From Guidelines to Bedside:
Clinical Case Scenario Approach
Mazen Kherallah, MD, FCCP
Treatment of Invasive Candidiasis in ICU
Clinical
Risk Factors
Markers
Signs & symptoms
Full blown disease
Treatment
Prophylaxis
Pre-emptive
Empiric
Directed
Possible disease
Proven
Temperature (°C)
41
40
39
38
37
36
Anti Mannan
(1.3)-Beta-D-glucan
Disease
likelihood
Remote
Probable
+
+
Overall Mortality
in Patients with Invasive Candida Infections
100%
85.9%
90%
80%
70%
60%
50%
53.4%
42.6%
40%
35.2%
37.9%
PATH
ECMM
30%
20%
10%
0%
EPIC II
SCOPE (nonICU)
SCOPE (ICU)
Mortality per Candida Species
60%
52.9%
50%
40%
35.6%
38.1%
41.1%
30%
23.7%
20%
10%
0%
C. Krusei
C. albicans
C. glabrata
C. tropicalis
C. parapsilosis
Horn DL, Neofytos D, Anaissie EJ, Fishman JA, Steinbach WJ, Olyaei AJ, et al: Epidemiology and outcomes of candidemia in
2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis 2009,48:1695-1703.
Delaying the Empiric Treatment of Candida Bloodstream
Infection until Positive Blood Culture Results Are Obtained: a
Potential Risk Factor for Hospital Mortality
Morrell M, Fraser VJ, Kollef MH, Antimicrob Agents Chemother 2005; 49:3640–5.
Case Study #1
• 39-year-old black man with DM who was
admitted 8 days ago for complications of endstage liver disease, including acute renal failure
and ascites, he also had diffuse lymphadenopathy
of unknown etiology.
• A week before hospitalization, the patient had
been discharged from another hospital, where he
had been admitted because of pancreatitis and
treated for Escherichia coli bacteremia and renal
insufficiency.
Case Study #1 (cont’d)
• On day 8, 1 out of 4 bottles of blood cultures was reported
positive for yeast.
• Patient’s clinical status had deteriorated because of worsening
respiratory distress.
C. tropicalis
C. Kefyr
C. lusitaniae
C. Krusei
C.
dubliniensis
C.
parapsilosis
C. albicans
C.
guilliermondii
C. glabrata
C. rugosa
What is the likelihood that this yeast would be
candida non-albicans in your unit?
A.
B.
C.
D.
E.
10%
25%
50%
75%
We have no data
Epidemiology: Spain (1994–2008)
13
3%
62
14%
C. albicans
77
18%
C. krusei
C. glabrata
0
0%
211
49%
50
11%
C. kefyr
C. parapsilosis
C. tropicalis
Other Candida spp.
20
5%
M. Ortega et al: J Antimicrob Chemother 2010; 65: 562–568
Epidemiology: IRAN (2005–2010)
29
5%
80
15%
10
2%
44
8%
2
0%
C. albicans
C. krusei
C. glabrata
96
18%
285
52%
C. kefyr
C. parapsilosis
C. tropicalis
Other Candida spp.
Badiee P, Alborzi A: IRAN. J. MICROBIOL. 3 (4) : 183-188
How would you approach the patient?
A.Repeat blood cultures and observe
B.Fluconazole
C.Caspofungin
D.Lipid Formulation Amphotericin B
Candidemia: Who do we treat?
Yeast in the blood is
unlikely to be a
contaminant and
always considered true
fungemia
Poor outcome occur
due to secondary
disease (endcarditis,
endophthalmitis)
All patients with
positive blood cultures
should be trated even
if the infection is
rapidly clearing
Treatment of Invasive Candidiasis in ICU
Clinical
Risk Factors
Markers
Signs & symptoms
Full blown disease
Treatment
Prophylaxis
Pre-emptive
Empiric
Directed
Possible disease
Proven
Temperature (°C)
41
40
39
38
37
36
Anti Mannan
(1.3)-Beta-D-glucan
Disease
likelihood
Remote
Probable
+
+
Selecting Antifungal Agent
The dominant
Candida species
and current
susceptibility data
in a particular
unit
Recent
azole
exposure
History of
intolerance
to an
antifungal
agent
Relevant
comorbidities
Severity of
Illness
Evidence of
involvement
of the CNS,
eye, cardiac
valves.
Recent Exposure to Caspofungin or Fluconazole Influences the
Epidemiology of Candidemia: a Prospective Multicenter
Study Involving 2,441 Patients
8%
13%
3%
14%
10%
C. albicans
C. glabrata
36%
29%
13%
C. parapsilosis
C. tropicalis
18%
56%
13%
c. krusei
21%
31%
35%
Proportion of the five major Candida species responsible for fungemia in patients with (n 159) or without (n 2,289) prior
exposure to fluconazole (P 0.001) or with (n 61) or without (n 2,387) prior exposure to caspofungin (P 0.001):
Olivier Lortholary et al. ANTIMICROBIAL AGENTS AND HEMOTHERAPY, Feb. 2011, p. 532–538
C. Kefyr
C. Tropicalis
C. lusitaniae
C. Krusei
C.
dubliniensis
C.
parapsilosis
C. albicans
C.
guilliermondii
C. glabrata
C. rugosa
Fluconazole Susceptibility
Epidemiology: KFSHRC (2011-2012)
0
0%
0
0%
2
6%
3
8%
C. albicans
10
29%
C. krusei
C. glabrata
18
51%
C. kefyr
C. parapsilosis
C. tropicalis
Other Candida spp.
2
6%
Candida species
Comorbidities and Risk Factors
Candida tropicalis
Neutropenia and bone marrow transplantation
Candida krusei
1. Fluconazole use
2. Neutropenia and bone marrow transplantation
Candida glabrata
1.
2.
3.
4.
5.
6.
Candida parapsilosis
1. Parenteral nutrition and hyperalimentation
2. Vascular catheters
3. Being neonate
Candida lusitaniae and
Candida guilliermondii
Previous polyene use
Candida rugosa
Burns
Fluconazole use
Surgery
Vascular catheters
Cancer
Older age
Diabetes Mellitus
Hachem R et al: The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic
malignancy. Cancer 2008, 112:2493-2499.
Cohen Y et al. Early prediction of Candida glabrata fungemia in nonneutropenic critically ill patients. Crit Care Med 2010, 38:826-830.
Wey SB et al: Risk factors for hospitalacquired candidemia. A matched case–control study. Arch Intern Med 1989, 149:2349-2353.
Candida Endocarditis
Candida endophthelmitis
•LFAmB 3–5 mg/kg with or without 5-FC
25 mg/kg qid;
•or AmB-d 0.6–1 mg/kg daily with or
without 5-FC 25 mg/kg qid; or an
echinocandinb (B-III)
Candida endocarditis
•AmB-d 0.7–1 mg/kg with 5-FC 25
mg/kg qid (A-III)
•or fluconazole 6–12 mg/kg daily (BIII);
CNS Candidiasis
•LFAmB 3–5 mg/kg with or without 5- FC 25
mg/kg qid for several weeks,
•followed by fluconazole 400–800 mg (6–12
mg/kg) daily (B-III)
Candidemia: non-neutropenic
Fluconazole (loading dose of 800 mg [12 mg/kg], then 400 mg [6 mg/kg] daily) or an echinocandin
(caspofungin: loading dose of 70 mg, then 50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose
of 200 mg, then 100 mg daily) is recommended as initial therapy for most adult patients (A-I)
Caspofungin
Fluconazole
Echinocandins
• Mild to moderate illness (A-III)
• No previous exposure to azoles
(A-III)
• No risk of C. glabrata
• C. Parapsilosis infections(B-III).
• No endocardial or CNS
involvement
• Moderately severe to severe
illness (A-III)
• Previous exposure to azoles
• (A-III)
• Allergy or intolerance to azoles or
AmB
• Risks of C. glabrata or C. krusei
(BIII)
2008 IDSA Candidiasis Guidelines
Treatment Guidelines for Candidiasis • CID 2009:48 (1 March) • 505
Case Study #2
• 65 year old patient in the ICU after hemicolectomy
for perforated cecal diverticulitis who was treated
with pip/taz and fluconazole and has been on
ventilator for the past 12 days
• Course was complicated with VAP but sputum
culture showed mixed organisms with candida sp.
Case Study #2 (cont’d)
• Now with fever to 39.0 as well as hypotension (70/40 mm Hg) and
tachycardia (120/,im).
• Physical examination is remarkable for toxic-appearing man who is
orotracheally intubated and sedated.
• He has a triple lumen central venous catheter at the right subclavian vein
site that was inserted 10 days ago for TPN
• The skin is mildly erythematous around the catheter site, but no
tenderness or drainage
Case Study #2 (cont’d)
• Serum creatinine 140
mmol/L, WBC 14,500, 90%
Neutrophils with toxic
granulation
• There is no clinical or
radiographic evidence of
pneumonia, sinusitis or other
source of infection.
• Treated with imipenem and
vancomycin after removing
the line but no improvement
for the past 2 days
How would you approach this case?
A. Repeat cultures and continue same antimicrobial
agents with close observation
B. Add colistin to current antimicrobial agents
C. Add colistin and fluconazole at 400 mg IV daily
D. Add colistin and caspofungin at 70 mg initial dose
then 50 mg daily
Promoting
Colonization
Alteration of Natural
Host Barriers
Organism
Anti Mannan
(1.3)-Beta-D-glucan
Host Factors
Patients at Risk for Invasive Candidiasis
Colonization Index
N◦ sites +/N◦ site screened
2X weekly
> 0.5 or ≥ 0.4 corrected
Candida Score
•
•
•
•
Surgery on ICU admission
TPN
Severe sepsis
Candida colonization
>2.5 points
Predictive Rule
≥ 4th day of ICU stay:
Sepsis+CVC+MV+1 of:
1.
2.
3.
4.
5.
TPN (day 1-3)
HD (day 1-3)
Major surgery (within 7 days)
Pancreatitis (within 7 days)
Immunosuppression or steroids
(within 7 days)
Start Empirical Antifungal Therapy
Patients treated: 10-15%
Candidiasis captured: 85-90%
Patients treated: 15-20%
Candidiasis captured: 75-85%
Patients treated: 10-15%
Candidiasis captured: 60-75%
Performances of (1®3)-b-D-glucan assay (BG), Candida
score (CS), and colonization index for detection of
invasive candidiasis in 95 patients
Posteraro et al. Critical Care 2011, 15:R249
Treatment of Invasive Candidiasis in ICU
Clinical
Risk Factors
Markers
Signs & symptoms
Full blown disease
Treatment
Prophylaxis
Pre-emptive
Empiric
Directed
Possible disease
Proven
Temperature (°C)
41
40
39
38
37
36
Anti Mannan
(1.3)-Beta-D-glucan
Disease
likelihood
Remote
Probable
+
+
Case Study #3
• 29 year old male with no
significant past medical history
who was admitted to the hospital
4 days ago after he suffered
multiple injuries secondary to road
traffic accident:
– Left multiple rib fractures with
pulmonary contusion and
hemothorax, required left
chest tube drainage and
mechanical ventilation
Case Study #3
• Splenic rupture with intraabdominal bleed required
splenectomy
• Intestinal injury that required
resection and anastomosis
• Patient started on TPN
through left sided subclavian
central venous line
Empiric antibiotic with
piperacillin/tazobactam was started on day #1
What would you do next?
Day #4: Patient is has no fever or leukocytosis, how would
you approach his antibiotic regimen:
A. Continue piperacillin/tazobactam for total of 10
days
B. Change to Imipenem/cilastatin
C. Add flucanozole
D. Add Caspofungin
E. Stop antibiotics and observe
3
Treatment of Invasive Candidiasis in ICU
Clinical
Risk Factors
Markers
Signs & symptoms
Full blown disease
Treatment
Prophylaxis
Pre-emptive
Empiric
Directed
Possible disease
Proven
Temperature (°C)
41
40
39
38
37
36
Anti Mannan
(1.3)-Beta-D-glucan
Disease
likelihood
Remote
Probable
+
+
Fluconazole Prophylaxis Prevents Intra-abdominal Candidiasis
in High-risk Surgical Patients
Eggimann P., Crit Care Med 1999, 27:1066-1070
Slide 38
Antifungal agents for preventing fungal infections in non-neutropenic
critically ill and surgical patients: Invasive Infections
E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638
Slide 39
Antifungal agents for preventing fungal infections in nonneutropenic critically ill and surgical patients: Mortality
E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638
Slide 40
Risk-based fluconazole prophylaxis of Candida
bloodstream infection in a medical intensive care unit
Faiz et al: Eur J Clin Microbiol Infect Dis (2009) 28:689–692
Risk-based fluconazole prophylaxis of Candida bloodstream
infection in a medical intensive care unit
Only 2.6%of patients met the rule and were administered prophylaxis,
Episodes per 1000 patient’s days
Incidence-density of
candidemia
4
3.5
3.4
3
2.5
2
1.5
0.79
1
0.5
0
Before
Faiz et al: Eur J Clin Microbiol Infect Dis (2009) 28:689–692
After
Randomized Study of Caspofungin Prophylaxis Followed by Preemptive Therapy for Invasive Candidiasis in the Intensive Care Unit
• Patients were hospitalized for at least 3 days, ventilated,
received antibiotics, had a central venous catheter at any time
in the first 3 days
• +1 of the following:
–
–
–
–
–
Major surgery
Parenteral nutrition or dialysis
Pancreatitis
Systemic steroids
Other immunosuppressive agents within 7 days prior to or on ICU
admission
Subjects were followed daily for IC. (1,3)-b-D-glucan (BG) levels were monitored 2x/week.
The primary endpoint was incidence of proven or probable IC by EORTC/MSG criteria.
MSG-01,www.clinicaltrials.gov, SHEA 2011 Texas (Society for Healthcare Epidemiology of America)
Randomized Study of Caspofungin Prophylaxis Followed by Preemptive Therapy for Invasive Candidiasis in the Intensive Care Unit
Placebo
CAS
P Value
Population n
84
102
Mean (+/-SD) age
55.4 (16.8)
57.7 (17.4)
Male sex (%)
59.5
62.7
Mean (+/-SD) APACHE II
24.9 (8.6)
25.0 (8.1)
Proven and probable IC (%) by Investigator
15.5
5.9
0.03
Proven and probable IC (%) by DRC
16.7
9.8
0.14
Proven IC (%) by DRC
4.8
1.0
0.1
DRC: data review committee
IC: Invasive Candidiasis.
MSG-01,www.clinicaltrials.gov, SHEA 2011 Texas (Society for Healthcare Epidemiology of America)
Case #4
• 67 year old female with history of COPD and CVA.
• Admitted with COPD exacerbation and has been dependent
on the ventilator for the past 2 weeks
• Developed VAP and sputum culture revealed C. albicans,
treated with Imipenem and vancomycin
• Chest x-ray did not improve, BAL was done and confirmed the
growth of c. albicans
How would you approach the patient?
A.Observation
B.Fluconazole
C.Caspofungin
D.Lipid Formulation Amphotericin B
Candida species isolated from
respiratory secretions?
Growth of Candida from respiratory secretions
rarely indicates invasive candidiasis and should
not be treated with antifungal therapy (A-III)
2008 IDSA Candidiasis Guidelines
Treatment Guidelines for Candidiasis • CID 2009:48 (1 March) • 505
Case #5
Your patient with candidemia who has been started
on caspofungin is stable on mechanical ventilation.
He is sedated and MAAS score is 0-1, his WBC is
decreasing and he has low grade fever.
• Your next step is:
A.
B.
C.
D.
Observation
Change to Fluconazole
Ophthalmic examination
Change to Ampho B
Candida Endophthalmitis
• All patients with candidemia should have
at least 1 dilated retinal examination
early in the course of therapy (A-II).
• Especially in patients who cannot
communicate regarding visual
disturbances.
• AmB-d combined with flucytosine (A-III)
• Fluconazole is an acceptable alternative
for less severe cases (BIII).
• LFAmB, voriconazole, or an echinocandin
for intolerant or treatment failure (B-III)
• At least 4–6 weeks (A-III).
Case #6
• 74 year old male who has
been in the intensive care unit
for the past 8 days intubated
on mechanical ventilation for
acute CVA.
• His urinalysis showed 10-15
WBC and urine culture grew C.
albicans
• Foley catheter is in place
How would you approach the patient?
A. Observation
B. Change Foley catheter and observe
C. Fluconazole
D. Caspofungin
E. Amphoterecin B bladder irrigation
Urinary tract infections due to Candida
species?
• Asymptomatic:
– Treatment is not recommended unless the patient
belongs to a group at high risk of dissemination (A-III).
– Elimination of predisposing factors often results in
resolution of candiduria (A-III).
– High-risk patients include neutropenic patients,
infants with low birth weight, and patients who will
undergo urologic manipulations.
• Symptomatic Cystitis/Pyelonephritis
– Fuconazole
– AmB-d
Summary
•
•
•
•
•
Candida in the blood always requires treatment
General risks are breach in skin or GI tract
Early treatment is the goal
Prophylaxis should be considered in patients at very high risk
Selection of antifungal agent depends on:
–
–
–
–
–
–
•
•
Recent azole exposure
History of intolerance to an antifungal agent
The dominant Candida species and current susceptibility data in a particular unit
Severity of Illness
Relevant comorbidities
Evidence of involvement of the CNS, eye, cardiac valves, and/or visceral organs.
Antifungal therapy is not recommended for asymptomatic UTI associated with
Foley catheter
Growth of Candida from respiratory secretions rarely indicates invasive candidiasis
and should not be treated with antifungal therapy
THANK YOU