Discuss the different anti-fungal treatment strategies for suspected systemic candidiasis in the intensive care units: prophylaxis, preemptive, empiric and definitive.

1. Treatment Strategies for Invasive
Candida Infections in ICU

2. Strategies Outline
Prophylaxis
Pre-emptive
Empiric
Definitive

3. 36
37
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39
40
41
Temperature(°C)
Treatment of Invasive Candidiasis in ICU
(1.3)-Beta-D-glucan +
Anti Mannan +
Treatment
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 +

4. Case 1
29 year old male with no significant past medical history who was
admitted to the hospital 6 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
◦ Splenic rupture with intra-abdominal 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
◦ All cultures are negative

5. What would you do next?
Day #6: Patient is afebrile and has no leukocytosis, how would you
approach his antibiotic regimen:
a. Continue piperacillin/tazobactam for total of 10 days
b. De-escalate to IV ampicillin/sulbactam
c. Stop all antibiotics and add antifungal
d. Stop antibiotics and observe

6. 36
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39
40
41
Temperature(°C)
Treatment of Invasive Candidiasis in ICU
Treatment
Disease
likelihood
Prophylaxis
Remote
What Risk factors does this patient have for
candida infection?
1. ICU stay for more than 3 days
2. Central venous line
3. Use of systemic antibiotic
4. Post-operative status
5. TPN
Risk FactorsClinical

7. Fluconazole Prophylaxis Prevents Intra-abdominal
Candidiasis in High-risk Surgical Patients
Eggimann P., Crit Care Med 1999, 27:1066-1070

8. 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

9. Antifungal agents for preventing fungal infections in
non-neutropenic critically ill and surgical patients:
Mortality
E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638

10. Antifungal agents for preventing fungal infections in
non-neutropenic critically ill and surgical patients:
Fungal colonization with C. glabrata or C. krusei
E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638

11. Antifungal agents for preventing fungal infections in
non-neutropenic critically ill and surgical patients:
Conclusion
E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638
Prophylaxis with fluconazole or ketoconazole in critically ill patients reduces
invasive fungal infections by one half and total mortality by one quarter.
No significant increase in azole-resistant Candida species associated with
prophylaxis
In patients at increased risk of invasive fungal infections, antifungal prophylaxis
with fluconazole should be considered

12. 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

13. Risk-based fluconazole prophylaxis of Candida bloodstream
infection in a medical intensive care unit
3.4
0.79
0
0.5
1
1.5
2
2.5
3
3.5
4
Before After
Episodesper1000patient’sdays Incidence-density of
Candidemia
Only 2.6%of patients met the rule and were administered prophylaxis,
Faiz et al: Eur J Clin Microbiol Infect Dis (2009) 28:689–692

14. Randomized Study of Caspofungin Prophylaxis Followed by Pre-emptive
Therapy for Invasive Candidiasis in the Intensive Care Unit
Ostrosky-Zeichner et al. Clin Infect Dis. 2014 May;58(9):1219-26
ICU Patients
• Hospitalized for at least 3 days
• Ventilated
• Received antibiotics
• Central venous catheter at any time in the first 3 days
At least one
of the
following:
• Parenteral nutrition
• HD
• Pancreatitis
• Systemic Steroids
• Other immunosuppressive agents within 7 days
prior to or on ICU admission
• Major Surgery
Daily F/U for
IC
• Daily for IC
• (1,3)-b-D-glucan (BG) levels were
monitored 2x/week.
Primary
Endpoint:
• Incidence of proven or
probable IC by
EORTC/MSG criteria.

15. Study Endpoints and Outcome
Ostrosky-Zeichner et al. Clin Infect Dis. 2014 May;58(9):1219-26

16. Case 2
48 years old female with past medical history of hypertension and diabetes mellitus
Developed acute cholecystitis and underwent laporascopic cholecystectomy
Hospital course was complicated with atelectasis and HAP required intubation.
Treated with IV piperacillin/tazobactam
Central venous catheter in place
Sputum culture revealed C. albicans
Day #7:
◦ Developed diarrhea and stool c-diff was negative
◦ Fever resolved and no leukocytosis
◦ Stool culture revealed c. albicans
◦ Positive serum (1-3)-ß-D-glucan

17. What would you do next?
A. Observe
B. Repeat serum (1-3)-ß-D-glucan.
C. Start flucanazole
D. Start caspofungin

18. 36
37
38
39
40
41
Temperature(°C)
Treatment of Invasive Candidiasis in ICU
(1.3)-Beta-D-glucan +
Anti Mannan +
Treatment
Disease
likelihood
Pre-emptive
Probable
Prophylaxis
Remote
Risk Factors MarkersClinical Risk factors does this patient have for candida
infection?
1. Post-operative
2. ICU stay
3. Mechanical ventilation
4. IV antibiotics
5. Central line
+
Positive: (1.3)-Beta-D-glucan
and candida colonization
+
No clinical syndrome

19. The Colonization Index (CI) & CCI
Number of colonized sites
Number of tested sites
CI=
Number of site with heavy colonization
Number of tested sites
CCI= CI X
Pittet D et al. Ann Surg. 1994 Dec;220(6):751-8

20. The Colonization Index (CI) & CCI
Pittet D et al. Ann Surg. 1994 Dec;220(6):751-8
0.5
0.4

21. The Colonization Index
Pittet D et al. Ann Surg. 1994 Dec;220(6):751-8

22. Structure of Candida: Antigen Detection
Ergosterol
-(1,6)-glucan
-(1,3)-glucan
Mannoproteins
Enolase
Yeo SF, 15:465-84, 2002, Reiss E, 6:311-323, 1993, Jones JM, 3:32-45, 1990

23. Glucatell® (1.3)-Beta-D-glucan:
Performance
Settings Sensitivity Specificity
Ostrosky, ICAAC ’03,
#M1034a
Invasive fungal infection
(189 with and 170 without IFI)
70% 87%
Odabasi (Clin Infect
Dis,)
283 during chemo for
leukemia/MDS
100% 96%
Mitsutake ‘96
39 pts w/ candidemia 84% 87%

24. But Not Cryptoccoccus
uses an alpha-glucan
Not
Mucormycosis
Except Rhizopus
oryzae
Panfungal Detection

25. Assessment of preemptive treatment to
prevent severe candidiasis in critically ill surgical
patients.
Piarroux R, Grenouillet F, Balvay P, et al Crit Care Med 2004; 32:2443–2449.

26. Randomized Study of Caspofungin Prophylaxis Followed by Pre-emptive Therapy for
Invasive Candidiasis in the Intensive Care Unit
Ostrosky-Zeichner et al. Clin Infect Dis. 2014 May;58(9):1219-26
ICU Patients
• Hospitalized for at least 3 days
• Ventilated
• Received antibiotics
• Central venous catheter at any time in the first 3 days
At least one
of the
following:
• Parenteral nutrition
• HD
• Pancreatitis
• Systemic Steroids
• Other immunosuppressive agents within 7 days
prior to or on ICU admission
• Major Surgery
Daily F/U for
IC
• Daily for IC
• (1,3)-b-D-glucan (BG) levels were
monitored 2x/week.
Primary
Endpoint:
• Incidence of proven or
probable IC by
EORTC/MSG criteria.

27. Randomized Study of Caspofungin Prophylaxis Followed by Pre-emptive Therapy for
Invasive Candidiasis in the Intensive Care Unit
Placebo CAS P Value
Population n 102 117
Mean (+/-SD) age 56.7 (16.6) 58.2 (17.6)
Male sex (%) 59.8 60.7
Mean (+/-SD) APACHE II 25.1 (8.7) 25.3 (8.0)
Proven and probable IC (%) by Investigator 25.5 13.7 0.02
Proven and probable IC (%) by DRC 30.4 18.8 0.04
Proven IC (%) by DRC 6.9 0.9 0.02
DRC: data review committee
IC: Invasive Candidiasis.
Pre-emptive Analysis
Ostrosky-Zeichner et al. Clin Infect Dis. 2014 May;58(9):1219-26

28. INTENSE NCT NCT01122368
8.9
11.1
0
2
4
6
8
10
12
%
Confirmed Invasive Fungal Infections
Micafungin
Placebo
http://www.clinicaltrials.jp/user/display/file/9463-EC-0002%20synopsis.pdf?fileId=983
No meaningful Difference

29. Case 3
65 year old male with PMH of CVA, HTN, AF, and diabetes, was admitted to the
hospital for right hip fracture repair.
Admitted post-operatively to ICU and developed atelectasis and pulmonary
embolism. He was intubated and placed on mechanical ventilation
Course was complicated with VAP and treated with pip/taz. He then has
ischemic colitis and s/p hemicolectomy
17 days in the ICU, he developed fever and leukocytosis and hypotension,
suspected to be secondary to line infection
Fever persisted for 3 days post IV imipenem/vancomycin and removal of the line
All cultures are negative!

30. What would you do?
A. Add colistin
B. Add tigecycline
C. Add fluconazole
D. Add caspofungin
E. Stop all antibiotics: drug fever

31. 36
37
38
39
40
41
Temperature(°C)
Treatment of Invasive Candidiasis in ICU
(1.3)-Beta-D-glucan +
Anti Mannan +
Treatment
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

32. The Candida Score
Coefficient (β) Rounded
Multifocal Candida species
colonization
1.112 1
Surgery on ICU admission 0.997 1
Severe sepsis 2.038 2
Total parenteral nutrition 0.908 1
Leon C et al. Crit Care Med. 2006 Mar;34(3):730-7
Calculation of the Candida score:

33. The Candida Score
Leon C et al. Crit Care Med. 2006 Mar;34(3):730-7
With a cut-off value of 2.5: sensitivity of 81% and a specificity of 74%, we shall
only need the presence of sepsis and any one of the three other remaining risk
factors or the presence of all of them together except sepsis in order to consider
starting antifungal treatment for one particular patient.

34. Rates of invasive candidiasis according
to the Candida score
Crit Care Med 2009 Vol. 37, No. 5

35. MSG-04: A PILOT, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLEDTRIALOF CASPOFUNGINEMPIRICALTHERAPY FOR INVASIVE
CANDIDIASISIN HIGH-RISKPATIENTSIN THECRITICALCARESETTING
Sepsis on Days 1-3 with
The patient fulfills at least 1 of
the following 5 criteria
• Mechanical ventilation +
• Central venous catheter +
• Received broad spectrum antibiotics
• Parenteral nutrition
• Renal dialysis
• Major surgery
• Pancreatitis
• Systemic steroids or the use of other immunosuppressive
agents

36. ClinicalTrials.gov

37. Case 4
A 58-year-old woman is admitted with fever, pain, and a peridiverticular abscess on CT scan. She
is started on piperacillin/tazobactam and pain medication, and a percutaneous drainage
catheter is inserted. By day 2 she is afebrile and nearly pain-free.
On day 4, a temperature of 38.2°C develops and her white blood cell count is 16,000 cells/mm3.
One out of 4 blood culture bottles results reveals Candida and germ-tube testing is negative.

38. Other than source control, how would you
approach the patient?
A. Repeat blood cultures and observe
B. Fluconazole
C. Caspofungin
D. Lipid Formulation Amphotericin B

39. 36
37
38
39
40
41
Temperature(°C)
Treatment Strategies of Invasive Candidiasis
in ICU
(1.3)-Beta-D-glucan +
Anti Mannan +
Treatment
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