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Invasive Candidiasis: Review Article
Invasive Candidiasis: Review Article
Review Article
Invasive Candidiasis
Bart Jan Kullberg, M.D., Ph.D., and Maiken C. Arendrup, M.D., Ph.D.
I
nvasive candidiasis is the most common fungal disease among hos- From the Department of Medicine and
pitalized patients in the developed world. Invasive candidiasis comprises both Radboudumc Center for Infectious Dis-
eases, Radboud University Medical Cen-
candidemia and deep-seated tissue candidiasis. Candidemia is generally viewed ter, Nijmegen, the Netherlands (B.J.K.);
as the more common type of the disease, and it accounts for the majority of cases and the Department of Microbiology and
included in clinical trials. Deep-seated candidiasis arises from either hematoge- Infection Control, Statens Serum Institut,
Copenhagen (M.C.A.). Address correspon-
nous dissemination or direct inoculation of candida species to a sterile site, such dence to Dr. Kullberg at the Department
as the peritoneal cavity (Fig. 1). Mortality among patients with invasive candidiasis of Medicine, Radboud University Medical
is as high as 40%, even when patients receive antifungal therapy. In addition, the Center, P.O. Box 9101, 6500 HB Nijmegen,
the Netherlands, or at b j
.
kullberg@
global shift in favor of nonalbicans candida species is troubling, as is the emerging radboudumc.nl.
resistance to antifungal drugs. During the past few years, new insights have sub-
N Engl J Med 2015;373:1445-56.
stantially changed diagnostic and therapeutic strategies. DOI: 10.1056/NEJMra1315399
Copyright © 2015 Massachusetts Medical Society.
Epidemiol o gy
According to conservative estimates, invasive candidiasis affects more than
250,000 people worldwide every year and is the cause of more than 50,000 deaths.
Incidence rates of candidemia have been reported to be between 2 and 14 cases
per 100,000 persons in population-based studies.1,2 Candidemia has often been
cited as the fourth most common bloodstream infection.3 Although this statistic
applies to intensive care units (ICUs), in most population-based studies candi-
demia is reported as the seventh to tenth most common bloodstream infection.
Incidence rates have been increasing or stable in most regions, although declining
rates have been reported in high-incidence areas after improvements in hygiene
and disease management were introduced.2,4,5
The incidence of candidemia is age-specific, with the maximum rates observed
at the extremes of age. Risk factors are summarized in Table 1.2,6,7 The presence
of central vascular catheters, recent surgery (particularly abdominal surgery with
anastomotic leakages), and the administration of broad-spectrum antibiotic ther-
apy constitute the major risk factors for invasive candidiasis. Although candidemia
has been described as the most common manifestation of invasive candidiasis,
blood-culture–negative forms include syndromes such as chronic disseminated
(hepatosplenic) candidiasis in patients with hematologic cancers and deep-seated
infection of other organs or sites, such as the bones, muscles, joints, eyes, or cen-
tral nervous system. Infections at most of these sites arise from an earlier or un-
diagnosed bloodstream infection. Conversely, the direct introduction of candida
may occur at a sterile site, resulting, for example, in ascending renal candidiasis
or candida peritonitis after intestinal surgery.8 Deep-seated infections may remain
localized or lead to secondary candidemia. The limited published data available
suggest that invasive abdominal candidiasis may be much more common than
recognized.8,9
INTESTINE
Peritonitis
Candidemia
BONE C I R C U L AT I O N Candida
I N T R AVA S C U L A R
Formation C AT H E T E R
Candidemia of biofilm
Candidemia
Candida released
from biofilm
LUNG Candidemia
Infectious
pulmonary
abscess
Candidemia KIDNEY
Endophthalmitis BLADDER
SPLEEN
LIVER Candida
Infectious
splenic
abscess
Critical illness, with particular risk among patients with long-term ICU stay
Abdominal surgery, with particular risk among patients who have anastomotic leakage or have had repeat laparotomies
Acute necrotizing pancreatitis
Hematologic malignant disease
Solid-organ transplantation
Solid-organ tumors
Neonates, particularly those with low birth weight, and preterm infants
Use of broad-spectrum antibiotics
Presence of central vascular catheter, total parenteral nutrition
Hemodialysis
Glucocorticoid use or chemotherapy for cancer
Candida colonization, particularly if multifocal (colonization index >0.5 or corrected colonization index >0.4)
* ICU denotes intensive care unit. For further information see Cleveland et al.,2 Arendrup et al.,6 and Lortholary et al.7
differences in susceptibility to azoles and echino- toll-like receptor 1–interferon-γ pathway, as com-
candins among these species. pared with a clinical control cohort matched for
Candida species differ considerably in viru- underlying disease.13 In a genomewide association
lence. C. parapsilosis and C. krusei are less virulent study in which susceptibility to candidemia was
than C. albicans, C. tropicalis, and C. glabrata.11 This
assessed, three new genes associated with an in-
variation is reflected in the low mortality among creased risk of disease were identified. Patients
patients with C. parapsilosis candidemia and in in the ICU who carried two or more alleles at
the fact that infection with C. krusei is highly un- these particular loci had a risk of candidemia that
common except in patients with severe immuno- was 19 times as high as the risk among patients
deficiency and prior exposure to an azole.6 Despite who did not have those alleles.14 Similarly, disease
its low virulence, C. parapsilosis can thrive in cer- progression and persistent candidemia despite
tain clinical settings owing to its ability to adhere antifungal therapy were associated with cyto-
to medical devices and its propensity to colonize kine polymorphisms that led to either increased
human skin, characteristics that facilitate noso- circulating levels of antiinflammatory interleu-
comial outbreaks.12 Other species that appear with kin-10 or decreased levels of proinflammatory
less frequency in clinical settings, such as C. dubli- interleukin-12b cytokine.15 These findings under-
niensis, C. lusitaniae, C. kefyr, and C. guilliermondii, are
score the importance of cytokine balance with
associated with specific susceptibility patterns or respect to both the susceptibility to acquiring in-
with specific hosts (e.g., C. dubliniensis has been vasive candidiasis and the ability to clear the in-
particularly common in HIV-infected patients). fection once it has been disseminated. The iden-
tification of specific alleles related to the risk of
disease and of cytokine pathways associated with
Im muno gene t ic s of C a ndida
Infec t ions unfavorable outcomes suggests that screening
strategies based on the presence or absence of
The majority of patients in the ICU do not acquire certain SNPs may help to identify patients at risk
invasive candidiasis, even if they share similar who could benefit from prophylactic antifungal
risk factors. Thus, it is likely that variation in the treatment or adjunctive immunotherapy.16
genes that confer susceptibility to candida infec-
tion makes certain patients more prone to infec- Di agnosis
tion. A large clinical study revealed that suscep-
tibility to candidemia was increased among The armamentarium available for diagnosing
European and North American patients who had invasive candidiasis includes direct detection, in
single-nucleotide polymorphisms (SNPs) in the which specimens of blood or tissue from normally
sterile sites are cultured, and indirect detection, been tested in one clinical trial that produced
in which surrogate markers and polymerase-chain- promising results (Table 2).30
reaction (PCR) assays are used (Table 2).18,21,22 No
test is perfect, and it is therefore necessary to Proph y l a x is
perform several diagnostic tests to achieve max-
imal accuracy. In view of the high mortality associated with in-
Culture is currently the only diagnostic ap- vasive candidiasis, prophylaxis for selected patients
proach that allows subsequent susceptibility test- in the ICU who are at high risk for the disease
ing. The sensitivity of blood cultures is far from would appear to be appropriate. Until now, the
ideal, with a sensitivity of 21 to 71% reported in use of antifungal prophylaxis in patients in the
autopsy studies.9 Whereas blood cultures may ICU has received little support from clinical
establish a diagnosis during the period when can- studies, except for its use in specific high-risk
dida resides in the bloodstream, cultures of blood groups.32 In patients who have had recent ab-
obtained from patients with hematogenous, deep- dominal surgery and have recurrent gastrointesti-
seated infections often yield negative results be- nal perforations or anastomotic leakage, flucon-
cause candida has been cleared from the blood- azole prophylaxis has been shown to be effective.33
stream at the time the blood sample is collected.9 In other selected patient groups in the ICU, the
Blood cultures are further limited by slow turn- results have been modest at best. Antifungal
around times and by the fact that a positive re- prophylaxis has generally shown trends toward
sult may be revealed only late in the course of reducing the incidence of candidemia by approxi-
disease. Positive blood cultures should prompt mately 50%, but this strategy has not been shown
the immediate initiation of therapy and a search to improve survival.34,35 The major challenge is to
for metastatic foci.18,31 select individual patients or subgroups that will
Candida mannan antigens and antimannan benefit most from prophylaxis in order to limit
antibodies and β-d-glucan are the primary sur- the number needed to treat and to avoid the
rogate markers for invasive candidiasis.18,21,22 The problem of selective pressure that leads to the
reported performance of assays for these mark- emergence of resistance.
ers varies somewhat according to case mix, the A recent randomized, placebo-controlled study
frequency of sampling, and the choice of com- used targeted caspofungin prophylaxis in patients
parator. Studies that include healthy controls or in the ICU who were determined to be at high
less severely ill patients may overestimate speci- risk for invasive candidiasis with the use of a
ficity, since there are many potential sources of clinical prediction rule.36 In this study, both se-
contamination of β-d-glucan testing that can rum β-d-glucan levels and cultures were used to
produce false positive results, and these are define invasive candidiasis. Overall, there were
found more frequently in patients at high risk no significant differences between the study
for invasive candidiasis (Table 2). The major di- groups in the incidence of candidemia, all-cause
agnostic benefit of β-d-glucan is its negative mortality, the use of antifungal drugs, or the
predictive value for invasive candidiasis in envi- length of stay. In these types of placebo-con-
ronments in which the prevalence is low to trolled studies, culture- and biomarker-based end
moderate. points may be less appropriate, since they are
A number of in-house PCR tests for the detec- likely to be biased in favor of the group receiving
tion of invasive candidiasis have been evaluated. the study drug. At this time, antifungal prophy-
However, limited validation and standardization laxis should be limited to patients in whom it
have hindered their acceptance and implementa- has proved to be beneficial: patients with gastro-
tion.27 Nguyen et al. reported that an in-house intestinal anastomotic leakage, patients under-
PCR assay had a sensitivity of 89% for deep-seated going transplantation of the pancreas or the
candidiasis that was not detected on blood cul- small bowel, selected patients undergoing liver
tures.28 Two commercial PCR tests have been mar- transplantation who are at high risk for candi-
keted — the SeptiFast and the fully automated diasis, and extremely low-birth-weight neonates
multiplex T2Candida Panel, which was released in settings with a high incidence of neonatal
in 2015.29,30 The T2Candida Panel has recently candidiasis.
Test and
Specimen Type Sensitivity Specificity Findings from Studies Comments
%
Culture (blood) 21–71 NA Per-patient sensitivity (based on autopsy studies) may Obtain daily blood cultures (total volume, 40–60 ml in 10-ml bottles for
be underestimated since patients with positive an- adults) and additional sets during febrile episodes; sensitivity can be in-
temortem blood cultures but with no evidence of creased by including a mycosis bottle.18
organ infection on autopsy were not included9,17
β-d (blood) 65–100 31–79 Performance depends on cutoff value and no. of Not specific for candida. Positive test result requires confirmation and identification
positive samples required19 of infecting organism (aspergillus, Pneumocystis jirovecii or candida).18,21
Sensitivity is species-dependent: C. krusei, 100%, Many potential sources for contamination: hemodialysis with cellulose mem-
3 cases; C. tropicalis, 91%, 11 cases; C. albicans, branes, human blood products (immunoglobulins or albumin), amoxicil-
83%, 36 cases; C. glabrata, 81%, 26 cases; lin–clavulanate or piperacillin–tazobactam, severe bacterial infections,
C. parapsilosis, 72%, 18 cases20 surgical sponges and gauzes containing glucan, and severe mucositis.22-24
High negative predictive value in several studies with intermediate preva-
lence.20 However, limited sensitivity in other studies suggests that nega-
tive predictive value may be insufficient in high-risk patients.19,21,25
Candida mannan antigen and antimannan antibodies tests may be preferable
for circumstances in which candida is main fungal pathogen and risk of
false positive β-d-glucan test is high.25,26
Candida mannan anti- Per patient, Per patient, Sensitivity and specificity results were given per Combined antigen–antibody test required for maximum sensitivity.
gen and anti- 83 (IQR, 79– 86 (IQR, 82– patient and per sample22 Used to detect blood-culture negative hepatosplenic candidiasis and CNS
mannan anti- 87); per sam- 90); per sam- Sensitivity is species-dependent and lower for candidiasis.22
bodies (blood ple, 62 (IQR, ple, 96 (IQR, C. parapsilosis and C. krusei (40–50%) than
Invasive Candidiasis
* CFS denotes cerebrospinal fluid, CNS central nervous system, ICU intensive care unit, IQR interquartile range, NA not available, and PCR polymerase chain reaction. For further infor-
mation see Cleveland et al.,2 Arendrup et al.,6 and Lortholary et al.7
† A spiked sample is a negative sample to which candida has been added.
Downloaded from nejm.org at GOTEBORGS UNIVERSITETSBIBL. on January 28, 2019. For personal use only. No other uses without permission.
1449
The n e w e ng l a n d j o u r na l of m e dic i n e
Standardized
Study Regimen Comparator Regimen Treatment Duration Step-Down Regimen Primary Outcome Success Rate* All-Cause Mortality Study
Fluconazole, Amphotericin B, 0.5– ≥14 Days after last posi- Not allowed Clinical and microbio- Fluconazole, 70%; Fluconazole, 40%; Rex et al.,
400 mg/day 0.6 mg/kg body tive blood culture logic success at amphotericin B, amphotericin B, 199444
weight/day and resolution of last available 79% (P = 0.22) 33% (P = 0.20)
clinical signs study visit
Caspofungin, Amphotericin B, 0.6– ≥14 Days after last posi- ≥10 Days, oral flucon- Clinical and microbio- Caspofungin, 73%; Caspofungin, 34%; Mora-Duarte
50 mg/day† 0.7 mg/kg/day tive culture azole, 400 mg/day logic success at amphotericin B, amphotericin B, et al., 200245
(0.7–1.0 mg/kg/ end of intravenous 62% (P = 0.09) 30% (P = 0.23)
day for patients therapy
with neutropenia)
Fluconazole, 800 Fluconazole, 800 Amphotericin B compo- >5 Days, oral flucon- Time to failure (death, Fluconazole plus am- Fluconazole plus am- Rex et al.,
mg/day, and mg/day nent, 5–8 days; azole, 800 mg/day alternative thera- photericin B, 69%; photericin B, 40%; 200346
amphotericin B, fluconazole, ≥14 py, or withdrawal) fluconazole, 56% fluconazole, 39%
0.6–0.7 mg/kg/ days after last posi- (P = 0.04)‡ (P = 0.89)
day tive blood culture
and resolution of
clinical signs
Voriconazole, Amphotericin B, 0.7– ≥14 Days after last posi- Voriconazole group, >3 Clinical and microbio- Voriconazole, 65%; Voriconazole, 36%; Kullberg et al.,
3 mg/kg, 1.0 mg/kg/day fol- tive culture days, oral voricon- logic success at 12 amphotericin B amphotericin B 200547
twice daily† lowed by flucon- azole, 200 mg twice wk after end of and fluconazole, and fluconazole,
azole, 400 mg/ daily; amphotericin B therapy 71% (P = 0.25) 42% (P = 0.23)
Invasive Candidiasis
* The standardized success rate was based on the modified intention-to-treat population for the last available study visit44,46,47 or the end of intravenous therapy.45,48-50
† Maintenance doses for fluconazole, caspofungin, voriconazole, and anidulafungin are shown. The loading doses, administered on the first day of treatment, are as follows: fluconazole,
800 mg; caspofungin, 70 mg; voriconazole, 6 mg per kilogram of body weight, two doses; and anidulafungin, 200 mg.
Downloaded from nejm.org at GOTEBORGS UNIVERSITETSBIBL. on January 28, 2019. For personal use only. No other uses without permission.
‡ These data are from a secondary analysis. P = 0.08 for the primary analysis, which was a Kaplan–Meier time-to-failure analysis.
1451
The n e w e ng l a n d j o u r na l of m e dic i n e
tients with APACHE II scores in all but the Dur at ion of Ther a py a nd
highest quartiles, suggesting that the survival S tep -D ow n C a r e
benefit associated with echinocandin treatment
is not limited to the sickest patients.38 In addi- Few data are available to support recommenda-
tion to treatment with an echinocandin antifun- tions regarding the total duration of therapy or
gal agent, the removal of intravenous catheters the step-down procedure from echinocandins to
was an independent determinant of improved intravenous or oral azoles.56 Since it is assumed
survival.38 that initial therapy with echinocandins is most
Several cohort studies in which multivariate effective in preventing death, the primary re-
models were used have consistently identified quirement for the transition to azoles should be
treatment with an echinocandin and catheter the clinical stabilization of the patient rather
removal as the management strategies associat- than identification of the infecting species and
ed with better outcomes.40,52 Additional data its susceptibility to azoles only — with the prob-
have provided reasonable support for the effica- able exception of C. parapsilosis infection.
cy of echinocandins in patients in the ICU, pa- Recent phase 4 studies have incorporated a
tients with deep-seated candidiasis, and patients step-down strategy to an oral azole as early as
infected with species other than C. albicans.53,54 5 days after the start of intravenous treatment
The observation that success rates among pa- with an echinocandin, provided that the infect-
tients infected with C. parapsilosis are as good as ing candida species has been cleared from the
those among patients infected with other species bloodstream and is probably susceptible to
should be regarded with some caution. C. parapsi- azoles and that the patient’s condition is clini-
losis is less susceptible to the echinocandins than cally stable and the patient is capable of taking
other candida species at the cellular and enzyme oral therapy.54 The outcomes of a strategy of early
level and tends to be associated with higher per- step-down with respect to efficacy and survival
sistence and breakthrough rates among patients were similar to those reported in previous studies
receiving an echinocandin.45 in which a minimum of 10 days of parenteral
Clinical trials and hence treatment guidelines echinocandin therapy were required.54 However,
are biased toward patients with candidemia, the intent of these studies was not to compare
since the infection is easier to recognize and the the effects of early step-down therapy with pro-
patients easier to enroll in clinical studies than longed echinocandin therapy in a randomized
patients with deep-seated candidiasis. In addi- fashion, and the patients who underwent the
tion, the comparison of trials is hampered, since transition to azoles were less severely ill than
the studies have been conducted over an extended other patients.
period during which many advances in care have
been introduced. Despite these caveats, echino- C athe ter M a nagemen t
candins are suggested to be associated with bet-
ter outcomes than those with azoles regardless of The concept supporting removal of intravascular
the type of invasive candidiasis, APACHE II score, catheters in patients with candidemia is based
and candida species (except for C. parapsilosis), and on the identification of catheters as a major risk
it is hard to justify withholding these agents as factor for candidemia, the presence of biofilms
the first choice for treatment.55 Nevertheless, of candida species attached to catheters, and the
some experts believe that there is a subgroup of observation that candidemia may persist until
ambulatory, stable, low-risk patients for whom catheters have been removed. However, no blind-
primary therapy with fluconazole is acceptable. ed, randomized studies have been designed to
Moreover, there are clinical scenarios in which determine the effect of catheter removal on out-
triazoles may be preferred, such as in the treat- comes and mortality. It is unlikely that such a
ment of meningitis, endophthalmitis, and uri- study will ever be performed, and retrospective
nary tract candidiasis (conditions in which echi- subgroup analyses have shown divergent out-
nocandins are limited by their pharmacokinetics) comes.38,57,58 Although a careful analysis could
or in the treatment of patients who have previ- not identify a significant effect of early catheter
ously been exposed to echinocandins for pro- removal within 24 or 48 hours after initiation of
longed periods. treatment,57 other studies found that catheter
C. albicans
C. dubliniensis
C. tropicalis
C. glabrata
C. krusei
S. cerevisiae
C. parapsilosis
Other candida species
Other fungi
C. albicans
C. tropicalis
C. glabrata
C. krusei
C. parapsilosis
Figure 2. Distribution of Candida Species According to Duration of Prophylaxis and Antifungal Agent Used for Prophylaxis.
Panel A shows the distribution of candida species isolated from the bloodstream of patients with candidemia in a Danish study.6 From
left to right, the graphs show the distribution in patients who had received no antifungal prophylaxis at the time of blood culture (258
patients), those who had received antifungal prophylaxis for less than 7 days at the time of culture (21 patients), and those who had re-
ceived antifungal prophylaxis for at least 7 days at the time of culture (28 patients) (P = 0.007 according to the chi-square test). Antifun-
gal prophylaxis included fluconazole in 37 patients (70%), voriconazole in 2 patients (4%), caspofungin in 6 patients (11%), and an am-
photericin B formulation in 8 patients (15%) (some patients received more than one drug). Panel B shows the distribution of candida
species isolated from the bloodstream of patients with candidemia in a French study.60 From left to right, the graphs show the distribu-
tion in patients who had received no antifungal prophylaxis at the time of blood culture (2289 patients with no fluconazole exposure,
and 2387 patients with no echinocandin exposure), those who had received fluconazole before the blood culture was performed (159
patients), and those who had received caspofungin before the blood culture was performed (61 patients).
removal at any time point was associated with a Emerging R e sis ta nce
reduction in mortality and higher clinical suc-
cess rates.39,40,58 In the pooled patient-level analy- Resistance to antifungal treatment can emerge
sis of seven randomized treatment trials, treat- either by means of the selection of species with
ment with an echinocandin and catheter removal intrinsic resistance or an induction of resistance
were identified as the two modifiable manage- in isolates from species that are normally sus-
ment strategies associated with better survival.38 ceptible. The former route is the most common,
Because patients have to be alive to have a cath- as illustrated by the emergence of C. glabrata after
eter removed, these types of analyses may not be the introduction of fluconazole and of C. parapsilo-
free of bias. Although the debate about this issue sis in settings in which there was increased use
will continue, it seems wise to remove all intra- of echinocandins (Fig. 2).6,60 In addition, insuf-
vascular catheters in patients with candidemia, ficient dosing of azoles has been associated with
if logistically feasible.31,55,59 the emergence of resistance.61
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