Idea Transcript
Treatment Strategies for Invasive Candida Infections in ICU M A ZE N KHE R A L L AH, M D, FCCP
Strategies Outline Prophylaxis Pre-emptive Empiric Definitive
Treatment of Invasive Candidiasis in ICU Clinical
Risk Factors
Markers
Signs & symptoms
Full blown disease
Treatment
Prophylaxis
Pre-emptive
Empiric
Directed
Temperature (°C)
41 40 39 38 37 36
Anti Mannan (1.3)-Beta-D-glucan
+ +
(1.3)-Beta-D-glucan Disease likelihood
Remote
Probable
+
Possible disease
(1.3)-Beta-D-glucan
Proven
+
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
What would you do next? Day #6: Patient is afebrile and has no leukocytosis, how would you approach his antibiotic regimen: a. b. c. d.
Continue piperacillin/tazobactam for total of 10 days De-escalate to IV ampicillin/sulbactam Stop all antibiotics and add antifungal Stop antibiotics and observe
Treatment of Invasive Candidiasis in ICU Clinical
Risk Factors
Treatment
Prophylaxis
What Risk factors does this patient have for candida infection?
Temperature (°C)
41
1. 2. 3. 4. 5.
40 39 38 37 36
Disease likelihood
Remote
ICU stay for more than 3 days Central venous line Use of systemic antibiotic Post-operative status TPN
Fluconazole Prophylaxis Prevents Intra-abdominal Candidiasis in High-risk Surgical Patients
Eggimann P., Crit Care Med 1999, 27:1066-1070
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
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
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
Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: Conclusion 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
E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638
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
Episodes per 1000 patient’s days
Only 2.6%of patients met the rule and were administered prophylaxis, Incidence-density of Candidemia 4 3.5
3.4
3 2.5 2 1.5 0.79
1 0.5 0 Before
After
Faiz et al: Eur J Clin Microbiol Infect Dis (2009) 28:689–692
Randomized Study of Caspofungin Prophylaxis Followed by Pre-emptive Therapy for Invasive Candidiasis in the Intensive Care Unit 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:
Ostrosky-Zeichner et al. Clin Infect Dis. 2014 May;58(9):1219-26
• Incidence of proven or probable IC by EORTC/MSG criteria.
Study Endpoints and Outcome
Ostrosky-Zeichner et al. Clin Infect Dis. 2014 May;58(9):1219-26
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
What would you do next? A. Observe B. Repeat serum (1-3)-ß-D-glucan. C. Start flucanazole D. Start caspofungin
Treatment of Invasive Candidiasis in ICU Clinical
Risk Factors
Markers
Treatment
Prophylaxis
Pre-emptive
Risk factors does this patient have for candida infection? 1. Post-operative 2. ICU stay 3. Mechanical ventilation 4. IV antibiotics 5. Central line
Temperature (°C)
41 40 39 38 37 36
+ Anti Mannan (1.3)-Beta-D-glucan
+ +
Positive: (1.3)-Beta-D-glucan and candida colonization
+ Disease likelihood
Remote
Probable
No clinical syndrome
The Colonization Index (CI) & CCI
CI=
CCI= CI X
Number of colonized sites Number of tested sites Number of site with heavy colonization Number of tested sites
Pittet D et al. Ann Surg. 1994 Dec;220(6):751-8
The Colonization Index (CI) & CCI
0.5
0.4
Pittet D et al. Ann Surg. 1994 Dec;220(6):751-8
The Colonization Index
Pittet D et al. Ann Surg. 1994 Dec;220(6):751-8
Structure of Candida: Antigen Detection Enolase -(1,6)-glucan
Mannoproteins
-(1,3)-glucan
Ergosterol
Yeo SF, 15:465-84, 2002, Reiss E, 6:311-323, 1993, Jones JM, 3:32-45, 1990
Glucatell® (1.3)-Beta-D-glucan: Performance Settings
Sensitivity
Specificity
Ostrosky, ICAAC ’03, #M1034a
Invasive fungal infection
70%
87%
Odabasi (Clin Infect Dis,)
283 during chemo for leukemia/MDS
100%
96%
39 pts w/ candidemia
84%
87%
Mitsutake ‘96
(189 with and 170 without IFI)
Panfungal Detection But Not Cryptoccoccus
uses an alpha-glucan
Not Mucormycosis Except Rhizopus oryzae
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.
Randomized Study of Caspofungin Prophylaxis Followed by Pre-emptive Therapy for Invasive Candidiasis in the Intensive Care Unit 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:
Ostrosky-Zeichner et al. Clin Infect Dis. 2014 May;58(9):1219-26
• Incidence of proven or probable IC by EORTC/MSG criteria.
Randomized Study of Caspofungin Prophylaxis Followed by Pre-emptive Therapy for Invasive Candidiasis in the Intensive Care Unit Pre-emptive Analysis 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. Ostrosky-Zeichner et al. Clin Infect Dis. 2014 May;58(9):1219-26
INTENSE NCT NCT01122368 Confirmed Invasive Fungal Infections 12
11.1
10 8.9
8
%
Micafungin 6
Placebo
4
2
0
No meaningful Difference http://www.clinicaltrials.jp/user/display/file/9463-EC-0002%20synopsis.pdf?fileId=983
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!
What would you do? A. Add colistin B. Add tigecycline C. Add fluconazole D. Add caspofungin E. Stop all antibiotics: drug fever
Treatment of Invasive Candidiasis in ICU Clinical
Risk Factors
Markers
Signs & symptoms
Full blown disease
Treatment
Prophylaxis
Pre-emptive
Empiric
Directed
(1.3)-Beta-D-glucan
(1.3)-Beta-D-glucan
Temperature (°C)
41 40 39 38 37 36
Anti Mannan (1.3)-Beta-D-glucan
Disease likelihood
Remote
Probable
+ +
Possible disease
Proven
The Candida Score Calculation of 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
The Candida Score
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. Leon C et al. Crit Care Med. 2006 Mar;34(3):730-7
Rates of invasive candidiasis according to the Candida score
Crit Care Med 2009 Vol. 37, No. 5
MSG-04: A PILOT, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED TRIAL OF CASPOFUNGIN EMPIRICAL THERAPY FOR INVASIVE CANDIDIASIS IN HIGH-RISK PATIENTS IN THE CRITICAL CARE SETTING
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
ClinicalTrials.gov
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.
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
Treatment Strategies of Invasive Candidiasis in ICU Clinical
Risk Factors
Markers
Signs & symptoms
Full blown disease
Treatment
Prophylaxis
Pre-emptive
Empiric
Directed
(1.3)-Beta-D-glucan
(1.3)-Beta-D-glucan
Temperature (°C)
41 40 39 38 37 36
Anti Mannan (1.3)-Beta-D-glucan
Disease likelihood
Remote
Probable
+ +
Possible disease
Proven