From Guidelines to Bedside: Clinical Case Scenario Approach Mazen Kherallah, MD, FCCP

Concept of Antifungal Treatments in Critically Ill Patients. Targeted Empirical Preemptive Prophylaxis Likelihood of Disease ProbableRemote Proven Possible Microbiological Evidence Eggimann et al. Annals of Intensive Care 2011, 1:37

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 disease Clinical

Overall Mortality in Patients with Invasive Candida Infections

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:

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. dubliniensisC. Krusei C. lusitaniae C. Kefyr C. parapsilosis C. glabrata C. 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) M. Ortega et al: J Antimicrob Chemother 2010; 65: 562–568

Epidemiology: IRAN (2005–2010) Badiee P, Alborzi A: IRAN. J. MICROBIOL. 3 (4) :

C. albicans C. dubliniensis C. Krusei C. lusitaniae C. KefyrC. parapsilosisC. glabrata C. guilliermondii C. Tropicalis C. rugosa Virulence

How would you approach the patient? A.Repeat blood cultures and observe B.Fluconazole C.Caspofungin D.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

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 disease Clinical

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 the Epidemiology of Candidemia: a Prospective Multicenter Study Involving 2,441 Patients 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. dubliniensisC. Krusei C. lusitaniae C. Kefyr C. parapsilosis C. glabrata C. guilliermondii C. TropicalisC. rugosa Fluconazole Susceptibility

Epidemiology: KFSHRC ( )

Candida speciesComorbidities and Risk Factors Candida tropicalisNeutropenia and bone marrow transplantation Candida krusei1.Fluconazole use 2.Neutropenia and bone marrow transplantation Candida glabrata1.Fluconazole use 2.Surgery 3.Vascular catheters 4.Cancer 5.Older age 6.Diabetes Mellitus Candida parapsilosis1.Parenteral nutrition and hyperalimentation 2.Vascular catheters 3.Being neonate Candida lusitaniae and Candida guilliermondii Previous polyene use Candida rugosaBurns 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: Cohen Y et al. Early prediction of Candida glabrata fungemia in nonneutropenic critically ill patients. Crit Care Med 2010, 38: Wey SB et al: Risk factors for hospitalacquired candidemia. A matched case–control study. Arch Intern Med 1989, 149:

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 Guidelines Treatment 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 agents C.Add colistin and fluconazole at 400 mg IV daily D.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 IndexCandida ScorePredictive Rule N ◦ sites +/N ◦ site screened 2X weekly > 0.5 or ≥ 0.4 corrected Surgery on ICU admission TPN Severe sepsis Candida colonization >2.5 points ≥ 4 th 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

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 disease Clinical

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 days B.Change to Imipenem/cilastatin C.Add flucanozole D.Add Caspofungin E.Stop antibiotics and observe

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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 disease Clinical

Fluconazole Prophylaxis Prevents Intra-abdominal Candidiasis in High-risk Surgical Patients Slide 38 Eggimann P., Crit Care Med 1999, 27:

Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: Invasive Infections Slide 39 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 Slide 40 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 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, 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 PlaceboCASP Value Population n84102 Mean (+/-SD) age55.4 (16.8)57.7 (17.4) Male sex (%) Mean (+/-SD) APACHE II24.9 (8.6)25.0 (8.1) Proven and probable IC (%) by Investigator Proven and probable IC (%) by DRC Proven IC (%) by DRC DRC: data review committee IC: Invasive Candidiasis. MSG-01, SHEA 2011 Texas (Society for Healthcare Epidemiology of America)

Case Study # 4 34 year old male for whom a diagnosis of chronic myelogenous leukemia was made on May 2010 A remission was achieved with chemotherapy and patient underwent a allogenic bone marrow transplantation in August 2010 Engraftment by day 21 post transplantation. 8 days later the patient is febrile and lethargic, physical examination with no sings of infection at the site of the catheter Patient was started on imipenem and vancomycin, blood culture was reported positive for candida parapsilosis

How would you approach the patient? Candida parapsilosis A.Fluconazole B.Caspofungin C.LFAmB D.Observation

C. albicans C. dubliniensis C. Krusei C. lusitaniae C. KefyrC. parapsilosisC. glabrata C. guilliermondii C. Tropicalis C. rugosa Candins Susceptibility

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 Guidelines Treatment Guidelines for Candidiasis CID 2009:48 (1 March) 505

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.Observation B.Fluconazole C.Caspofungin D.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 Guidelines Treatment 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.Observation B.Change to Fluconazole C.Ophthalmic examination D.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 WBC and urine culture grew C. albicans Foley catheter is in place

How would you approach the patient? A. Observation B. Change Foley catheter and observe C. Fluconazole D. Caspofungin E. 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

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