This lecture discusses principles of selecting antifungal agents in the intensive care unit in the treatment of suspected candidasis or confirmed fungemia.

1. SelectingAntifungalAgentforYourCriticallyIllPatientwith
CandidemiaorSuspectedInvasiveCandidiasis

2. Case Study #1
 49-year-old black man with DM and status post liver transplantation on
immunosuppressive agents who was admitted 16 days ago for drug-induced
acute pancreatitis which was complicated with acute renal failure and
pseudocyst. He also had diffuse lymphadenopathy of unknown etiology.
 A week ago patient was treated for Escherichia coli bacteremia with IV
piperacillin/tazobactam. Central line is in place.

3. Case Study #1 (cont’d)
 On day 17, 1 out of 4 bottles of blood cultures was reported positive for yeast.
 Patient’s clinical status had deteriorated because of worsening respiratory
distress and hypotension.

4. Other than source control,
how would you approach the
patient?
 Repeat blood cultures and observe
 Fluconazole
 Anidulafungin
 Caspofungin
 Lipid Formulation Amphotericin B

5. 36
37
38
39
40
41
Temperature(°C)
Treatment of Invasive Candidiasis in
ICU
(1.3)-Beta-D-glucan +
Anti Mannan +
Treatmen
t
Disease
likelihood
Pre-emptive
Probable
Prophylaxis
Remote
Directed
Proven
Empiric
Possible disease
Risk Factors Markers Signs & symptoms Full blown diseaseClinical
(1.3)-Beta-D-glucan + (1.3)-Beta-D-glucan +

6. Candidemia: Whom 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 treated
even if the infection is
rapidly clearing

7. Selecting Antifungal Agent
Recent azole
exposure
Severity of
Illness
The dominant
Candida
species and
current
susceptibility
data in your
unit
Relevant
comorbidities
Evidence of
involvement
of the CNS,
eye, cardiac
valves.
Renal or Liver
Failure,
Intolerance
Or Drug-drug
Interaction

8. Recent Exposure to Caspofungin or
Fluconazole Influences the Epidemiology of
Candidemia: a Prospective Multicenter Study
Involving 2,441 Patients
56%
18%
13%
10%
3%
C. albicans
C. glabrata
C. parapsilosis
C. tropicalis
c. krusei
36%
29%
14%
13%
8%
21%
35%
31%
13%
Olivier Lortholary et al. ANTIMICROBIAL AGENTS AND HEMOTHERAPY, Feb. 2011, p. 532–538
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):

9. Selecting Antifungal Agent
Recent azole
exposure
Severity of
Illness
The dominant
Candida
species and
current
susceptibility
data in your
unit
Relevant
comorbidities
Evidence of
involvement
of the CNS,
eye, cardiac
valves.
Renal or Liver
Failure,
Intolerance
Or Drug-drug
Interaction

10. High APACHE II Score, Hemodynamic Instability or Severe Sepsis

11. Selecting Antifungal Agent
Recent azole
exposure
Severity of
Illness
The dominant
Candida
species and
current
susceptibility
data in your
unit
Relevant
comorbidities
Evidence of
involvement
of the CNS,
eye, cardiac
valves.
Renal or Liver
Failure,
Intolerance
Or Drug-drug
Interaction

12. C. albicans
C. dubliniensis
C. Krusei
C. lusitaniae
C. Kefyr
C. parapsilosis
C. glabrata C.
guilliermondii
C. tropicalis
C. rugosa

13. C. albicans
C. dubliniensis
C. Krusei
C. lusitaniae
C. Kefyr
C. parapsilosis
C. glabrata C.
guilliermondii
C. Tropicalis
C. rugosa
Fluconazole Susceptibility

14. What is the likelihood that this yeast
would be candida non-albicans in
your unit?
 10%
 25%
 50%
 75%
 We have no data

15. Epidemiology: KFSHRC (2011-
2012)
51%
6%
29%
0%
8%
0% 6%
C. albicans
C. krusei
C. glabrata
C. kefyr
C. parapsilosis
C. tropicalis
Other Candida spp.
>15% Rate of C. glabrata and C. krusei

16. Selecting Antifungal Agent
Recent azole
exposure
Severity of
Illness
The dominant
Candida
species and
current
susceptibility
data in your
unit
Relevant
comorbidities
Evidence of
involvement
of the CNS,
eye, cardiac
valves.
Renal or Liver
Failure,
Intolerance
Or Drug-drug
Interaction

17. 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. Fluconazole use
2. Surgery (mainly abdomen)
3. Vascular catheters
4. Cancer
5. Older age
6. Diabetes Mellitus
Candida parapsilosis 1. Parenteral nutrition and hyperalimentation
2. Vascular catheters
3. Being neonate
Candida lusitaniae and
Candida guilliermondii
Previous polyene use
Candida rugosa Burns
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.

18. Selecting Antifungal Agent
Recent azole
exposure
Severity of
Illness
The dominant
Candida
species and
current
susceptibility
data in your
unit
Relevant
comorbidities
Evidence of
involvement
of the CNS,
eye, cardiac
valves.
Renal or Liver
Failure,
Intolerance
Or Drug-drug
Interaction

19. •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 (B-
III);
Candida endophthelmitis
Candida endocarditis
•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)
CNS Candidiasis

20. Selecting Antifungal Agent
Recent azole
exposure
Severity of
Illness
The dominant
Candida
species and
current
susceptibility
data in your
unit
Relevant
comorbidities
Evidence of
involvement
of the CNS,
eye, cardiac
valves.
Renal or Liver
Failure,
Intolerance
Or Drug-drug
Interaction

21. Anidulafungin has least complex metabolism
and interaction profile of the available
echinocandins
Caspofungin Micafungin Anidulafungin
Hepatic metabolism?
Yes
(N-acetylation)
Yes
(Arylsulfatase and catechol-O-
methyltransferase; some
CYP3A hydroxylation)
No
CYP3A4 inhibitor? No Weak No
Drug
Interactions?
Cyclosporine; Tacrolimus
Rifampin; Efavirenz; Nevirapine;
Phenytoin; Dexamethasone;
Carbamazepine
Sirolimus
Nifedipine
No known interactions
Dose
adjustments?
Yes
 Moderate to severe hepatic
insufficiency
and/or
 With CYP inducers
No No
Cancidas [Summary of Product Characteristics]. Hoddesdon, Hertfordshire, UK: Merck Sharp & Dohme Limited; 2007.
Mycamine for Injection [package insert]. Tokyo, Japan: Astellas Pharma, Inc; 2006.
Ecalta [Summary of Product Characteristics]. Sandwich, Kent; UK: Pfizer Limited; June 2007. DRAFT.
Comparisons do not imply interchangeability or comparable efficacy and safety.
See prescribing information of respective agents for complete information.

22. Anidulafungin clearance unchanged
in impaired hepatic or renal function
*Anidulafungin is not dialyzable and may be administered without regard to timing of hemodialysis.
Vazquez JA. Clin Ther. 2005;27:657-673.
0 20 100 120 140 16040 60 80
0
0.5
1.0
1.5
2.0
2.5
3.0
Control (n=8)
Mild (n=6)
Moderate (n=6)
Severe (n=6)
Anidulafungin
concentration(g/mL)
0 20 100 120 140 16040 60 80
0
0.5
1.0
1.5
2.0
2.5
3.0
Control (n=8)
Mild (n=6)
Moderate (n=6)
Severe (n=6)
Time after study drug administration (h) Time after study drug administration (h)
Hepatic Impairment Renal Impairment*

23. Anidulafungin has no known
interaction with cyclosporine
0
2
4
6
8
10
12
0 6 12 18 24
Time (hours)
Plasmaanidulafunginconcentration(mg/L)
Anidulafungin has no known
interaction with cyclosporine
0
2
4
6
8
10
12
0 6 12 18 24
Anidulafungin alone (day 4)
Anidulafungin with cyclosporine (day 8)
Dowell JA et al. J Clin Pharmacol. 2005;45:227-233.

24. Anidulafungin has no known
interaction with tacrolimusMeantacrolimuswholebloodconcentration(ng/mL)
Time (hours)
0 8 16 24
0
10
20
30
40
Dowell JA et al. J Clin Pharmacol. 2007;47:305-314.
Tacrolimus alone (day 1)
Tacrolimus with anidulafungin (day 13)

25. Safety of Anidulafungin in
Solid Organ Transplant
Recipients.
 86 SOT recipientsfrom 14 centers who received anidulafungin for at least 48 hours for the treatmentof
invasive fungal infections (IFIs) or as prophylaxis. All patientswere followedfor at least 1 week after the
end of treatment(EOT)or until death. well-tolerateddrug in SOT recipients.
Aguado JM et al; TOSCANA Study Group. Liver Transpl. 2012 Jun;18(6):680-5.
There was no need for
the modification of
immunosuppressive
drug doses
No discontinuation of
anidulafungin because
of severe side effects
1 patient developed
mild liver toxicity, that
normalized without the
discontinuation of
anidulafungin.

26. Anidulafungin vs Amphotericin B Safety in
High Risk Hepatic Transplant Recipients
(AVALTRA)

27. Candidemia: non-neutropenic
Fluconazole (loading doseof 800 mg [12 mg/kg], then 400 mg [6 mg/kg] daily) or
an echinocandin (Anidulafungin: loading doseof 70 mg, then 50 mg daily;
micafungin: 100 mg daily; anidulafungin: loading doseof 200 mg, then 100 mg
daily) is recommended as initial therapy for mostadult patients (A-I)
Fluconazole
• 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
Echinocandins
• 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)
Anidulafungin
2008 IDSA Candidiasis Guidelines
Treatment Guidelines for Candidiasis • CID 2009:48 (1 March) • 505

28. Other than source control,
how would you approach the
patient?
 Repeat blood cultures and observe
 Fluconazole
 Anidulafungin
 Caspofungin
 Lipid Formulation Amphotericin B

29. Thankyou