Empiric Echinocandin Therapy in Sepsis:

Echino-“Can It Work” or Echino-“Can You Not”?

Luke Smedley, PharmD

PGY-2 Critical Care Pharmacy Resident
Department of Pharmacotherapy and Pharmacy Services, University Hospital
Division of Pharmacotherapy, University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center, UT Health San Antonio
San Antonio, Texas
August 8 and 17, 2018

Learning Objectives

1. Differentiate various diagnostic tools for invasive candidiasis and describe situations where
false positives or false negatives may arise
2. Appraise the data surrounding azole versus echinocandin therapy for invasive candidiasis
3. Defend the choice to initiate or defer initiation of echinocandin therapy in a patient with
sepsis without proven invasive candidiasis
Assessment Questions:

1. Which diagnostic tool provides the fastest results confirming the presence of a
Candida spp. in the bloodstream?
a. BioFire FilmArray® Blood Culture ID Panel
b. (1-3)-β-D-glucan
c. T2Candida®
d. Traditional blood culture

2. True or false: in clinical trials, fluconazole therapy has been consistently shown to
have better outcomes than echinocandin therapy.

3. True or false: due to their once daily dosing and limited side-effect profile,
echinocandins can safely be given to all patients with septic shock without
consequences.

***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an
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Faculty (Speaker) Disclosure: Luke Smedley has indicated he has no relevant financial relationships to
disclose relative to the content of this presentation.

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Invasive Candidiasis

1. Introduction1-4
a. Most common fungal disease in hospitalized patients
b. Ranks in top three or four pathogens causing nosocomial bloodstream infections (BSIs) in developed
countries

Table 1. Incidence rates, pathogen distribution, and crude mortality of nosocomial BSIs5
BSIs per 10,000 Percentage of BSIs Crude mortality, %
Pathogen admissions ^ICU Non-ICU ICU Non-ICU
CoNS* 15.8 35.9 26.6 25.7 13.8
Staphylococcus aureus 10.3 16.8 23.7 34.4 18.9
Candida spp. 4.6 10.1 7.9 47.1 29.0
Escherichia coli 2.8 3.7 7.6 33.9 16.9
Klebsiella spp. 2.4 4.0 5.5 37.4 20.3
Pseudomonas aeruginosa 2.1 4.7 3.8 47.9 27.6
*Coagulase-negative Staphylococcus spp.
^Intensive Care Unit

i. Approximately 50% of candidemia cases occur in the ICU6

c. Epidemiologic studies of sepsis and septic shock have shown that approximately 3% of cases are due to fungal
pathogens7
d. Rates of community-acquired candidiasis rising due to:
i. Increased usage of long-term intravenous access devices (e.g. peripherally inserted central catheters
[PICC] lines and tunneled catheters)
ii. Outpatient parenteral antimicrobial therapy
2. Early appropriate treatment of invasive candidiasis (IC) is extremely important, as mortality is high with inappropriate
treatment and inadequate source control
a. In a study of patients with septic shock and a positive blood culture for Candida spp., mortality was
independently predicted by inadequate source control (AdjOR 77.4, 95% CI 21.52-278.38, p = 0.001) and
delayed antifungal treatment (AdjOR 33.75, 95% CI 9.65-118.04, p = 0.005) in a multivariate analysis8
i. Patients who survived were more likely to have received an echinocandin than patients who did not
(76.8% vs 49.0%, p < 0.001)
b. Another study of patients with septic shock attributed to Candida spp. found appropriate antifungal therapy
(OR 5.99, p = 0.048) and source control (OR 2.99, p = 0.001) to be independent predictors of hospital survival
in a multivariate analysis9

3
 Figure 1. Pathogenesis of invasive candidiasis2

3. Pathophysiology2
a. Candida spp. can cause infections of various organ systems2,10
i. Non-invasive infections generally occur as cutaneous or mucosal infections
ii. Invasive infections include BSIs, intra-abdominal infections, peritonitis, osteomyelitis, and other deep-
seated organ infections
b. Generally commensal organisms, but can turn into opportunistic pathogens
i. Occurs in context of mucosal microbiota changes and/or weakening of host’s immune system
c. Predisposing conditions for invasive infection
i. Long-term and/or repeated use of broad-spectrum antibiotics
1. Commensal gut microbiota species induce release of anti-Candida spp. protective factors
from mucosa11
2. Depletion of microbiota species removes protective factors and enables Candida spp.
overgrowth
ii. Breach of gastrointestinal and cutaneous barriers
1. Can occur with chemotherapy-induced mucositis, gastrointestinal surgery/perforation, or
central venous catheters
2. Enable commensal Candida spp. to travel from mucocutaneous sites to bloodstream
iii. Iatrogenic immunosuppression
1. Includes chemotherapy-induced neutropenia and corticosteroid therapy
2. Impairs innate immune defenses in tissues, which facilitates Candida spp. invasion from
bloodstream to organs
a. Can lead to infections in liver, spleen, kidneys, heart, or brain
d. Myeloid phagocytes (i.e. neutrophils, monocytes, macrophages, dendritic cells) are key in controlling and
preventing development of invasive candidiasis12,13
4. Causative pathogens1,2
a. At least 15 different species known to cause disease
b. Most common pathogenic species
i. Candida albicans – most prevalent species
4
 ii. Candida glabrata – second most common species in US and northwestern Europe
1. More common in patients > 60 years of age and in solid organ transplant
iii. Candida tropicalis and Candida parapsilosis – more common in Latin America, Southern Europe, India,
and Pakistan
1. C. parapsilosis more common in pediatric and neonatal patients14
iv. Candida krusei – more common in patients with underlying hematological malignancies who received
antifungal prophylaxis with fluconazole
c. Candida auris is emerging as a pathogen in certain areas of the world15
i. Often multidrug-resistant and develops resistance during therapy
ii. Frequently misclassified as other Candida spp.

Diagnosis and Diagnostic Challenges

1. Gold standard for IC diagnosis is positive culture2,16

a. Sensitivity of blood culture for diagnosis is approximately 50% in patients with autopsy-proven IC2,10
i. Due to low inoculum during candidemia episodes (< 1 colony-forming unit (cfu)/mL)
b. Strategies to improve sensitivity of blood cultures include frequent sampling, larger culture volumes, use of
specialized fungal culture bottles, and sampling prior to receipt of antifungal therapy
i. Infectious Diseases Society of America (IDSA) guidelines for diagnosis of infection mention that
specialized blood cultures may be used, but are not required
c. Blood cultures have slow turnaround times (median time to positivity of 2-3 days, range 1 to ≥7 days)
d. PCR-based tests (e.g. BioFire FilmArray® Blood Culture ID panel) allow for identification of five most common
species (C. albicans, C. glabrata, C. krusei, C. tropicalis, and C. parapsilosis) from positive blood culture
i. Study of FilmArray® versus traditional blood culture identification methods showed that FilmArray®
identified infecting Candida spp. in a mean of 1 hr 12 min ± 23 min from positive blood culture
compared to 3-5 days for traditional blood culture methods17
e. Patients with non-candidemic IC require positive culture and/or histopathology from suspected infection site
2. T2 magnetic resonance assay (T2Candida®)10
a. Allows for pathogen detection from whole blood rather than needing to wait for positive blood culture
b. T2Candida Panel is approved by FDA with a sensitivity and specificity of 91.1% and 99.4%, respectively18
i. May also identify patients with lower inoculum who would normally have negative blood cultures
c. A study of time evaluating T2Candida versus traditional blood culture saw a reduction in time to appropriate
antifungal therapy (22 hrs vs 39 hrs, p = 0.003)19
d. T2Candida does not provide information on specific species; can only place in one of three groups:
i. C. albicans or C. tropicalis
ii. C. glabrata, C. krusei, Saccharomyces cerevisiae, or C. bracarensis
iii. C. parapsilosis, C. metapsilosis, or C. orthopsilosis
3. (1-3)-β-D-glucan10
a. β-D-glucan is a cell wall constituent in Candida spp., Aspergillus spp., and Pneumocystis jirovecii
b. Approved in US as an adjunct to cultures for diagnosis of invasive fungal infections
c. Sensitivity and specificity for diagnosis of IC was 75-80% and 80% in multiple meta-analyses20-22
d. False-positives are common in ICU patients

5
 Table 2. Causes of false-positive (1-3)-β-D-glucan tests10
Other systemic infections Exposure to β-lactam therapy
Hemodialysis Fungal colonization
Exposure to albumin Exposure to intravenous immunoglobulin (IVIG)
Use of surgical gauze containing glucan Disruptions of gastrointestinal mucosa

4. Guideline recommendations
a. IDSA 201610
i. No specific recommendations about how to diagnose candidemia or IC
ii. Due to low sensitivity and specificity of diagnostic tests, most treatment is initiated based on clinical
gestalt

Management

1. Non-pharmacological treatment10
a. Source control is most important aspect of candidiasis management
i. Central lines should be removed if possible in patients with proven or suspected candidemia
ii. Patients with a drainable source should receive appropriate drainage and/or debridement
iii. Patients with candidiasis of implantable devices should have devices removed if possible or receive
long-term suppression therapy
b. Non-neutropenic patients with candidemia need a dilated ophthalmological exam to rule out ocular candidal
infections
i. As many as 16% of patients with candidemia will have ocular involvement that could lead to
endophthalmitis
2. Pharmacological treatment10
a. Echinocandins are recommended as initial therapy in critically ill, non-neutropenic patients with IC
i. De-escalate to fluconazole after 5-7 days if patient is clinically stable, has isolate susceptible to
fluconazole, and negative repeat blood cultures
b. Echinocandins inhibit (1-3)- -D-glucan synthesis by binding to (1-3)- -D-glucan synthase
i. Compromises integrity and shape of fungal cell wall
ii. Causes osmotic lysis of cell, resulting in fungicidal activity against Candida spp.

Table 3. Pharmacologic characteristics of echinocandins23,24

Mode of Fungicidal Activity Concentration-dependent
PK/PD Target AUC/MIC > 3000 for non-parapsilosis spp.
AUC/MIC > 285 for C. parapsilosis
Absorption Poorly absorbed through GI tract
Only available IV
Distribution Limited distribution to CNS and eyes
Very high protein binding (>95%)
Metabolism Caspofungin and micafungin undergo hepatic metabolism
Dose reductions recommended for caspofungin in hepatic dysfunction
Elimination Long half-life (10-26 hrs)
Dosed once daily
Eliminated through nonenzymatic degradation to inactive products
Excreted via feces

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Dosing Caspofungin: 70 mg loading dose, then 50 mg every 24 hours (50 mg/m2/day)
Micafungin: 100 mg every 24 hours (1-3 mg/kg/day)
Anidulafungin: 200 mg loading dose, then 100 mg every 24 hours (no weight-
based dose)
Spectrum of Activity Potently fungicidal against majority of Candida spp.
Higher MICs for C. parapsilosis and C. guilliermondii
Fungistatic against Aspergillus spp.
Side Effects Side effects are rare, but more common with caspofungin
Phlebitis, fever, abdominal pain, nausea/vomiting, diarrhea, headache, rash,
pruritis, leukopenia, neutropenia, thrombocytopenia, hypokalemia, abnormal
LFTs
Abbreviations: AUC = area under the time-concentration curve, CNS = central nervous system, GI = gastrointestinal, IV = intravenous,
LFT = liver function test, MIC = minimum inhibitory concentration

3. Multiple studies favor use of an echinocandin for management of IC

Table 4. Studies of fluconazole versus echinocandins for invasive candidiasis

Study
Reboli AC, Rotstein C, Pappas PG, et al.
Anidulafungin versus fluconazole for
invasive candidiasis. N Engl J Med.
25
2007;356:2472-82.
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
26
trials. Clin Infect Dis. 2012;54:1110-22.
Eschenauer GA, Carver PL, Lin SW, et al.
Fluconazole versus an echinocandin for
Candida glabrata fungaemia: a
retrospective cohort study. J Antimicrob
27
Chemother. 2013;68:922-6.
Intervention
Prospective, randomized controlled trial of
anidulafungin (200 mg IV on day 1, then
100 mg IV daily) vs fluconazole (800 mg IV
on day, then 400 mg IV daily)
Patient-level meta-analysis of treatments
for IC
Retrospective cohort study of fluconazole
versus an echinocandin for candidemia
due to C. glabrata
Results
Global response at end of IV therapy:
75.6% anidulafungin vs fluconazole
60.2% (p = 0.01)
o Remained significant when
adjusted for baseline
characteristics of
immunosuppressive therapy,
diabetes, prior azole therapy,
presence of C. glabrata, and
catheter removal
Remained significant at end of all
treatment and 2-week follow-up
Lost statistical superiority at 6-week
follow-up
Echinocandin use associated with
improved 30-day all-cause mortality
(OR 0.65, 95% CI 0.45-0.94, p = 0.02)
Also associated with higher success
rate at end of therapy (OR 2.33, 95%
1.27-4.35, p = 0.01)
In multivariate analysis, echinocandin
use was associated with increased
odds of complete response at day 14
(OR 2.305, 95% CI 1.124-4.727, p =
0.023)
Echinocandin use was not associated
with 28-day survival (OR 1.843, 95% CI
0.835-4.069, p = 0.13)

4. Multiple mechanisms of resistance have been reported28

a. Adaptive stress response
i. When synthesis of (1-3)- -D-glucan is inhibited, cell wall increases synthesis of chitin
ii. Compensatory increase in chitin synthesis occurs in response to echinocandin exposure in Candida
spp.

7
 iii. Has been seen in most Candida spp., but is more common in C. albicans
iv. Elevated cell wall chitin content is associated with protection against echinocandins
v. Some studies show paradoxical effect of high levels of caspofungin on C. albicans, where C. albicans is
able to grow at higher serum concentrations
1. May be due to higher chitin contents in fungal cell wall, reducing ability of caspofungin to
exhibit its mechanism of action
b. Acquired FKS mutations
i. Glucan synthase (molecular target of echinocandins) is made of at least two subunits: FKS1p
(encoded by genes FKS1, FKS2, and FKS3) and Rho1p
ii. Amino acid substitutions in FKS subunits confer reduced echinocandin susceptibility
iii. These mutations can be gained, and have been seen in C. albicans, C. tropicalis, C. krusei, and C.
glabrata
c. Intrinsic FKS mutations
i. C. parapsilosis and C. guilliermondii have naturally occurring mutations in FKS genes that confer
reduced susceptibility to echinocandins
ii. These species have consistently higher MIC values than other Candida spp.
iii. Echinocandins have still shown clinical efficacy in treatment of these species
5. Resistance is emerging as use of echinocandins increases
a. Pre-exposure to fluconazole or caspofungin was associated with decreased prevalence of C. albicans and an
increased prevalence of less susceptible species, such as C. glabrata and C. krusei, in a multicenter
prospective observational study of candidemia29
i. Recent exposure to caspofungin was independently associated with increased risk of infection with
isolate with decreased echinocandin susceptibility (OR 4.79, 95% CI 2.47-9.28, p < 0.001)
b. A single-center study evaluating echinocandin resistance in C. glabrata showed resistance increased from
4.9% of isolates in 2001 to 12.3% in 201030
i. In addition, prior echinocandin therapy independently predicted presence of an FKS mutant strain of
C. glabrata (OR 19.647, 95% CI 7.19-58.1)

Empiric Antifungal Therapy in Critically Ill Patients

1. Various treatment strategies have been suggested to reduce mortality with IC31
a. Prophylaxis = treat patients with high-risk of IC (> 5-10%) to prevent development of infection
b. Pre-emptive therapy = treat patients with one or more biological markers of infection risk (e.g. elevated β-D-
glucan, widespread Candida spp. colonization)
c. Empiric treatment = treat patients with continued signs of infections and clinical suspicion of IC without
proven fungal infection
2. Guidelines suggest therapy should be considered in critically ill patients with risk factors for IC and no other cause of
fever10

Table 5. Risk factors for invasive candidiasis10

Candida spp. colonization Increased severity of illness
Exposure to broad-spectrum antibiotics Recent major surgery
Abdominal surgery/procedures Hemodialysis
Total parenteral nutrition (TPN) High-dose corticosteroids
Use of central venous catheters Necrotizing pancreatitis

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3. Epidemiologic studies cited by guidelines for risk factors were done in surgical ICU patients32,33
a. Largest epidemiologic study of patients with candidemia identified risk factors listed above, but only prior
surgery (RR 7.3, 95% CI 1.0-53.8, p = 0.05), acute renal failure (RR 4.2, 95% CI 2.1-8.3, p < 0.001), and receipt
of parenteral nutrition (RR 3.6, 95% CI 1.8-7.5, p < 0.001) remained significant in multivariate analysis32
b. In subgroup of patients who actually underwent surgery, above risk factors remained significant as well as
triple-lumen catheter placement (RR 5.4, 95% CI 1.2-23.6, p = 0.03)
4. Risk factors included in guidelines are broad and apply to almost every ICU patient, however incidence of candidiasis
in the ICU is only about 10%10

Clinical Controversy #1

How do we predict who has invasive candidiasis in critically ill patients?

Table 6. Risk scores for prediction of invasive candidiasis and/or candidemia

Study
León C, Ruiz-Santana S,
Saavedra P, et al. A bedside
scoring system ("Candida
score") for early antifungal
treatment in
nonneutropenic critically ill
patients with Candida
colonization. Crit Care Med.
34
2006;34:730-7.
Shorr AF, Tabak YP,
Johannes RS, et al.
Candidemia on presentation
to the hospital:
development and validation
of a risk score. Crit Care.
35
2009;13:R156.
Hermsen ED, Zapapas MK,
Maiefski M, et al. Validation
and comparison of clinical
prediction rules for invasive
candidiasis in intensive care
unit patients: a matched
case-control study. Crit
36
Care. 2011;15:R198.
Abbreviations: AUROC = area under the receiver operating curve, CVC = central venous catheter, LOS = length of stay, NPV = negative
predictive value, OR = odds ratio, PPV = positive predictive value,
Patient Population Risk Scoring
Patients admitted for at
least seven days to ICU
Excluded neutropenic
patients
Admitted to acute care
hospital
ICU stay ≥ 4 days
Excluded patients with
IC or receipt of
antifungal agents prior
to day 4 of ICU stay
Results
TPN = 1 point A score of > 2.5 had sensitivity
Surgery on ICU admission = of 81% and specificity of 74%
1 point for diagnosis of IC
Multifocal Candida spp. OR of proven infection with
colonization = 1 point score > 2.5 was 7.75 (95% CI
Severe sepsis = 2 points 4.74-12.66)
AUROC = 0.847 (95% CI 0.8-
0.894)
Age < 65 years Candidemia rates by score (P <
Temp ≤ 98° F OR severe 0.0001)
altered mental status o 0 = 0.4%
Cachexia o 1 = 0.8%
Previous hospitalization o 2 = 1.6%
within 30 days o 3 = 3.2%
Admitted from other o 4 = 4.2%
healthcare facility o 5 = 9.6%
Mechanical ventilation at o 6 = 27.3%
admission AUROC = 0.70
NPV 99% with score < 3
Broad-spectrum antibiotics Sensitivity 84.1% and
on any of days 1-3 of ICU specificity 60.2% for score >
stay = 1.537 points 2.45
CVC on any of days 1-3 of PPV 4.7% and NPV 99.4% for
ICU stay = 0.873 points score > 2.45
TPN on any of days 1-3 of AUROC = 0.77
ICU stay = 0.922 points
Corticosteroids from 7 days
before ICU admission to day
3 of ICU stay = 0.402 points
Abdominal surgery = 0.879
points
Increasing pre-ICU LOS =
0.039 per day

9
1. Further studies confirmed no score is perfect, either having low sensitivity (thus missing many patients with IC) or low
specificity (including many patients without IC)
a. Validation study of Candida score in patients with sepsis or septic shock showed Candida score > 3 had PPV of
23.8% and NPV of 100% for IC37
b. Study comparing use of (1-3)- -D-glucan levels versus Candida score or Candida colonization index showed
varied sensitivity, specificity, PPV, and NPV38

Table 7. Sensitivity, specificity, PPV, and NPV of various prediction tools38

Sensitivity (%) Specificity (%) PPV (%) NPV (%)
Prediction Method (95% CI) (95% CI) (95% CI) (95% CI)
(1-3)- -D-glucan > 80 pg/mL 92.9 (66.1-99.8) 93.7 (85.8-97.9) 72.2 (46.5-90.3) 98.7 (92.8-99.9)
Candida score 3 85.7 (57.2-98.2) 88.6 (79.5-94.7) 57.1 (34.0-78.2) 97.2 (90.3-99.7)
Colonization index 0.5 64.3 (35.1-87.2) 69.6 (58.2-79.5) 27.3 (13.3-45.5) 91.7 (81.6-97.2)

2. Development of a clinical prediction rule for candidemia specifically in patients presenting with sepsis or septic shock

Table 8. Guillamet CV, Vazquez R, Micek ST, et al. Development and validation of a clinical prediction rule for candidemia
in hospitalized patients with severe sepsis and septic shock. J Crit Care. 2015;30:715-20.39
Design and Methods
Retrospective, cohort study to develop and internally validate a prediction rule to identify patients with sepsis or septic shock at
risk for candidemia
Population Inclusion Exclusion
Presence of positive blood culture combined with Isolation of usual blood culture contaminants (e.g.
primary or secondary ICD-9-CM codes indicative CoNS, Corynebacterium spp.)
for sepsis and acute organ dysfunction and/or o Included if had multiple cultures positive
need for vasopressors for same organism or if clinical scenario
o Sepsis had to be temporally related (± 24 qualified organism as true pathogen
hours) to positive blood cultures
Factors Evaluated Presence of CVC for ≥48 hours prior to positive blood cultures
Mechanical ventilation
Septic shock (versus sepsis)
Prior antibiotic use within preceding 30 days
Diabetes mellitus
Presence of immunosuppression (e.g. hematologic malignancies, solid organ or bone marrow transplants,
AIDS, long term or high dose corticosteroid administration, or administration of chemotherapy and/or
radiation therapy)
TPN
Recent surgery
Duration of hospitalization prior to bloodstream infection
Recent hospitalization within preceding 90 days
Endpoints Presence of candidemia
Baseline n = 2597
Characteristics Candidemia Non-candidemia
p-value
Variable (n = 266) (n = 2331)
Age in yrs, mean ± SD 61.4 ± 16 60.3 ± 15.8 0.275
Sex, male, n (%) 125 (47) 1299 (55.8) 0.008
Admission source, n (%) <0.001
Home 124 (46.6) 1540 (66.1)
Nursing home 31 (11.7) 197 (8.5)
Transferred from outside hospital 107 (40.2) 559 (24)
Charlson comorbidity score, median (IQR) 4 (2-7) 4 (2-7) 0.532

10
 Diabetes mellitus, n (%) 71 (26.7) 630 (27) 0.907
Cirrhosis, n (%) 40 (15) 345 (14.8) 0.918
Hemodialysis, n (%) 46 (17.3) 291 (12.5) 0.023
Immunosuppression, n (%) 84 (31.6) 819 (35.3) 0.259
TPN, n (%) 51 (19.2) 125 (5.4) <0.001
Surgery, n (%)
Abdominal 54 (20.3) 209 (13.3) 0.001
Any surgery 99 (37.2) 602 (25.8) <0.001
CVC, n (%) 213 (80.1) 1320 (56.6) <0.001
Prior hospitalization, n (%) 142 (58.9) 1190 (51.1) 0.168
Prior antibiotics, n (%) 197 (74.1) 1215 (52.1) <0.001
Days hospitalization prior to candidemia,
6 (0-17) 1 (0-10) <0.001
median (IQR)
APACHE II score (mean ± SD) 17.1 ± 6.5 16.3 ± 6.2 0.049
Septic shock, n (%) 129 (48.5) 990 (42.5) 0.060
Mechanical ventilation, n (%) 94 (35.5) 584 (25.1) <0.001
Mortality, n (%) 125 (47) 662 (28.4) <0.01

Candida sp., n (%) Untreated (n = 1391)

Candida albicans 113 (42.5)
Candida glabrata 75 (28.2)
Candida parapsilosis 43 (16.2)
Candida tropicalis 20 (7.5)
Candida krusei 11 (4.1)
Candida lusitaniae 3 (1.1)
Candida dubliniensis 3 (1.1)
Candida guillermondii 2 (0.8)
Results
Univariate analysis Multivariate analysis
Variable OR (95% CI) p-value Adjusted OR (95% CI) p-value
Duration of hospitalization (per day) 1.02 (1.0-1.0) <0.001
Mechanical ventilation 1.6 (1.2-2.1) <0.001 1.8 (1.2-2.3) 0.002
TPN 4.2 (3.0-6.0) <0.001 2.5 (1.7-3.8) <0.001
CVC 3.7 (2.6-5.2) <0.001 2.2 (1.5-3.3) <0.001
Septic shock 1.3 (1.0-1.6) 0.061
Prior antibiotics 2.6 (2.0-3.5) <0.001 2.4 (1.7-3.4) <0.001
APACHE II score
1.02 (1.0-1.0) 0.049
(per point increase)
Diabetes mellitus 0.98 (0.7-1.3) 0.907
Source of infection
Intra-abdominal 1.4 (1.0-2.0) 0.81
CVC 1.6 (1.2-2.3) 0.005
Lung 0.05 (0.02-0.1) <0.001 0.04 (0.01-0.1) <0.001
Source of admission
Home 0.4 (0.3-0.6) <0.001
Nursing home 1.4 (1.0-2.1) 0.082 2.3 (1.4-3.6) 0.001
Outside hospital 2.1 (1.6-2.8) <0.001 1.8 (1.3-2.6) <0.001
Abdominal surgery 1.7 (1.2-2.3) 0.002
Any surgery 1.7 (1.3-2.2) <0.001
Probability prediction equation (using 1 if factor is present and 0 if factor absent):
o (0.93 x TPN) + (0.88 x prior antibiotics within 30 days) + (0.61 x transfer from outside hospital) + (0.81 x admission from
nursing home) + (0.52 x mechanical ventilation) + (0.8 x presence of CVC for at least 48 hours) + (-3.22 x lung as
presumed infection source) – 3.61
Area under the receiver operating characteristic curve (AUROC) for prediction equation was 0.798 (95% CI 0.77-0.82), indicating

11
 that the prediction equation will assign a randomly chosen positive patient a higher prediction score than a randomly chosen
negative patient 80% of the time
Integer score, where score >3 indicates high risk of candidemia:
o Prior antibiotics within 30 days = 2 points
o CVC at least 48 hours = 2 points
o Admitted from nursing home = 2 points
o TPN = 2 points
o Transferred from outside hospital = 1 point
o Mechanical ventilation = 1 point
o Lung as presumed source of infection = -6 points
AUROC for integer score with value of 3 to predict candidemia was 0.72 (0.7-0.74)
Specificity of score of 3 or higher was 87.6% (83-91.3%) and sensitivity was 55.9% (53.9-57.9%)
PPV of score of 3 or higher was 18.5% (16.4-20.7%) and NPV was 97.5% (96.5-98.3%)
o Using cutoff score of 2 provided a negative predictive value of 98.8%
Authors’ The developed and validated prediction rule outperformed previous prediction rules
Conclusions Locally derived prediction models may be superior by accounting for local case mix and risk factor
distribution
Reviewer’s Critique
Strengths Limitations
Large sample size Retrospective study
Specifically evaluated patients with sepsis or septic shock Score has not been externally validated
Prediction equation had highest AUROC of all available Although prediction equation had best AUROC, simplified
prediction scores (other scores ranged between 0.595 and version had lower AUROC than other rules
0.762) Unable to include dose of corticosteroids in analysis
Only evaluated risk of candidemia and not invasive
candidiasis
Conclusion: Use of a complicated risk prediction equation was superior to all other models for prediction of candidemia in sepsis and
septic shock, however the simplified version, which would be easier to implement in practice, was no better than other models.

3. Take-Home Points
a. First study to develop risk score specifically in patients with sepsis or septic shock
b. Useful for assessing risk to decide whether antifungal treatment is warranted
c. Risk tool still has limitations, including difficulty implementing into practice, low PPV, and limitation to
candidemia only

Clinical Controversy #2

Which patients should be treated empirically with an echinocandin versus fluconazole?

Table 9. Ostrosky-Zeichner L, Harrington R, Azie N, et al. A risk score for fluconazole failure among patients with
candidemia. Antimicrob Agents Chemother. 2017;64:e02091-16.40
Design and Methods
Retrospective, cohort study to develop a risk score for fluconazole failure in patients with candidemia
Population Inclusion Exclusion
Aged 18 years or older Second hospitalization in study period (4/01/2004
At least one positive blood culture for Candida to 03/31/2013)
spp.
Initiation of IV fluconazole treatment during
hospital stay and no more than 5 days before
positive Candida spp. blood culture
12
Factors Evaluated Patient demographics (e.g. age, sex, race)
Index hospitalization characteristics
Candida sp. isolated
Time from admission until start of fluconazole treatment
Fluconazole use prior to positive blood culture
Underlying diagnosis
Procedures received (e.g. CVC placement, drain placement, ileostomy)
Treatments (e.g. parenteral or enteral nutrition, corticosteroids, other antifungals)
Endpoints Failure of fluconazole, defined as patients who met any of the following criteria
o Switched to or added another antifungal after fluconazole initiation
o Had a subsequent positive blood culture for Candida infection during index hospitalization and at
least 10 days after fluconazole initiation
o Died during period from index date to end of index hospitalization
Baseline n = 987
Characteristics Fluconazole failure No fluconazole failure
p-value
Variable (n = 488) (n = 499)
Age in yrs, mean ± SD 60.95 ± 16.55 61.24 ± 17.68 0.7
Sex, male, n (%) 252 (51.6) 255 (51.1) 0.866
Days from admission to fluconazole
22.88 ± 66.52 12.76 ± 15.2 <0.001
initiation, mean ± SD
Fluconazole use prior to positive blood
429 (87.9) 418 (83.8) 0.062
culture, n (%)
Charlson comorbidity index, mean ± SD 1.66 ± 2.42 1.51 ± 2.24 0.598
Diagnoses, n (%)
Hematological malignancy 17 (3.5) 7 (1.4) 0.034
Renal failure (including hemodialysis) 120 (24.6) 134 (26.9) 0.416
Hepatitis 33 (6.8) 22 (4.4) 0.107
Gastroenteritis 36 (7.4) 33 (6.6) 0.638
Abscess 34 (7.0) 45 (9.0) 0.235
Venous thromboembolism 22 (4.5) 30 (6.0) 0.29
Diabetes 75 (15.4) 77 (15.4) 0.978
Severe sepsis/bacteremia 75 (15.0) 84 (16.8) 0.421
Procedures, n (%)
Use, replacement, or removal of central
192 (39.3) 199 (39.9) 0.863
line
Use of nonoperative intubation or
103 (21.1) 63 (12.6) <0.001
irrigation
Ileostomy 13 (2.7) 8 (1.6) 0.248
Mechanical ventilation 168 (34.4) 121 (24.2) <0.001
Treatments, n (%)
Parenteral nutrition 81 (16.6) 96 (19.2) 0.280
Enteral nutrition 44 (9.0) 30 (6.0) 0.073
Corticosteroids 30 (6.1) 28 (5.6) 0.72
Other antifungals* 108 (22.1) 81 (16.2) 0.019
*other antifungals = amphotericin B, flucytosine, itraconazole, voriconazole, posaconazole, or an echinocandin

Fluconazole failure No fluconazole failure

p-value
Candida sp. isolated, n (%) (n = 488) (n = 499)
Candida albicans 256 (52.5) 291 (58.3) 0.064
Candida glabrata 134 (27.5) 84 (16.8) <0.001
Candida krusei 6 (1.2) 2 (0.4) 0.173
Candida parapsilosis 48 (9.8) 62 (12.4) 0.196
Other Candida spp. 47 (9.6) 65 (13.0) 0.093

13
 Results
Risk factor Coefficient Standard Error Odds Ratio
Days to initiation of fluconazole after
0.02 0.01 1.02
admission
Candida sp.
Candida glabrata 0.68 0.20 1.98
Candida krusei 2.1 1.12 8.20
Hematologic malignancy 1.18 0.60 3.25
Venous thromboembolism -0.67 0.41 0.51
Nonoperative intubation or irrigation 0.43 0.29 1.54
Mechanical ventilation 0.12 0.24 1.13
Enteral nutrition 0.44 0.32 1.56
Other antifungal use 0.34 0.21 1.4
AUROC was 0.65, meaning model will give a randomly selected positive case a higher score than a randomly selected negative
case 65% of the time
# correctly
Sensitivity Specificity PPV NPV
Risk score cutoff predicted*
0.1 163 100 0 49 0
0.2 162 99 2 50 75
0.3 158 97 17 53 85
0.4 127 78 42 57 66
0.5 91 56 68 63 61
0.6 53 33 84 66 56
0.7 25 15 95 74 63
0.8 10 6 98 77 52
0.9 5 3 100 100 51
Authors recommend a cutoff of 0.5 to balance sensitivity and specificity
Authors’ This study identified clinical factors that may predict fluconazole failure in hospitalized patients with
Conclusions candidemia
Reviewer’s Critique
Strengths Limitations
First study to provide scoring system to predict fluconazole Retrospective, claims-based study
failure AUROC is less than generally accepted cutoff for a “good”
Included many different variables to assess risk of failure model (0.7 or higher)
Recommended cutoff of 0.5 only provided 56% sensitivity
and 68% specificity
Conclusion: This prediction model for risk of fluconazole failure may be used in combination with other tools to assess whether
patients at high risk of candidiasis may benefit from initial echinocandin therapy over fluconazole therapy.

1. Take-Home Points
a. Although this tool may help predict patients who need echinocandin therapy rather than fluconazole therapy,
the tool did not perform well enough to recommend in clinical practice
b. Has not been validated as a tool to make initial treatment decisions
c. Risk score does not have the best accuracy, with an AUROC of 0.65

14
Clinical Controversy #3

What is the clinical benefit of early antifungal therapy in critically ill patients with sepsis?

Table 10. Timsit JF, Azoulay E, Schwebel C, et al. Empirical micafungin treatment and survival without invasive fungal
infection in adults with ICU-acquired sepsis, Candida colonization, and multiple organ failure: the EMPIRICUS randomized
controlled trial. JAMA. 2016;316:1555-64.41
Design and Methods
Multicenter, double-blind, placebo-controlled trial to evaluate whether micafungin increases 28-day invasive fungal infection-free
survival in patients with ICU-acquired sepsis, Candida spp. colonization at multiple sites, and multiple organ failure
Population Inclusion Exclusion
2
Mechanically ventilated for at least 5 days Neutropenia (< 500 WBCs/mm )
At least 1 colonization site (other than rectal Previous organ or stem cell transplant
swab or stool) positive for Candida sp. Ongoing systemic immunosuppression agent
At least 1 additional organ dysfunction (SOFA therapy other than 2 mg/kg/day of prednisolone
score ≥ 3) or equivalent
Previous treatment for > 4 days using broad- Recent chemotherapy (within past six months)
spectrum antibacterial agents within last 7 days Proven invasive infection at time of
Arterial or CVC randomization
New finding of ICU-acquired sepsis of unknown Antifungal treatment with an echinocandin agent
origin (based on SIRS criteria) for more than one day or with any other
antifungal agent for more than 72 hours during
the week prior to inclusion
Intervention Micafungin 100 mg IV daily x 14 days (n = 128) vs placebo (n = 123)
Endpoints 28-day survival free of proven invasive fungal infection
o Also assessed in subgroups: medical vs surgical, low vs high SOFA score, low vs high (1-3)-β-D-
glucan level, low vs high colonization index, Candida score < 3 vs ≥ 3
New proven invasive fungal infections during follow-up
Survival at days 28 and 90
Antifungal-free survival at day 28
Incidence of ventilator-associated bacterial pneumonia
Evolution throughout 28-day study period of SOFA score and (1-3)-β-D-glucan
Baseline N = 251
Characteristics Micafungin (n = 128) Placebo (n = 123)
Age in years, median (IQR) 65 (56-74) 64 (52-74)
Men, n (%) 81 (66) 82 (64)
Weight in kg, median (IQR) 84 (72-97) 80 (68-95)
Chronic disease categories, n (%)
Cardiac 30 (24) 34 (27)
Respiratory 20 (16) 33 (26)
Hepatic 11 (9) 14 (11)
Renal 15 (12) 7 (6)
Immunosuppression 4 (3) 8 (6)
Receiving corticosteroids, n (%) 11 (9) 11 (9)
Admission category, n (%)
Medical 92 (75) 94 (73)
Emergency surgery 29 (24) 31 (24)
Scheduled surgery 2 (2) 3 (2)
Main surgical procedures, n (%)
Cardiac 25 (20) 94 (73)
Abdominal 5 (4) 31 (24)
Other surgery or trauma 2 (2) 4 (3)
15
 Main reason for ICU admission, n (%)
Acute respiratory failure 48 (39) 54 (41)
Septic shock 37 (31) 48 (37)
Cardiogenic shock 21 (17) 17 (13)
Coma 15 (12) 10 (8)
Acute pancreatitis 7 (6) 7 (6)
Duration of ICU stay prior to inclusion in days,
11 (7-17) 10 (7-15)
median (IQR)
Variables assessed at inclusion
SOFA score, median (IQR) 8 (5-12) 8 (6-11)
Candida score, median (IQR) 3 (2.5-4) 3 (2-4)
No. of positive colonization sites,
3 (2-4) 3 (2-4)
median (IQR)
Epinephrine or norepinephrine use, n (%) 70 (57) 71 (56)
Dialysis or hemofiltration, n (%) 42 (34) 40 (31)
Parenteral nutrition, n (%) 30 (24) 35 (27)
Results
Micafungin Placebo
p-
28-day IC- 28-day IC- Hazard Ratio
Total number Total number value
free survival free survival
All patients 87 128 74 123 1.35 (0.87-2.08) 0.18
SOFA score
≤8 51 66 52 68 1.11 (0.53-2.33) 0.78
>8 36 62 22 55 1.69 (0.96-2.94) 0.07
Candida score ≥ 3 64 96 47 85 1.37 (0.83-2.27) 0.21
(1-3)-β-D-glucan, pg/mL
> 80 58 91 47 84 1.41 (0.85-2.33) 0.19
≤ 80 29 37 27 39 0.98 (0.30-2.94) 0.97

Micafungin Placebo
p-
28-day 28-day Hazard Ratio
Total number Total number value
Survival Survival
All patients 90 128 86 123 1.04 (0.64-1.67) 0.88
SOFA score
≤8 53 66 58 68 0.79 (0.32-1.96) 0.62
>8 37 62 28 55 1.28 (0.71-2.27) 0.42
Candida score ≥ 3 66 96 58 85 0.95 (0.55-1.67) 0.87
(1-3)-β-D-glucan, pg/mL
> 80 61 91 58 84 0.98 (0.55-1.75) 0.96
≤ 80 29 37 28 39 0.85 (0.27-2.63) 0.78

Absolute Difference
Micafungin (n = 128) Placebo (n = 123)
(95% CI)
# of invasive fungal infections at follow-up (day 28)
≥1 4 (3) 15 (12) 9.1 (2.5 – 16.3)
2 0 2 (2) 1.6 (-1.5 – 5.7)
Invasive fungal infections by species
Candida albicans 3 10 19.4 (-29.7 – 49.4)
Candida glabrata 0 2 11.1 (-38.5 – 32.8
Candida parapsilosis 0 3 16.7 (-33.5 – 39.2)
Candida inconspicua 1 0 25.0 (-2.0 – 69.9)
Trichosporon 0 2 11.1 (-38.5 – 32.8)
Aspergillus fumigatus 0 1 5.6 (-43.7 – 25.8)

16
Authors’ Among nonneutropenic critically ill patients with ICU-acquired sepsis, Candida species colonization at
Conclusions multiple sites, and multiple organ failure, empirical treatment with micafungin did not increase fungal
infection-free survival at day 28
Reviewer’s Critique
Strengths Limitations
Double-blind, placebo-controlled randomized trial Underpowered (expected 18% difference, found 8%
Excluded transplant and neutropenic patients difference)
Only included patients at highest risk of invasive candidiasis Included invasive candidiasis diagnosed by samples found
(exposure to broad-spectrum antibiotics, presence of central before initiation of therapy as an occurrence of the primary
venous catheter) endpoint
Low percentage of abdominal surgery and acute pancreatitis
as these patients are at higher risk of IC
Reviewer’s Underpowered to find an improvement in mortality with use of empiric echinocandin therapy in patients at
Conclusions highest risk of invasive candidiasis
Abbreviations: SAPS = Simplified Acute Physiology Score, SIRS = Systemic Inflammatory Response Syndrome, SOFA = Sequential Organ Failure Score

1. Why didn’t we see a difference?

a. Patients at risk for invasive candidiasis are extremely sick
i. Median SOFA score was 8, correlating with 15-20% mortality42,43
ii. Risk factors for IC are seen in patients with many chronic issues with a higher baseline risk of death
iii. Presence of IC could arguably be considered marker of disease severity in ICU patients
iv. Questions futility of echinocandin intervention in patients at high-risk
b. Micafungin was started late in hospital stay
i. Study only evaluated patients who had received broad-spectrum antibiotics for four or more days
ii. With knowledge that early treatment is associated with better outcomes, delayed micafungin
initiation may have resulted in lower rate of efficacy
c. Higher doses may have been needed to hit pharmacokinetic/pharmacodynamic targets
i. In population pharmacokinetic study of critically ill patients based on data from EMPIRICUS trial,
results showed higher doses may be needed to meet AUC:MIC targets for efficacy44
1. Covariates that significantly influenced clearance (CL), central distribution volume (Vc), and
peripheral distribution volume (Vp) were body weight, serum albumin, and SOFA score
2. In simulations of patients with C. albicans or C. glabrata with MICs > 0.015 mg/L, micafungin
doses of at least 150 mg were needed to achieve high probability of target attainment (PTA)
a. 100 mg dose adequate for isolates with MICs < 0.015 mg/L
3. In simulations of patients with C. parapsilosis, doses between 150 mg and 300 mg were
necessary to reach a PTA of 90% for isolates with MICs = 0.25-0.5 mg/L
a. High PTA never able to be obtained with isolates with MIC > 1 mg/L
b. 100 mg dose only adequate in patients with isolates with MICs ≤ 0.125 mg/L
c. Lower PTAs seen in models of patients with serum albumin < 2.5 g/dL
ii. Micafungin pharmacokinetics in obese, critically ill, and morbidly obese critically ill patients showed
difficulty meeting AUC/MIC targets45
1. 100 mg dose was never able to achieve > 90% fractional target attainment (FTA) for any
Candida spp.
2. 150 mg dose met 90% FTA for C. albicans in patients ≤115 kg, but never achieved > 90% for
other species
3. 200 mg dose meet 90% FTA for C. albicans in all patients and C. glabrata in patients ≤ 115 kg,
but never met goal for C. tropicalis or C. parapsilosis
17
Recommendation

1. Guillamet score should be used to assess the risk of candidemia in patients with septic shock presenting from the
community
a. Full calculation should be used rather than simplified scoring system better accuracy
2. Patients in the ICU for ≥7 days can be assessed with Candida score better accuracy than Guillamet score
3. For patients with either score ≥ 3, prior antifungal history should be assessed
a. Patients with history of fluconazole use should receive empiric echinocandin therapy
i. Should be given at least 150 mg of micafungin or 200 mg if ≥ 115 kg
b. Patients with no history of antifungal therapy AND low SOFA score (< 8) may be initially managed with
fluconazole
4. Blood cultures should be drawn before receipt of antifungal therapy, and T2Candida® and/or Biofire PCR testing
should be utilized if possible to enable targeted therapy
5. Empiric therapy can be discontinued in the following situations:
a. Negative blood cultures after 5 days
b. No clinical improvement after 4-5 days without proven IC
c. Back-to-back negative (1-3)-β-D-glucan on separate days
6. If blood cultures come back positive, therapy can be de-escalated based on organism and susceptibilities

Conclusion

1. Although early treatment of IC is extremely important, diagnosis remains immensely difficult

2. Patients presenting with sepsis or septic shock with extensive exposure to the healthcare system should be assessed
for risk of IC
3. Care should be taken to avoid overuse of echinocandins in light of emerging resistance
4. Although IC is associated with high mortality, patients who are diagnosed are generally chronically ill, and the disease
may be a marker of disease severity

18
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