Treatment of Candidemia and Invasive Candidiasis in Adultsatment of Candidemia and Invasive Candidiasis in Adults

Treatment of candidemia and invasive candidiasis in adults
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2012 UpToDate
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Author
Carol A Kauffman, MD
Section Editor
Kieren A Marr, MD
Deputy Editor
Anna R Thorner, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2012. | This topic last updated: abr 25, 2012.
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].
In all cases, candidemia requires treatment with an antifungal agent [2]; 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 [3-5] and have shown that mortality is highest in those patients who were not treated with an antifungal drug
[4,5]. Furthermore, prompt initiation of therapy is crucial.
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 "Hepatosplenic candidiasis (chronic disseminated candidiasis)" and "Candida
infections of the central nervous system" and "Candida osteomyelitis and arthritis".)
The treatment of candidemia in neonates and children is discussed in detail separately. (See "Treatment of Candida
infection in neonates" and "Treatment of candidemia in children".)
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 United States Food
and Drug Administration (FDA) in 1990. The azoles work primarily by inhibiting the cytochrome P450-dependent enzyme
lanosterol 14-alpha-demethylase [6]. 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). Some laboratories only screen C. glabrata isolates for susceptibility to
fluconazole because this species has varying susceptibility. Antifungal susceptibility testing is discussed in greater detail
separately. (See "Antifungal susceptibility testing".)
http://www.uptodate.com/contents/treatment-of-candidemia-and-invasive-candidiasis-in-adults?view=print[23/06/2012 06:41:58 a.m.]
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 [7-10]. 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 [2].
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 that are a log or more less than fluconazole [11]. 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 [12]. (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 [13].
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 [14].
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 do not have activity against Cryptococcus or Trichosporon species [14].
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 [14]. 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 [2]:
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.)
For most patients with invasive candidiasis, the most important issue is whether the isolate is susceptible to fluconazole.
Some laboratories only screen C. glabrata isolates for susceptibility to fluconazole because this species has varying
susceptibility. Increasingly, resistance among C. glabrata isolates has been noted to voriconazole, as well as fluconazole.
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 [15]. Individual cases and small series of non-mucosal infection with fluconazoleresistant C. albicans have been reported from several tertiary care centers, and usually occur in immunosuppressed
patients who are taking fluconazole chronically for prophylaxis [16-18].
Most C. albicans isolates are susceptible to the echinocandins, although resistance has been reported [19,20]. 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 [21]. 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 [22].
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 [23]. C. krusei isolates are usually susceptible to
posaconazole [24].
In the large surveillance study described above, all C. krusei isolates were susceptible to the echinocandins (caspofungin,
micafungin, and anidulafungin) [23]. However, individual cases of resistance to the echinocandins have been reported [2527].
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 [2,28]. 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 [29,30].
The echinocandins have generally retained excellent activity against C. glabrata, although isolated cases of resistance have
been reported [31-35].
Of note, there is increasing concern that some C. glabrata bloodstream isolates with resistance to fluconazole and
voriconazole are also 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 [30]. Of the 162 isolates that were resistant to fluconazole, 18
(11.1 percent) were resistant to one or more of the echinocandins; all of these isolates contained an FKS1 or FKS2
mutation. 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.
Amphotericin B has delayed killing kinetics against C. glabrata in vitro [36]; 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; however, the minimal inhibitory
concentrations for C. parapsilosis with all the echinocandins are higher than for other Candida species [28]. The clinical
implications of these in vitro data are unclear. In the study that established the efficacy of caspofungin in the treatment of
invasive candidiasis, five of nine patients with persistent candidemia were infected with C. parapsilosis [37]. However, the
overall response rate to caspofungin in these patients was the same as in the amphotericin B comparator arm.
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 [38].
An international surveillance study of 9371 C. parapsilosis isolates collected between 2001 and 2005 found the following
[39]:
High rates of susceptibility to fluconazole (91 to 96 percent) and voriconazole (95 to 98 percent) were seen in all
geographic regions except Africa and the Middle East (79 and 86 percent susceptible to fluconazole and
voriconazole, respectively).
Isolates from the surgical intensive care unit (ICU) were the least susceptible to fluconazole (86 percent).
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 [20,40,41].
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.
MANAGEMENT
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].
Several randomized trials have shown that fluconazole is as effective as amphotericin B for the treatment of candidemia in
immunocompetent patients [7-9,47]. The echinocandins appear to be as effective as and better tolerated than amphotericin
B formulations and, in one study, more effective than fluconazole [37,48-50]. 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 [2], and data are derived from small subset analyses of
randomized trials, open-label studies, and retrospective studies [9,37,48,51-53]. 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' below.)

Azoles Several large randomized trials have shown that fluconazole is as effective as amphotericin B for the
treatment of candidemia in immunocompetent patients [7-9,47]. One study compared the two drugs in 206 patients, 75
percent of whom had intravenous catheters in place at the time of candidemia [7]. The two drugs achieved an equivalent
overall success rate (72 versus 79 percent for fluconazole and amphotericin B, respectively). Nephrotoxicity was
significantly less with fluconazole (2 versus 37 percent). Another study noted success rates of 57 percent for fluconazole
and 62 percent for amphotericin B and confirmed the superior safety profile of fluconazole [8].
In another randomized trial, fluconazole was compared to anidulafungin for treatment of invasive candidiasis in 245
patients: 89 percent had candidemia and only 3 percent were neutropenic [49]. 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 non-neutropenic patients who were
treated with either voriconazole alone or amphotericin B for three to seven days followed by fluconazole [54]. 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 and mycological response at 12 weeks (the primary
endpoint of this study) demonstrated 41 percent efficacy in both groups. Use of a 12 week primary end point led to
unusually low overall responses rates for both regimens, reflecting the serious underlying illnesses seen in patients with
candidemia, rather than drug failure [55].
The clinical role for voriconazole in comparison with echinocandins remains unclear. A major concern is the crossresistance 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' below.)
Echinocandins Several randomized trials have compared the efficacy of echinocandins to either an
amphotericin B formulation or fluconazole among patients with invasive candidiasis [37,48-50]. 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 [37]. 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 non-inferiority trial compared micafungin to liposomal amphotericin B [48]. 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 [50].
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 [49]. (See 'Azoles' above.)
Data are more limited in neutropenic patients with candidemia compared with non-neutropenic patients. Efficacy data for
the echinocandins in neutropenic patients comes from small subset analyses of randomized trials and open-label studies
[37,48,51,52]. 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)
to one another and to caspofungin (70 mg once followed by 50 mg daily) [51]. 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 [50]. 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 [56]. 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 [79,47] (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 (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 [57]. 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).
Choice of initial antifungal agent When choosing an antifungal agent in patients with suspected candidemia,
the following factors should be considered [2]:
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 of 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).
Non-neutropenic patients In non-neutropenic 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) [2]. (See 'Azoles' above.)
In non-neutropenic 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 [2]. 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 [2]:
Most neutropenic patients with candidemia should be treated with an echinocandin or an amphotericin B formulation
since neutropenic patients are at increased risk for fluconazole-resistant Candida spp, such as C. glabrata and C.
krusei, especially if they have recently received azole prophylaxis (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 [2]. 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 [2]. 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 [7,58,59]. 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 [60]. Nevertheless, based on in vitro data, it is still prudent to
avoid use of fluconazole for 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 now 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. (See 'Echinocandins' above.)
An amphotericin B formulation may be used as an alternative agent for C. glabrata or C. krusei infection when necessary.
In patients with C. glabrata or C. krusei infections being treated with amphotericin B, higher doses of amphotericin B are
recommended (1 mg/kg daily of amphotericin B deoxycholate or 5 mg/kg daily of lipid-based formulations), particularly in
immunocompromised hosts [2,28]. 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 Patients with Candida isolates likely to be susceptible to fluconazole (eg, C. albicans)
who are clinically stable can be switched from an echinocandin to fluconazole [2].
Voriconazole is recommended as oral step-down therapy only for patients with C. krusei or voriconazole-susceptible C.
glabrata [2]. 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 [2]. 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 before antifungal therapy is discontinued [2].
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 "Endogenous endophthalmitis due to Candida species" and "Candida
osteomyelitis and arthritis" and "Candida endocarditis" and "Hepatosplenic candidiasis (chronic disseminated 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 not generally given for the treatment of
candidemia.
A controlled trial randomly assigned 219 non-neutropenic 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 [10]. There was more rapid clearing of fungemia with initial combination
therapy, but the success rates overall were similar in the two groups.
Ophthalmologic evaluation All patients who have candidemia should undergo an ophthalmologic examination by
an ophthalmologist to look for evidence of endophthalmitis, whether or not they have ocular symptoms, as recommended
in the IDSA guidelines for treatment of candidiasis [2].
Catheter removal Central intravenous catheters should be removed in patients with candidemia [2,61]. Clearance of
fungemia occurs more quickly when catheters are removed [62,63], and higher mortality has been documented if catheters
remain [4,57,63-65]. In addition, treatment with an antifungal agent is required [2]; 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), in
whom the source is often the gastrointestinal tract rather than the central venous catheter [66,67]. Some clinicians will
attempt to retain the catheters in such patients. A case can be made for the gastrointestinal tract as the source of
candidemia in many patients, especially those who are neutropenic or who have disruption of gastrointestinal tract integrity
due to graft-versus-host disease or chemotherapy [68,69]. An extension of this argument, put forth by the same authors, is
that not all catheters have to be removed in non-neutropenic patients with candidemia [66].
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 [67]. 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 [70]. 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 0.350.72) [57].
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 [71,72]. Despite the controversy, the current consensus, including that noted by the IDSA guidelines,
remains that in most patients with candidemia, intravascular catheters should be removed, realizing that in some patients
this may not be feasible [2,61-63,71,73].
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, non-neutropenic 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 with whether the patient has a history of prior exposure to antifungal agents [74]. 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) [2]. 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, broadspectrum antibiotics, recent surgery [particularly abdominal surgery]), serologic markers for invasive candidiasis (eg, betaD-glucan), if available, and culture data regarding Candida colonization at non-sterile 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 [75]. 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 antifungal agent' above.)
OUTCOMES Untreated candidemia has a mortality rate of over 60 percent [3]. With treatment, the overall mortality of
candidemia is approximately 30 to 40 percent [57,72]. A delay in treatment can increase mortality [76-78]. 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) [76].
Other factors that have been associated with increased mortality in 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 [57,64,79]. C. parapsilosis has been associated with lower
mortality rates than other Candida species [57]. In ICU patients, diabetes mellitus, immunosuppression, and mechanical
ventilation were associated with death in one study [80], 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 [64].
Among cancer patients, persistent neutropenia, higher APACHE III score, and visceral dissemination were associated with
poor prognosis [68].
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 antifungal agent' above.)
For non-neutropenic patients with candidemia who are clinically stable, 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 'Non-neutropenic
patients' above and 'Neutropenic patients' above.)
For non-neutropenic and neutropenic patients with candidemia who are clinically unstable, have received prior azole
therapy, or are in institutions in which C. glabrata or C. krusei are common isolates, we suggest an echinocandin
(caspofungin, micafungin, anidulafungin) rather than fluconazole for initial therapy (Grade 2B). Treatment can be
changed to fluconazole if a fluconazole-susceptible Candida species is identified. (See 'C. glabrata and C.
krusei' above and 'Choice of initial antifungal 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 should undergo an ophthalmologic examination by an ophthalmologist to look for
evidence of endophthalmitis, whether or not they have ocular symptoms. (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 "Endogenous
endophthalmitis due to Candida species" and "Candida osteomyelitis and arthritis" and "Candida endocarditis" and
"Hepatosplenic candidiasis (chronic disseminated 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 non-sterile sites
(see 'Empiric antifungal therapy' above).
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REFERENCES
1. Fridkin SK. The changing face of fungal infections in health care settings. Clin Infect Dis 2005; 41:1455.
2. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009
update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 48:503.
3. Fraser VJ, Jones M, Dunkel J, et al. Candidemia in a tertiary care hospital: epidemiology, risk factors, and predictors
of mortality. Clin Infect Dis 1992; 15:414.
4. Nguyen MH, Peacock JE Jr, Tanner DC, et al. Therapeutic approaches in patients with candidemia. Evaluation in a
multicenter, prospective, observational study. Arch Intern Med 1995; 155:2429.
5. Nucci M, Colombo AL, Silveira F, et al. Risk factors for death in patients with candidemia. Infect Control Hosp
Epidemiol 1998; 19:846.
6. Zonios DI, Bennett JE. Update on azole antifungals. Semin Respir Crit Care Med 2008; 29:198.
7. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment
of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med
1994; 331:1325.
8. Phillips P, Shafran S, Garber G, et al. Multicenter randomized trial of fluconazole versus amphotericin B for treatment
of candidemia in non-neutropenic patients. Canadian Candidemia Study Group. Eur J Clin Microbiol Infect Dis 1997;
16:337.
9. Anaissie EJ, Darouiche RO, Abi-Said D, et al. Management of invasive candidal infections: results of a prospective,
randomized, multicenter study of fluconazole versus amphotericin B and review of the literature. Clin Infect Dis 1996;
23:964.
10. Rex JH, Pappas PG, Karchmer AW, et al. A randomized and blinded multicenter trial of high-dose fluconazole plus
placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic
subjects. Clin Infect Dis 2003; 36:1221.
11. Cuenca-Estrella M, Rodriguez D, Almirante B, et al. In vitro susceptibilities of bloodstream isolates of Candida
species to six antifungal agents: results from a population-based active surveillance programme, Barcelona, Spain,
2002-2003. J Antimicrob Chemother 2005; 55:194.
12. Pfaller MA, Diekema DJ, Messer SA, et al. Activities of fluconazole and voriconazole against 1,586 recent clinical
isolates of Candida species determined by Broth microdilution, disk diffusion, and Etest methods: report from the
ARTEMIS Global Antifungal Susceptibility Program, 2001. J Clin Microbiol 2003; 41:1440.
13. Denning DW. Echinocandin antifungal drugs. Lancet 2003; 362:1142.
14. Bennett JE. Echinocandins for candidemia in adults without neutropenia. N Engl J Med 2006; 355:1154.
15. Pfaller MA, Diekema DJ, Gibbs DL, et al. Results from the ARTEMIS DISK Global Antifungal Surveillance study,
1997 to 2005: an 8.5-year analysis of susceptibilities of Candida species and other yeast species to fluconazole and
voriconazole determined by CLSI standardized disk diffusion testing. J Clin Microbiol 2007; 45:1735.
16. White TC, Marr KA, Bowden RA. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance.
Clin Microbiol Rev 1998; 11:382.
17. Marr KA, White TC, van Burik JA, Bowden RA. Development of fluconazole resistance in Candida albicans causing
disseminated infection in a patient undergoing marrow transplantation. Clin Infect Dis 1997; 25:908.
18. Oxman DA, Chow JK, Frendl G, et al. Candidaemia associated with decreased in vitro fluconazole susceptibility: is
Candida speciation predictive of the susceptibility pattern? J Antimicrob Chemother 2010; 65:1460.
19. Hernandez S, Lpez-Ribot JL, Najvar LK, et al. Caspofungin resistance in Candida albicans: correlating clinical
outcome with laboratory susceptibility testing of three isogenic isolates serially obtained from a patient with
progressive Candida esophagitis. Antimicrob Agents Chemother 2004; 48:1382.
20. Kofteridis DP, Lewis RE, Kontoyiannis DP. Caspofungin-non-susceptible Candida isolates in cancer patients. J
Antimicrob Chemother 2010; 65:293.
21. Orozco AS, Higginbotham LM, Hitchcock CA, et al. Mechanism of fluconazole resistance in Candida krusei.
Antimicrob Agents Chemother 1998; 42:2645.
22. Fukuoka T, Johnston DA, Winslow CA, et al. Genetic basis for differential activities of fluconazole and voriconazole
against Candida krusei. Antimicrob Agents Chemother 2003; 47:1213.
23. Pfaller MA, Diekema DJ, Gibbs DL, et al. Candida krusei, a multidrug-resistant opportunistic fungal pathogen:
geographic and temporal trends from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005. J Clin
Microbiol 2008; 46:515.
24. Pfaller MA, Messer SA, Boyken L, et al. Selection of a surrogate agent (fluconazole or voriconazole) for initial
susceptibility testing of posaconazole against Candida spp.: results from a global antifungal surveillance program. J
Clin Microbiol 2008; 46:551.
25. Hakki M, Staab JF, Marr KA. Emergence of a Candida krusei isolate with reduced susceptibility to caspofungin during
therapy. Antimicrob Agents Chemother 2006; 50:2522.
26. Pelletier R, Alarie I, Lagac R, Walsh TJ. Emergence of disseminated candidiasis caused by Candida krusei during
treatment with caspofungin: case report and review of literature. Med Mycol 2005; 43:559.
27. Kahn JN, Garcia-Effron G, Hsu MJ, et al. Acquired echinocandin resistance in a Candida krusei isolate due to
modification of glucan synthase. Antimicrob Agents Chemother 2007; 51:1876.
28. Spellberg BJ, Filler SG, Edwards JE Jr. Current treatment strategies for disseminated candidiasis. Clin Infect Dis
2006; 42:244.
29. Panackal AA, Gribskov JL, Staab JF, et al. Clinical significance of azole antifungal drug cross-resistance in Candida
glabrata. J Clin Microbiol 2006; 44:1740.
30. Pfaller MA, Castanheira M, Lockhart SR, et al. Frequency of Decreased Susceptibility and Resistance to
Echinocandins among Fluconazole-Resistant Bloodstream Isolates of Candida glabrata. J Clin Microbiol 2012;
50:1199.
31. Krogh-Madsen M, Arendrup MC, Heslet L, Knudsen JD. Amphotericin B and caspofungin resistance in Candida
glabrata isolates recovered from a critically ill patient. Clin Infect Dis 2006; 42:938.
32. Dodgson KJ, Dodgson AR, Pujol C, et al. Caspofungin resistant C. glabrata. Clin Microbiol Infect 2005; 11 (Suppl
2):364.
33. Thompson GR 3rd, Wiederhold NP, Vallor AC, et al. Development of caspofungin resistance following prolonged
therapy for invasive candidiasis secondary to Candida glabrata infection. Antimicrob Agents Chemother 2008;
52:3783.
34. Costa-de-Oliveira S, Marcos Miranda I, Silva RM, et al. FKS2 mutations associated with decreased echinocandin
susceptibility of Candida glabrata following anidulafungin therapy. Antimicrob Agents Chemother 2011; 55:1312.
35. Pfeiffer CD, Garcia-Effron G, Zaas AK, et al. Breakthrough invasive candidiasis in patients on micafungin. J Clin
Microbiol 2010; 48:2373.
36. Cantn E, Pemn J, Gobernado M, et al. Patterns of amphotericin B killing kinetics against seven Candida species.
Antimicrob Agents Chemother 2004; 48:2477.
37. Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N
Engl J Med 2002; 347:2020.
38. Colombo AL, Ngai AL, Bourque M, et al. Caspofungin use in patients with invasive candidiasis caused by common
non-albicans Candida species: review of the caspofungin database. Antimicrob Agents Chemother 2010; 54:1864.
39. Pfaller MA, Diekema DJ, Gibbs DL, et al. Geographic and temporal trends in isolation and antifungal susceptibility of
Candida parapsilosis: a global assessment from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005.
J Clin Microbiol 2008; 46:842.
40. Pasquale T, Tomada JR, Ghannoun M, et al. Emergence of Candida tropicalis resistant to caspofungin. J Antimicrob
Chemother 2008; 61:219.
41. Garcia-Effron G, Kontoyiannis DP, Lewis RE, Perlin DS. Caspofungin-resistant Candida tropicalis strains causing
breakthrough fungemia in patients at high risk for hematologic malignancies. Antimicrob Agents Chemother 2008;
52:4181.
42. Hawkins JL, Baddour LM. Candida lusitaniae infections in the era of fluconazole availability. Clin Infect Dis 2003;
36:e14.
43. Girmenia C, Pizzarelli G, Cristini F, et al. Candida guilliermondii fungemia in patients with hematologic malignancies.
J Clin Microbiol 2006; 44:2458.
44. Pfaller MA, Diekema DJ, Mendez M, et al. Candida guilliermondii, an opportunistic fungal pathogen with decreased
susceptibility to fluconazole: geographic and temporal trends from the ARTEMIS DISK antifungal surveillance
program. J Clin Microbiol 2006; 44:3551.
45. Ells R, Kock JL, Pohl CH. Candida albicans or Candida dubliniensis? Mycoses 2011; 54:1.
46. Gafter-Gvili A, Vidal L, Goldberg E, et al. Treatment of invasive candidal infections: systematic review and metaanalysis. Mayo Clin Proc 2008; 83:1011.
47. Abele-Horn M, Kopp A, Sternberg U, et al. A randomized study comparing fluconazole with amphotericin B/5flucytosine for the treatment of systemic Candida infections in intensive care patients. Infection 1996; 24:426.
48. Kuse ER, Chetchotisakd P, da Cunha CA, et al. Micafungin versus liposomal amphotericin B for candidaemia and
invasive candidosis: a phase III randomised double-blind trial. Lancet 2007; 369:1519.
49. Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med
2007; 356:2472.
50. Shorr AF, Wu C, Kothari S. Outcomes with micafungin in patients with candidaemia or invasive candidiasis due to
Candida glabrata and Candida krusei. J Antimicrob Chemother 2011; 66:375.
51. Pappas PG, Rotstein CM, Betts RF, et al. Micafungin versus caspofungin for treatment of candidemia and other
forms of invasive candidiasis. Clin Infect Dis 2007; 45:883.
52. Betts R, Glasmacher A, Maertens J, et al. Efficacy of caspofungin against invasive Candida or invasive Aspergillus
infections in neutropenic patients. Cancer 2006; 106:466.
53. Anaissie EJ, Vartivarian SE, Abi-Said D, et al. Fluconazole versus amphotericin B in the treatment of hematogenous
candidiasis: a matched cohort study. Am J Med 1996; 101:170.
54. Kullberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for
candidaemia in non-neutropenic patients: a randomised non-inferiority trial. Lancet 2005; 366:1435.
55. Graybill JR. Voriconazole for candidosis: an important addition? Lancet 2005; 366:1413.
56. Betts RF, Nucci M, Talwar D, et al. A Multicenter, double-blind trial of a high-dose caspofungin treatment regimen
versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis 2009;
48:1676.
57. Andes DR, Safdar N, Baddley JW, et al. Impact of Treatment Strategy on Outcomes in Patients with Candidemia and
Other Forms of Invasive Candidiasis: A Patient-Level Quantitative Review of Randomized Trials. Clin Infect Dis 2012;
54:1110.
58. Malani A, Hmoud J, Chiu L, et al. Candida glabrata fungemia: experience in a tertiary care center. Clin Infect Dis
2005; 41:975.
59. Rex JH, Pfaller MA, Barry AL, et al. Antifungal susceptibility testing of isolates from a randomized, multicenter trial of
fluconazole versus amphotericin B as treatment of nonneutropenic patients with candidemia. NIAID Mycoses Study
Group and the Candidemia Study Group. Antimicrob Agents Chemother 1995; 39:40.
60. Bodey GP, Mardani M, Hanna HA, et al. The epidemiology of Candida glabrata and Candida albicans fungemia in
immunocompromised patients with cancer. Am J Med 2002; 112:380.
61. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular
catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 49:1.
62. Rex JH, Bennett JE, Sugar AM, et al. Intravascular catheter exchange and duration of candidemia. NIAID Mycoses
Study Group and the Candidemia Study Group. Clin Infect Dis 1995; 21:994.
63. Asmundsdttir LR, Erlendsdttir H, Gottfredsson M. Improving survival of patients with candidaemia: analysis of
prognostic factors from a long-term, nationwide study in Iceland. Scand J Infect Dis 2005; 37:111.
64. Labelle AJ, Micek ST, Roubinian N, Kollef MH. Treatment-related risk factors for hospital mortality in Candida
bloodstream infections. Crit Care Med 2008; 36:2967.
65. Stamos JK, Rowley AH. Candidemia in a pediatric population. Clin Infect Dis 1995; 20:571.
66. Nucci M, Anaissie E. Should vascular catheters be removed from all patients with candidemia? An evidence-based
review. Clin Infect Dis 2002; 34:591.
67. Nucci M, Anaissie E, Betts RF, et al. Early removal of central venous catheter in patients with candidemia does not
improve outcome: analysis of 842 patients from 2 randomized clinical trials. Clin Infect Dis 2010; 51:295.
68. Anaissie EJ, Rex JH, Uzun O, Vartivarian S. Predictors of adverse outcome in cancer patients with candidemia. Am
J Med 1998; 104:238.
69. Nucci M, Anaissie E. Revisiting the source of candidemia: skin or gut? Clin Infect Dis 2001; 33:1959.
70. Raad I, Hanna H, Boktour M, et al. Management of central venous catheters in patients with cancer and candidemia.
Clin Infect Dis 2004; 38:1119.
71. Brass EP, Edwards JE. Should the guidelines for management of central venous catheters in patients with
candidemia be changed now? Clin Infect Dis 2010; 51:304.
72. Clancy CJ, Nguyen MH. The end of an era in defining the optimal treatment of invasive candidiasis. Clin Infect Dis
2012; 54:1123.
73. Walsh TJ, Rex JH. All catheter-related candidemia is not the same: assessment of the balance between the risks
and benefits of removal of vascular catheters. Clin Infect Dis 2002; 34:600.
74. Spanakis EK, Aperis G, Mylonakis E. New agents for the treatment of fungal infections: clinical efficacy and gaps in
coverage. Clin Infect Dis 2006; 43:1060.
75. Schuster MG, Edwards JE Jr, Sobel JD, et al. Empirical fluconazole versus placebo for intensive care unit patients: a
randomized trial. Ann Intern Med 2008; 149:83.
76. Garey KW, Rege M, Pai MP, et al. Time to initiation of fluconazole therapy impacts mortality in patients with
candidemia: a multi-institutional study. Clin Infect Dis 2006; 43:25.
77. Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of candida bloodstream infection until positive blood
culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005;
49:3640.
78. Blot SI, Vandewoude KH, Hoste EA, Colardyn FA. Effects of nosocomial candidemia on outcomes of critically ill
patients. Am J Med 2002; 113:480.
79. Pappas PG, Rex JH, Lee J, et al. A prospective observational study of candidemia: epidemiology, therapy, and
influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis 2003; 37:634.
80. Leroy O, Gangneux JP, Montravers P, et al. Epidemiology, management, and risk factors for death of invasive
Candida infections in critical care: a multicenter, prospective, observational study in France (2005-2006). Crit Care
Med 2009; 37:1612.
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