From Guidelines to Bedside: Clinical Case Scenario Approach
Mazen Kherallah, MD, FCCP
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Tem
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ture
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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
EPIC II PATH ECMM SCOPE (non-ICU) SCOPE (ICU)0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
42.6%35.2% 37.9%
53.4%
85.9%
Overall Mortalityin Patients with Invasive Candida Infections
C. Krusei C. albicans C. glabrata C. tropicalis C. parapsilosis0%
10%
20%
30%
40%
50%
60%52.9%
35.6%38.1%
41.1%
23.7%
Mortality per Candida Species
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 end-stage 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. albicans
C. dubliniensis
C. KruseiC. lusitaniae
C. Kefyr
C. parapsilosis
C. glabrataC.
guilliermondii
C. tropicalis
C. rugosa
What is the likelihood that this yeast would be candida non-albicans in your unit?
A. 10%B. 25%C. 50%D. 75%E. We have no data
Epidemiology: Spain (1994–2008)
21149%
205%
5012%
7718%
6214%
133%
C. albicansC. kruseiC. glabrataC. kefyrC. parapsilosisC. tropicalisOther Candida spp.
M. Ortega et al: J Antimicrob Chemother 2010; 65: 562–568
Epidemiology: IRAN (2005–2010)
28552%96
18%
8015%
448%
295%
102%
20%
C. albicansC. kruseiC. glabrataC. kefyrC. parapsilosisC. tropicalisOther Candida spp.
Badiee P, Alborzi A: IRAN. J. MICROBIOL. 3 (4) : 183-188
How would you approach the patient?
A.Repeat blood cultures and observeB.FluconazoleC.CaspofunginD.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
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41
Tem
pera
ture
(°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
Selecting Antifungal Agent
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.
Recent Exposure to Caspofungin or Fluconazole Influences theEpidemiology of Candidemia: a Prospective Multicenter
Study Involving 2,441 Patients
56%
18%
13%
10%
3%
C. albicansC. glabrataC. parapsilosisC. tropicalisc. krusei
36%
29%
14%
13%
8%
21%
35%
31%
13%
Fluconasole
Caspofungin
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):
C. albicans
C. dubliniensis
C. KruseiC. lusitaniae
C. Kefyr
C. parapsilosis
C. glabrataC.
guilliermondii
C. Tropicalis
C. rugosa
Fluconazole Susceptibility
Epidemiology: KFSHRC (2011-2012)
1851%
26%
1029%
39%
26%
C. albicansC. kruseiC. glabrataC. kefyrC. parapsilosisC. tropicalisOther Candida spp.
Candida species Comorbidities and Risk Factors
Candida tropicalis Neutropenia and bone marrow transplantation
Candida krusei 1. Fluconazole use2. Neutropenia and bone marrow transplantation
Candida glabrata 1. Fluconazole use2. Surgery3. Vascular catheters4. Cancer5. Older age6. Diabetes Mellitus
Candida parapsilosis 1. Parenteral nutrition and hyperalimentation2. Vascular catheters3. 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.
•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
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)
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)
Caspofungin
2008 IDSA Candidiasis GuidelinesTreatment 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 agentsC. Add colistin and fluconazole at 400 mg IV dailyD. Add colistin and caspofungin at 70 mg initial dose
then 50 mg daily
Promoting Colonization
Alteration of Natural Host Barriers Host Factors
(1.3)-Beta-D-glucan
Anti Mannan
Organism
Patients at Risk for Invasive Candidiasis
Colonization Index Candida Score Predictive Rule
N◦ sites +/N◦ site screened2X weekly
> 0.5 or ≥ 0.4 corrected
• Surgery on ICU admission• TPN• Severe sepsis• Candida colonization
>2.5 points
≥ 4th day of ICU stay:Sepsis+CVC+MV+1 of:1. TPN (day 1-3)2. HD (day 1-3)3. Major surgery (within 7 days)4. Pancreatitis (within 7 days)5. 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
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41
Tem
pera
ture
(°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
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 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
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 daysB. Change to Imipenem/cilastatinC. Add flucanozoleD. Add CaspofunginE. Stop antibiotics and observe
3
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39
40
41
Tem
pera
ture
(°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
Fluconazole Prophylaxis Prevents Intra-abdominal Candidiasis in High-risk Surgical Patients
Slide 38Eggimann P., Crit Care Med 1999, 27:1066-1070
Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: Invasive Infections
Slide 39E. 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
Slide 40E. 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
Before After0
0.5
1
1.5
2
2.5
3
3.5
43.4
0.79
Incidence-density ofcandidemia
Epis
odes
per
100
0 pa
tient
’s d
ays
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
Randomized Study of Caspofungin Prophylaxis Followed by Pre-emptive 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
The primary endpoint was incidence of proven or probable IC by EORTC/MSG criteria.
Subjects were followed daily for IC. (1,3)-b-D-glucan (BG) levels were monitored 2x/week.
MSG-01,www.clinicaltrials.gov, SHEA 2011 Texas (Society for Healthcare Epidemiology of America)
Randomized Study of Caspofungin Prophylaxis Followed by Pre-emptive 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 committeeIC: 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.ObservationB.FluconazoleC.CaspofunginD.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 GuidelinesTreatment 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. ObservationB. Change to FluconazoleC. Ophthalmic examinationD. 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. ObservationB. Change Foley catheter and observeC. FluconazoleD. CaspofunginE. 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
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