from guidelines to bedside: clinical case scenario approach

From Guidelines to Bedside: Clinical Case Scenario Approach

Mazen Kherallah, MD, FCCP

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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.

http://aac.asm.org/content/49/9/3640/F1.large.jpg

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%


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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Anti Mannan +

Treatment

Disease likelihood

Pre-emptive

Probable

Prophylaxis

Remote

Directed

Proven

Empiric

Possible disease


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%


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%



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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Anti Mannan +

Treatment

Disease likelihood

Pre-emptive

Probable

Prophylaxis

Remote

Directed

Proven

Empiric

Possible disease


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

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Anti Mannan +

Treatment

Disease likelihood

Pre-emptive

Probable

Prophylaxis

Remote

Directed

Proven

Empiric

Possible disease


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


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


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

from guidelines to bedside: clinical case scenario approach

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