 'Echinocandins' above.)

Some studies have shown increased rates of echinocandin resistance among C. glabrata bloodstream isolates. Resistance should be suspected in patients who have received echinocandins in the recent past and in patients who develop candidemia while receiving an echinocandin for prophylaxis or empiric therapy (eg, for neutropenic fever); in these situations, an amphotericin B formulation should be used until antifungal susceptibility testing results are available. (See 'C. glabrata' above.)

Candida krusei is usually susceptible to echinocandins and voriconazole but is uniformly resistant to fluconazole. These isolates can also demonstrate high minimum inhibitory concentrations (MICs) to amphotericin B, and, for this reason, higher doses of this drug should be used for C. krusei infection (1 mg/kg daily of amphotericin B deoxycholate or 5 mg/kg daily of lipid-based formulations). We prefer lipid formulations of amphotericin B to amphotericin B deoxycholate because the lipid formulations have fewer toxicities. (See 'Amphotericin B' above.)

Dosing — The dosing of fluconazole, the echinocandins, and amphotericin B formulations is discussed above. (See 'Azoles' above and 'Echinocandins' above and 'Amphotericin B' above.)

Oral step-down therapy — Nonneutropenic patients with Candida isolates likely to be fluconazole susceptible (eg, C. albicans) or proven to be fluconazole susceptible by antifungal susceptibility testing who are clinically stable can be switched from an echinocandin to fluconazole [7]. (See "Antifungal susceptibility testing".)

Voriconazole is recommended as oral step-down therapy only for patients with C. krusei or voriconazole-susceptible C. glabrata [7]. For other Candida isolates, it does not offer a clear advantage compared with fluconazole.

Duration — The appropriate duration of therapy for candidemia has not been studied. A minimum of two weeks of therapy after blood cultures become negative has been used in most clinical trials and is the recommended duration in the 2009 Infectious Diseases Society of America (IDSA) guidelines [7]. Daily blood cultures should be performed after initiating therapy in order to determine the date of sterilization. If blood cultures remain positive, then a search for a metastatic focus, such as an abscess or endocarditis, must be undertaken. In addition, all patients should have resolution of symptoms attributable to candidemia and resolution of neutropenia (eg, absolute neutrophil count >500 cells/microL and showing a consistent increasing trend) before antifungal therapy is discontinued [7]. (See "Overview of neutropenic fever syndromes", section on 'Neutropenia' and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Duration'.)

A longer duration of therapy and consultation with an infectious disease specialist are warranted in patients who have metastatic foci of infection or endocarditis. (See "Treatment of endogenous endophthalmitis due to Candida species" and "Candida osteoarticular infections" and "Candida endocarditis" and "Chronic disseminated candidiasis (hepatosplenic candidiasis)".)

Combination therapy — Whether more than one antifungal agent should be used together for the treatment of candidemia has not been established, although combination therapy is generally not given for the treatment of candidemia.

A controlled trial randomly assigned 219 nonneutropenic patients with candidemia to fluconazole (800 mg/day) alone for two weeks or fluconazole (800 mg/day) plus amphotericin B (0.7 mg/kg per day) for the first four to seven days followed by fluconazole alone to finish the two-week course [6]. There was more rapid clearing of fungemia with initial combination therapy, but the success rates overall were similar in the two groups.

Evidence — Several randomized trials have shown that fluconazole is as effective as amphotericin B for the treatment of candidemia in immunocompetent patients [3-5,53]. The echinocandins appear to be as effective as and better tolerated than amphotericin B formulations and, in one study, more effective than fluconazole [54-57]. The majority of patients in these studies were not neutropenic.

Data are more limited in neutropenic patients with candidemia. No randomized trials have been adequately powered to evaluate the efficacy of antifungal therapy in neutropenic patients [7], and data are derived from small subset analyses of randomized trials, open-label studies, and retrospective studies [5,54,55,58-60]. Based upon the widespread use of fluconazole prophylaxis in neutropenic patients and the resulting increased prevalence of non-albicans Candida species with reduced susceptibility to fluconazole, most neutropenic patients with candidemia are treated with an echinocandin or an amphotericin B formulation. (See 'Neutropenic patients' above.)

Azoles — Several large randomized trials have shown that fluconazole is as effective as amphotericin B for the treatment of candidemia in immunocompetent patients [3-5,53].

In a randomized trial, fluconazole was compared with anidulafungin for treatment of invasive candidiasis in 245 patients: 89 percent had candidemia and only 3 percent were neutropenic [56]. The combined clinical and microbiologic response rates were significantly higher in patients assigned to the anidulafungin arm both at the end of therapy (74 versus 57 percent) and at two-week follow-up (65 versus 49 percent). Mortality rates at 60 days were similar.

The effectiveness of voriconazole for candidemia was shown in a randomized trial in nonneutropenic patients who were treated with either voriconazole alone or amphotericin B for three to seven days followed by fluconazole [61]. Voriconazole therapy led to sterilization of the bloodstream as rapidly as sequential therapy. Success rates at the end of treatment (66 percent for voriconazole and 71 percent for sequential therapy) were similar to those noted in previous trials with other antifungal regimens for the treatment of candidemia. The clinical role for voriconazole in comparison with echinocandins remains unclear. A major concern is the cross-resistance to voriconazole that is seen among many isolates of C. glabrata that are fluconazole resistant. (See 'C. glabrata' above and 'C. glabrata and C. krusei' above.)

Echinocandins — Several randomized trials have compared the efficacy of echinocandins with either an amphotericin B formulation or fluconazole among patients with invasive candidiasis [54-57]. The majority of patients had candidemia and were not neutropenic.

The echinocandins appear to be as effective as and better tolerated than amphotericin B formulations and, in one study, more effective than fluconazole as illustrated by the following observations:

In one randomized trial, caspofungin was shown to be equivalent in efficacy to amphotericin B [54]. Patients were randomly assigned to the two different treatment arms controlling for neutropenia and APACHE II scores. In an analysis that excluded patients who did not have a documented infection or received less than one day of the treatment drug, the two drugs demonstrated equivalent efficacy (73 percent for caspofungin versus 62 percent for amphotericin B). Caspofungin was associated with less toxicity.

A randomized multinational noninferiority trial compared micafungin to liposomal amphotericin B [55]. In a modified intent-to-treat analysis, success rates for clinical and microbiologic cure were similar (74 and 70 percent for micafungin and liposomal amphotericin B, respectively). Micafungin was associated with fewer adverse events. In a later subset analysis of only those patients who had infection with C. glabrata or C. krusei, outcomes were similar between those receiving micafungin and those receiving liposomal amphotericin B [57].

In another randomized trial, anidulafungin resulted in superior combined clinical and microbiologic response compared with fluconazole (65 versus 49 percent at two-week follow-up), although 60-day mortality rates were similar, as discussed above [56]. (See 'Azoles' above.)

Data are more limited in neutropenic patients with candidemia compared with nonneutropenic patients. Efficacy data for the echinocandins in neutropenic patients comes from small subset analyses of randomized trials and open-label studies [54,55,58,59]. Although the efficacy of the echinocandins in neutropenic patients cannot be firmly established based upon these studies, the response rates to the echinocandins appear to be similar to or better than formulations of amphotericin B.

A separate issue is the relative efficacy of the different echinocandins. This was addressed in a randomized trial of adults with candidemia and other forms of invasive candidiasis that compared two doses of micafungin (100 mg or 150 mg daily) with one another and with caspofungin (70 mg once followed by 50 mg daily) [58]. The lower dose of micafungin was equivalent to both the higher dose of micafungin and to caspofungin.

In a later subset analysis of only those patients who had infection with C. glabrata or C. krusei, outcomes were similar among the three treatment groups [57]. In another trial, two different doses of caspofungin (70 mg once followed by 50 mg daily versus 150 mg daily) were compared in patients being treated for invasive candidiasis [62]. Similar rates of mortality (at eight weeks) and significant adverse effects were observed between the groups.

Amphotericin B — Amphotericin B formulations have been proven to be effective in several randomized trials [3-5,53] (see 'Azoles' above). However, amphotericin B formulations are often avoided due to their increased toxicity compared with azoles and echinocandins. They remain useful in cases when resistance to the other antifungal classes is suspected or proven.

Comparison of trial data — A 2008 meta-analysis of 15 randomized trials compared different antifungal agents for the treatment of invasive candidiasis and found that there were no differences in mortality between fluconazole and amphotericin B or the echinocandins [46]. However, there was a higher rate of microbiologic failure in patients who received fluconazole compared with amphotericin B (relative risk [RR] 1.52; 95% CI 1.12-2.07) or the echinocandin anidulafungin (RR 2.0; 95% CI 1.16-3.44).

A 2012 patient-level quantitative review evaluated observational data gathered from 1915 patients included in seven randomized treatment trials of candidemia and invasive candidiasis, including those described above [63]. Patients who were treated with an echinocandin had improved survival compared with those treated with an azole or an amphotericin B formulation (odds ratio 0.65, 95% CI 0.45-0.94).

OPHTHALMOLOGIC EVALUATION — All patients who have candidemia, whether or not they have ocular symptoms, should undergo an ophthalmologic examination by an ophthalmologist to look for evidence of endophthalmitis, as recommended in the Infectious Diseases Society of America (IDSA) guidelines for treatment of candidiasis [7]. (See "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis", section on 'Ophthalmic examination'.)

CATHETER REMOVAL — Central intravenous catheters should be removed in patients with candidemia [7,64]. Clearance of fungemia occurs more quickly when catheters are removed [65,66], and higher mortality has been documented if catheters remain [38,48,63,66-68]. In addition, treatment with an antifungal agent is required [7]; it should never be assumed that removal of a catheter alone is adequate therapy for candidemia.

Some authorities have suggested that catheter removal may not be necessary in neutropenic patients with candidemia (eg, patients with hematologic malignancies undergoing cytotoxic chemotherapy, hematopoietic cell transplant recipients with graft-versus-host disease), in whom the source is often the gastrointestinal tract rather than the central venous catheter [69,70]. Some clinicians will attempt to retain the catheters in such patients [71,72]. An extension of this argument, put forth by the same authors, is that not all catheters have to be removed in nonneutropenic patients with candidemia [69].

Several studies, albeit with limitations, have evaluated whether central venous catheter removal is beneficial:

A retrospective subgroup analysis of two randomized trials of patients with candidemia was performed in order to assess the potential benefit of early central venous catheter removal [70]. In the univariate analysis, early removal of the central venous catheter (within 24 or 48 hours) did not improve time to mycologic eradication or rates of persistent of recurrent candidemia but was associated with improved treatment success and survival. However, in the multivariate analysis, these benefits were lost.

A study in cancer patients used a fivefold difference in quantitative cultures taken from the central catheter and a peripheral vein to help define catheter-associated candidemia [73]. Using these criteria, patients with non-catheter sources did not benefit from catheter removal in addition to antifungal agents.

In contrast to the studies described above, an individual patient-level quantitative review that evaluated observational data gathered from seven randomized treatment trials of candidemia and invasive candidiasis found that removal of a central venous catheter was associated with decreased mortality (odds ratio 0.50, 95% CI 0.35-0.72) [63].

There are multiple limitations to observational studies and subgroup analyses of randomized trials, including unrecognized confounders, treatment bias, lack of standardized criteria for catheter removal or data on time to removal, and lack of statistical power [74,75]. Despite the controversy, the current consensus, including that noted by the Infectious Diseases Society of America (IDSA) guidelines, remains that in most patients with candidemia, intravascular catheters should be removed, realizing that in some patients this may not be feasible [7,64-66,74,76].

EMPIRIC ANTIFUNGAL THERAPY — Empiric antifungal therapy is given routinely to patients with neutropenic fever since they are at substantial risk for invasive candidiasis. This is discussed in detail separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Addition of an antifungal agent'.)

In addition, nonneutropenic patients who have persistent fever or unexplained hypotension despite broad-spectrum antibacterial agents may have candidemia or invasive candidiasis. These patients may benefit from early empiric or preemptive therapy with an antifungal agent. The choice of agent should be guided by the hemodynamic stability of the patient and whether the patient has a history of prior exposure to antifungal agents [77]. If the etiologic agent has not been identified, the approach to empiric therapy will be influenced by whether the patient is known to be colonized with resistant Candida species and the proportion of candidemias due to resistant species within a particular medical center or patient unit. (See "Epidemiology and pathogenesis of candidemia in adults", section on 'Risk factors'.)

The 2009 Infectious Diseases Society of America (IDSA) guidelines recommend that empiric antifungal therapy should be considered in critically ill patients who are at risk for invasive candidiasis and who have persistent fevers despite antibacterial therapy (table 2) [7]. Criteria for the need for empiric therapy remain poorly defined and should include the clinical assessment of risk factors (eg, central venous catheters, total parenteral nutrition, hemodialysis, trauma, broad-spectrum antibiotics, recent surgery [particularly abdominal surgery]), serologic markers for invasive candidiasis (eg, beta-D-glucan), if available, and culture data regarding Candida colonization at nonsterile sites. (See "Epidemiology and pathogenesis of candidemia in adults", section on 'Risk factors'.)

It is not clear whether the empiric use of fluconazole is beneficial. One multicenter randomized trial in the intensive care unit (ICU) setting found no difference in rate of invasive candidiasis or outcomes between patients given fluconazole empirically and those given placebo; invasive candidiasis occurred in only nine patients in the fluconazole group and in 11 patients in the placebo group (5 versus 9 percent), a nonsignificant difference [78]. However, this trial was underpowered, with so few patients developing invasive candidiasis that a significant treatment benefit could not be shown.

We emphasize that empiric antifungal therapy should be given only to patients who are thought to be at substantial risk of invasive candidiasis. In such patients, we favor therapy with either an echinocandin or fluconazole, depending upon the risk of resistant Candida species. (See "Epidemiology and pathogenesis of candidemia in adults", section on 'Risk factors' and 'Choice of initial agent' above.)

PROPHYLAXIS IN ICU PATIENTS — Because mortality remains high in patients with candidemia, antifungal prophylaxis has been studied as a means to prevent its occurrence. However, the optimal approach remains unclear. Currently, there are no recommendations for antifungal prophylaxis among intensive care unit (ICU) patients [7]. We suggest not routinely using prophylactic antifungal agents in the ICU setting. However, consideration can be given to the use of prophylaxis in selected patients in ICUs that have high rates (>5 percent) of invasive candidiasis. Only patients at the highest risk for invasive disease should be targeted for prophylaxis; risk factors include central venous catheters, parenteral nutrition, hemodialysis, trauma, broad-spectrum antibiotics, and recent surgery (particularly abdominal surgery) (see "Epidemiology and pathogenesis of candidemia in adults"). In such patients, either an echinocandin or fluconazole can be used, depending upon the risk of resistant Candida species.

Broad use of fluconazole in an ICU setting has been shown to decrease invasive candidiasis in several trials [79,80]. However, most ICUs have not adopted routine fluconazole prophylaxis because widespread use would likely contribute to increasing fluconazole resistance. In a small study, more selective fluconazole prophylaxis for patients at high risk for intraabdominal candidiasis was beneficial [81]. At least four meta-analyses have been published on the subject of antifungal prophylaxis in the ICU setting [82-85]. All four noted a reduction in invasive candidiasis, but only one showed a reduction in mortality (risk ratio 0.60, 95% CI 0.45-0.81) [82].

Two studies assessed the efficacy of caspofungin prophylaxis in the ICU setting. A small prospective observational study found that caspofungin prevented intraabdominal candidiasis [86]. In a randomized trial, adults who were deemed to be at high risk for invasive candidiasis (by utilizing a clinical prediction rule) were randomly assigned to receive caspofungin or placebo; there was a trend toward disease reduction in the caspofungin arm [87]. There were 10 Candida infections in 102 patients in the caspofungin arm and 14 in the 84 patients who received placebo, a nonsignificant difference. There were no differences in mortality between the two groups.

OUTCOMES — Untreated candidemia has a mortality rate of over 60 percent [47]. With treatment, the overall mortality of candidemia is approximately 30 to 40 percent [63,75]. A delay in treatment can increase mortality [88-90]. In one retrospective cohort study of 230 patients with candidemia, the number of days that passed from notification of the first positive culture for yeast to the initiation of fluconazole correlated with increased mortality rates as follows: day 0 (15 percent); day 1 (24 percent); day 2 (37 percent); day 3 (41 percent) [88].

Among candidemic patients with septic shock, the outcomes are even poorer. In a retrospective cohort study of hospitalized patients with septic shock and a positive blood culture for Candida spp, 155 of 224 patients (64 percent) died during hospitalization [91]. The in-hospital mortality rate among the 142 patients who had adequate source control within 24 hours of the onset of septic shock and antifungal therapy administered within 24 hours of the onset of septic shock was 53 percent, compared with 98 percent among the 82 patients for whom these goals were not attained. On multivariate analysis, both failure to achieve timely source control (adjusted odds ratio [aOR] 77.4, 95% CI 21.5-278.4) and delayed antifungal therapy (aOR 33.8, 95% CI 9.7-118.0) were highly associated with in-hospital mortality. Other factors that were independently associated with in-hospital mortality on multivariate analysis included red blood cell transfusion, solid tumor with metastases, class IV congestive heart failure, and higher APACHE II score.

Factors that have been associated with increased mortality in other studies of hospitalized patients with candidemia include higher APACHE II scores, inadequate fluconazole dosing, retention of a central venous catheter, increasing age, use of immunosuppressive therapy, and infection with C. tropicalis [63,67,92]. C. parapsilosis has been associated with lower mortality rates than other Candida species [63]. In ICU patients, diabetes mellitus, immunosuppression, and mechanical ventilation were associated with death in one study [93], whereas, in non-ICU patients, glucocorticoid use at the time that a positive blood culture was drawn was associated with increased mortality in another study [67].

Among cancer patients, persistent neutropenia, higher APACHE III score, and visceral dissemination have been associated with poor prognosis [71].

SUMMARY AND RECOMMENDATIONS

The choice of antifungal therapy for invasive candidiasis, including candidemia, depends upon a variety of factors including history of recent azole exposure; prevalence of different Candida species and current antifungal susceptibility data in the clinical unit and medical center; severity of illness; relevant comorbidities (eg, neutropenia, recent abdominal surgery); evidence of involvement of the central nervous system, cardiac valves, eyes, and/or visceral organs; and history of intolerance to an antifungal agent. (See 'Choice of initial agent' above.)

For nonneutropenic patients with candidemia who are clinically stable, who have not been exposed to recent azole therapy, and who are in clinical units or medical centers in which C. glabrata or C. krusei are uncommonly isolated (<15 percent of all species causing candidemia), we suggest fluconazole rather than an echinocandin (Grade 2B). We also suggest fluconazole for the uncommon neutropenic patients who meet these criteria (Grade 2B). The usual dose of fluconazole is an 800 mg loading dose followed by 400 mg orally daily. (See 'Nonneutropenic patients' above and 'Neutropenic patients' above.)

For nonneutropenic and neutropenic patients with candidemia who are clinically unstable or in patients who have risks for infection with azole-resistant organisms, such as with prior drug exposure, we suggest an echinocandin (caspofungin, micafungin, anidulafungin) rather than fluconazole for initial therapy (Grade 2B). For patients at risk for echinocandin resistance (eg, prior recent exposure to an echinocandin), an amphotericin B formulation should be used until antifungal susceptibility testing results are available. Treatment can be changed to fluconazole (or an echinocandin) if the isolate is found to be susceptible. (See 'C. glabrata and C. krusei' above and 'Choice of initial agent' above.)

The echinocandins are administered intravenously as follows:

Caspofungin is given at an initial dose of 70 mg on the first day of treatment, followed by 50 mg daily; dose reduction is required with hepatic dysfunction.

Anidulafungin is given at an initial dose of 200 mg on the first day, followed by 100 mg daily.

Micafungin is given at a dose of 100 mg daily for candidemia; no loading dose is needed. (See 'Echinocandins' above.)

Blood cultures should be checked daily after initiating antifungal therapy until they become negative. (See 'Duration' above.)

All patients who have candidemia, whether or not they have ocular symptoms, should undergo an ophthalmologic examination by an ophthalmologist to look for evidence of endophthalmitis. (See 'Ophthalmologic evaluation' above.)

In the patient with candidemia alone, treatment should be continued for 14 days after blood cultures have yielded no yeast. In addition, all patients should have resolution of symptoms attributable to candidemia and resolution of neutropenia before antifungal therapy is discontinued. Patients with candidemia and metastatic foci of infection (eg, eye, bone, heart, liver, spleen) require a longer duration of therapy. (See 'Duration' above and "Treatment of endogenous endophthalmitis due to Candida species" and "Candida osteoarticular infections" and "Candida endocarditis" and "Chronic disseminated candidiasis (hepatosplenic candidiasis)".)

Central intravenous catheters should be removed in patients with candidemia, when feasible. However, catheter removal is controversial in neutropenic patients, in whom the gastrointestinal tract is often the source. Some clinicians will attempt to retain the catheter in these patients. (See 'Catheter removal' above.)

Empiric antifungal therapy recommendations in patients with neutropenic fever are discussed in detail elsewhere. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Addition of an antifungal agent'.)

We suggest not giving empiric antifungal therapy to most patients in the intensive care unit (ICU) (Grade 2B). However, this approach, using either an echinocandin or fluconazole, is reasonable in a subset of high-risk ICU patients who have all of the following characteristics:

Persistent fever despite broad-spectrum antibiotics

Risk factors for invasive candidiasis

Positive serologic markers for invasive candidiasis and/or isolation of Candida from multiple nonsterile sites (see 'Empiric antifungal therapy' above)

We suggest not routinely using prophylactic antifungal agents in the ICU setting (Grade 2C); it is reasonable to give antifungal prophylaxis with either an echinocandin or fluconazole to high-risk patients in ICUs in which the incidence of invasive candidiasis is >5 percent. (See 'Prophylaxis in ICU patients' above.)

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