improving outcomes in critically ill patients

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Dr John Thanakumar Chennai Importance of antifungal treatment in the critically ill patients especially surgical patients is stressed. Acknowledge the contribution of Pfizer in the data.

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Improving Outcomes in Critically Ill patients :

Improving Outcomes in Critically Ill patients Early Diagnosis & Prompt Initiation of Antifungal R x Dr JOHN THANAKUMAR MS, MNAMS, FRCS, FRCS, Dip MIS Minimal Access Surgery, Bariatrics and GI www.lapsurge.org Acknowledgement: Some slides provided Pfizer India

Agenda:

Agenda Incidence Albicans vs non albicans Delay is death Identify clinical features Identify risk groups When to start anitfungal tmt What antifungal drugs to choose

47th Annual ICAAC* 2007 :

47th Annual ICAAC* 2007 5,715 patients with presumed septic shock in ICUs of 22 hospitals Candida were determined to be responsible in 7.8% cases (n = 443), Septic shock was more likely fungal than a bacterial with catheter-associated infections, systemic disseminated infections, leukemia and lymphoma, organ transplant, or metastatic cancer. Systemic fungal infections, which often lead to septic shock, are associated with mortality rates much higher than bacterial infections. Onset of hypotension in patients with likely/confirmed infections should be a signal that septic shock was underway and that antimicrobial therapy should be started right away. *Interscience Conference on Antimicrobial Agents and Chemotherapy ‘It would be reasonable to include antifungal medication as part of empiric treatment in patients with septic shock’

‘Physicians should seek ways to reduce the time to diagnosis and treatment of fungal infections’:

‘Physicians should seek ways to reduce the time to diagnosis and treatment of fungal infections’ Poorer overall survival rates for fungal infection (52.4% vs 86.5%, respectively) were due primarily to delayed treatment Patients who received effective therapy within 6 hours of hypotension onset, the in-hospital survival rate exceeded 60%, with no marked difference between types of infection 47th Annual ICAAC* 2007

Importance of Candida infection in ICU:

Importance of Candida infection in ICU Candidemia is the fourth leading cause of nosocomial bloodstream infections after coagulase-negative staphylococci, Staphylococcus aureus , and Enterococcus species Among Candida species, C. albicans remains the most common species causing invasive infection Candidemia is associated with high mortality and morbidity Pfaller MA and Diekema DJ. Clinical Microbiology Reviews 2007.

Changing epidemiology of fungal pathogens:

Changing epidemiology of fungal pathogens Today, non-albicans Candida have become more frequent Abi-Said D, Clin Infect Dis. 1997 Price MF, Antimicrob Agents Chemother. 1994 Candida krusei Candida glabrata Candida tropicalis

Non-albicans candida are increasing in India:

Non-albicans candida are increasing in India Isolation of non-albicans species (%) Matthews MS, Mycoses 2001 Veram AK, Ind J Med Res 2003 Prasad KN, J infect 2004 191 fungal isolates from 1970 blood cultures of postoperative patients on therapy with more than one antibiotic Patients with candidemia (n=21) in 4871 patients with blood stream infections in 2002 28 episodes of fungal peritonitis (1993-2001)

Clinical Indicators of Candidemia:

Clinical Indicators of Candidemia  Persistent fever despite antibiotic therapy  Hypotension  Leukocytosis  Colonization by Candida in wound or surgical drain site  High-grade candiduria (without catheterization)  Candida endophthalmitis  Suppurative phlebitis Anaissie and Solomkin. In: American college of Surgeons: Care of the Surgical Patient. 1994.

Risk factors for Invasive Candidiasis:

Risk factors for Invasive Candidiasis  ≥ 3 antibiotics  Neutropenia  BSAs ≥ 4 d  Immunosuppression  Time ≥ 4 d in ICU  Mechanical ventilation ≥ 48 h  Concomitant infection  Diabetes mellitus  High APACH E II score  Candida colonies at ≥ 2 sites  Abdominal surgery  Candida (> 100,000 colonies/mL)  CVP  Oral candidiasis  TPN Edwards. In: Principles and Practice of Infectious Diseases . 1990; Dean et al. World J Surg. 1998;22:127-134; Fass et al. J Antimicrob Chemother .1996;38:915-916; Cornwell et al. Am Surg. 1995;61:847-850. BSA = broad-spectrum antibiotics; ICU = intensive care unit; APACHE = Acute Physiology and Chronic Health Evaluation.

Challenges of Diagnosing Opportunistic Infections at the Bedside:

Challenges of Diagnosing Opportunistic Infections at the Bedside 8

Challenges of treatment:

Challenges of treatment When to start Rx? Consider fungal disease early and treat aggressively when on broad-spectrum antibiotics Diagnosis is often presumptive Wingard JR, Biology of Blood and Marrow Transplantation 2004 Rex JH. Managing fungal infections in the new millennium. http://medscape.com. Accessed on 22-11-04

Risk Assessment Tool:

Risk Assessment Tool Facilitate diagnosis and Initiation of appropriate Treatment for SFI

S.T.A.R:

S.T.A.R Pittet D, Anaissie E, Solomkin JS. When to start antifungal therapy in the non-neutropenic critically ill? In: Year Book of Intensive Care and Emergency Medicine. De. JL Vincent. Springer. Berlin.1996;567-77 JL Vincent, E Anaissie, H Bruining et al. Epidemiology, diagnosis and treatment of systemic Candida infection in surgical patients under intensive care. Intens Care Med 1998;24:206-216 Identify patients at risk Underlying disease (Major) Others (Minor) Identify patients with suspected SFI 2 Major + 2 Minor or 1 Major + 3 Minor

Risk factors for Invasive Candidiasis:

Risk factors for Invasive Candidiasis  ≥ 3 antibiotics  Neutropenia  BSAs ≥ 4 d  Immunosuppression (due to cancer/chemotherapy, steroids, other therapies  Time ≥ 4 d in ICU  Mechanical ventilation ≥ 48 h  Concomitant infection  Diabetes mellitus  High APACH E II score  Candida colonization of ≥ 2 sites  Abdominal surgery  Candida (> 100,000 colonies/mL)  Central venous catheterization  Oral candidiasis  Total parenteral nutrition (TPN) If one or no risk factor ACTION: consider alternative etiology If 2 MAJOR + 2 MINOR OR 1 MAJOR + 3 MINOR ACTION: Monitor patient closely

Identifying patients with suspected fungal infection:

Identifying patients with suspected fungal infection Pittet D, Anaissie E, Solomkin JS. When to start antifungal therapy in the non-neutropenic critically ill? In: Year Book of Intensive Care and Emergency Medicine. De. JL Vincent. Springer. Berlin.1996;567-77 If one of the above present ACTION: Consider addition of antifungal and aggressive microbiological workup

Use of STAR in hypothetical patient:

Use of STAR in hypothetical patient Unexplained fever in a ventilated ICU patient who had undergone major abdominal surgery Receiving broad spectrum antibiotics, and is receiving TPN through a central line. He has a Foley’s catheter and has been in the ICU for 10 days

Slide 17:

1 MAJOR criteria - Major abdominal surgery + 6 MINOR criteria: 1 –Prolonged ICU stay (>7 days) + (2-5) on image + 6 – Foley’s catheter (not shown) 2 3 4 5

How to use STAR:

How to use STAR This patient has 1 Major and 6 Minor Risk factors – High Risk Fever not responding to broad spectrum antibiotics in this patient at high risk of SFI should prompt the clinician to perform an aggressive microbiology workup for fungal pathogens Starting empirical antifungal therapy awaiting the results is appropriate in such patients.

Selection of anti-fungals :

Selection of anti-fungals Pappas PG, et al. Infectious Diseases Society of America. Clin Infect Dis . 2004;38:161-189.

Antifungal drugs:

Antifungal drugs Polyene antifungals - eg Nystatin, Amphotericin Imidazole - eg Miconazole, Ketoconazole Triazole - eg Fluconazole Echinocandin - eg Micafungin, Caspofungin, Anidulafungin

Echinocandin-Micafungin,Caspofungin, Anidulafungin:

Echinocandin - Micafungin,Caspofungin, Anidulafungin Echinocandins have become one of the first line tmt Advantages: Broad range,Neutropenic pts, Azole resistant pts, long half life, low toxcity, better than fluconazole in yeast infections Disadvantages: Not in pregnancy, Dose adjustments required except Anidulafungin(Eraxis)

Slide 22:

IDSA 2009 Guidelines Pappas et al. CID 2009 Dosing guidelines Echinocandin dosing in adults: anidulafungin, 200 mg loading dose, then 100 mg/day ; caspofungin, 70 mg loading dose, then 50 mg/day; and micafungin, 100 mg/day

Anidulafungin undergoes spontaneous chemical degradation at physiologic conditions:

Anidulafungin undergoes spontaneous chemical degradation at physiologic conditions Anidulafungin is the only echinocandin not hepatically metabolized or renally excreted Because anidulafungin elimination is not dependent on hepatic/renal function There are no known drug interactions of clinical significance There are no required dose adjustments Inactive peptide converted to peptidic degradants and eliminated in feces Chain breaks Active molecule

Slide 24:

Control Anidulafungin Fluconazole Effect on Bio-Films Ghannoum et al. 2008, Data on File

In clinical studies mortality rates with fluconazole -33-39%:

In clinical studies mortality rates with fluconazole -33-39% Rex et al, 1994 Fluconazole 400 mg/day n=103 33% 40% Ampho B alone n=103 Phillips et al, 1997 Ampho B alone n=53 Rex et al, 2003 Fluconazole 800 mg/day n=107 39% 40% Fluconazole plus ampho B n=112 Rex JH et al. N Engl J Med . 1994;331:1325-1330. Phillips P et al. Eur J Clin Microbiol Infect Dis . 1997;16:337-345. Rex JH et al. Clin Infect Dis . 2003;36:1221-1228. Mora Duarte, et al. N Engl J Med, 2002Vol. 347, No. 25 Mortality (% patients) Deaths through end of follow-up (EOT + ~60 days) Day 60 mortality Deaths within 90 days of starting study therapy 100 80 40 20 0 60 Caspofungin Ampho Tericin B 34% 30% Mora Duarte,et al. 2002 Fluconazole 400 mg/day n=50 38% 34% 23% 31% Anidulafungin (n=127) Fluconazole (n=118) Reboli et al, 2007 Reboli AC et al. N Engl J Med . 2007;356:2472-2482.

Risk Assessment Tool:

Risk Assessment Tool Delaying appropriate initial antifungal therapy Dangers of unnecessary antifungal use STAR POOR OUTCOMES

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