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The Evolution of Fungal Infections in the Surgical Patient Bradley J. Phillips, MD Burn-Trauma-ICU Adults & Pediatrics.

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Presentation on theme: "The Evolution of Fungal Infections in the Surgical Patient Bradley J. Phillips, MD Burn-Trauma-ICU Adults & Pediatrics."— Presentation transcript:

1 The Evolution of Fungal Infections in the Surgical Patient Bradley J. Phillips, MD Burn-Trauma-ICU Adults & Pediatrics

2 PROHIBITED Kaplan-Meier curves Too many n = ___, p values Multivariate analysis finger pointing

3 Overview What is it? Where did it come from? Is it bad? (aka will it keep me up at night?) How do I fix it? Anything else?

4 Fungal Infection What is it?

5 The players Candida Aspergillus Cryptococcus Histoplasma Coccidioides Blastomyces

6 Candida Subtypes C. albicans C. tropicalis C. parapsilosis C. kruzei Torulopsis glabrata

7 Candida in general Two forms: yeast and mycelial (dimorphism) Yeast- colonizes humans Asexual reproduction (budding) into blastospores, which elongate and stick together: pseudohyphae Most dimorphic fungi, the yeast is invasive- not so with Candida: reverse dimorphism

8 Candida albicans Commensal organism- lives normally in GI, GU tracts and skin 25% outpatients colonized with C. albicans 50-80% of hospitalized patients colonized Eukaryotic cell Cell membrane sterol: ergosterol synthesized from lanosterol

9 Candida tropicalis Second most common Candida isolate of inpatients Not too virulent unless hematopoetic malignancy or uncontrolled diabetes Associated with embolic skin lesions Mortality rate 70% +

10 Candida parapsilosis Third most common isolate Associated with central lines and TPN Also associated with solid tumor and HIV Less virulent than other Candida, better prognosis Rare/ no evidence of dissemination to fungemia; has been found w/ HIV endocarditis

11 Candida kruzei Fourth most common (1-3%), although gaining in ICU popularity Hits neutropenic patients + hematopoetic malignancy No more virulent than C. albicans Resistant to fluconazole

12 Torulopsis glabrata Not a true Candida- only exists in the yeast form (not dimorphic) Colonizes GI, GU tracts, rarely skin Less virulent than C. albicans, similar to C. parapsilosis Solid tumor, uncontrolled diabetics Renal infection in diabetics Mortality 50-70%; somewhat azole resistant

13 Fungal Infection Where did it come from?

14 The patient

15 Where did it come from? The patient Thirty years ago, yeast was a contaminant or a nuisance Increasing ICU stays, increasing risk factors

16 Risk factors for fungal infection APACHE score >10 Ventilator for >48 hr broad spectrum antibiotics Indwelling catheters Malnutrition Prolonged hypotension Immunosuppression: chemotherapy, transplants HIV Cancer survivors Diabetics Burns TPN

17 Broad spectrum antibiotics Increasing frequency over past two decades Indigenous intestinal bacterial flora suppress Candida growth, and adherence Antibiotics with anaerobic activity or high intestinal concentrations cause a higher and more sustained increase in Candida colonization as detected by stool culture Stone, Candida translocation

18 Central venous access Overgrowth of Candida in the GI and GU tracts correspond to increased skin colonization rates The skin is the source for fungus, while the catheter is the wick C. parapsilosis has been found in the plastic of central lines and IV tubing- manufacturing contamination

19 Parenteral Nutrition (TPN) Additive risk to the central line TPN reduces compliment fixation, depresses macrophage function, and inactivates immunoglobulins Atrophy of gut mucosa- ?low glutamine? TPN increases risk of and rates of fungal intestinal translocation TPN may be contaminated, esp. w/ C. parapsilosis and C. tropicalis

20 Immunosuppression Surgery Trauma Burns Malignancy Bacterial sepsis hypoperfusion Corticosteroids Chemotherapy Diabetes Post-transplant medications Congenital (SCID, etc.)

21 Antifungal Immunology Cellular immunity>>humoral immunity T-cells: superficial immunity, prevention of colonization PMN/ Macrophage: phagocytosis Complement, circulating immunoglobulins and arachadonic acid derivatives play a minor role against fungi

22 Burns Loss of skin (mechanical barrier) Gut atrophy correlates with percent burn Ileus- no enteral feeds Depression of CD3 and CD4 cell count Indwelling catheters TPN Decreased PMN phagocytosis- burnspecific polypeptide Use of antibiotics Decreased IL2 production

23 Is it bad?/ Will it keep me up? Yes, fungemia is bad for the patient Mortality rates: 70% (Bone marrow failure, Richardson 1998) 32% (Liver transplant, Rabkin 2000) 20% (Candidemia, Rex, 1994) 57% (Postop surgery, Eubanks, 1993) 70% (ICU, Watts, 1999)

24 Morbidity of Fungal infection Candiduria Abdominal abscess Endocarditis Endophthalmitis Myocarditis Skin lesions Esophagitis Pharyngitis Pneumonia Peritonitis Suppurative thrombophlebitis Meningitis

25 SICU length of stay Patients ICULOS HospLOS Total No broad 40% 3 17 Spec Abx Br.Sp.Abx 60% “High risk” 17% 20 39

26 Fungal Infection How do I fix it?

27 Diagnose (find it) Treat (kill it) Prevention (keep it away)

28 Diagnosis Not so easy to do Colonization vs. infection/disseminated disease Can’t find Candida if you don’t look

29 Lab tests Yeast + pseudohyphae on histology: definitive for infection Easy to get if tissue is resected or excised Most diagnoses of infection rely on inferential evidence

30 Lab tests Culture results (peritoneal, urine, drain fluid, eschar, ulcer bed) positive- Colonization? Infection?- must place test result in context of patient setting Blood cx notoriously unreliable- Candida is difficult to grow, concomitant bacterial infection decreases Candida yield 50% of patients with invasive Candidiasis have positive blood cultures

31 Improving Lab Results Arterial blood culture (Bayard, 1989) Serology: mannan, beta-1-3-glucan (cell wall) D-arabinitol (metabolite) enolase (cell cytoplasm) Candida antigen titers

32 Physical exam Patient doesn’t look good Endophthalmitis- 30% Skin lesions associated with progressive myalgias

33 Treatment Remove infected central lines and prosthetic devices Drainage/ debridement Pharmacotherapy: Polyenes Antimetabolites Azoles

34 Polyenes Nystatin Topical only Cutaneous infection, thrush, infected burns No enteral absorption Reduced Candida overgrowth in GI tract- does it help? Amphotericin B Structurally similar to membrane sterols: Binds to ergosterol>cholesterol Creates lethal pores- K enters, glucose leaks Resistance: decreased ergosterol content or structural modification of ergosterol

35 Amphotericin B Effective against Candida and Torulopsis Route: IV, intrathecal, intravesical Different products: Liposomal (AmBiosome) Colloidal dispersion (Amphotec) Lipid complex (Abelcet)

36 Amphotericin B Toxicity: Hypokalemia, hypomagnesemia, renal failure Fever, rigors Mild anemia, thrombocytopenia Full drug course: days

37 Antimetabolite 5-Fluorocytosine Fluoronated cytosine- enters cell- deaminated to 5FU- phosphorolation- into RNA Inhibits protein and DNA synthesis Synergistic w/ AmphoB; easy resistance Toxic: anemia/aplasia; lousy wound healing

38 Azoles Imidazoles (2N) Ketoconazole Miconazole Triazoles (3N) Itraconazole Fluconazole Mechanism of Action: Block ergosterol synthesis: inhibit C14-alpha demethylase interaction with cytochrome P450, which stops the conversion of lanosterol to ergosterol

39 Problems with Azoles Ketoconazole: only po; needs acid in stomach to be absorbed; slows adrenal and gonadal steroid production; lipophilic- not dialyzable, poor urine excretion Miconazole: IV only, horrendous toxicity Itraconazole: only po; needs acid in stomach to be absorbed; very lipophilic- three day loading dose, lousy urine excretion

40 Fluconazole PO, IV; oral absorption not affected by gastric pH or food Water soluble- minimal plasma protein binding- tissue concentrations exceed 50% of the plasma level Excellent penetration into CSF and urine Minimally metabolized: 80% excreted unchanged in urine

41 Fluconazole Must adjust dosing if GFR is < 50ml/ min Removed during hemodialysis Effective against: Cryptococcus Coccidioides Histoplasma Blastomyces Candida albicans, tropicalis, parapsilosis Ineffective against Aspergillus, C. kruzei T glabrata: Dose dependent kill

42 Prevention Remove unnecessary lines/ catheters Enteral feeds over TPN Control blood glucose Restore normotensive state; early extubation Use least possible dose of effective immunosuppressants Pharmaceutical prophylaxis?

43 Pharmaceutical prophylaxis Slotman, patient w/ candiduria equal risk of death as fungemia Nassoura, candiduria: AmphoB bladder irrigation- 63% dissemination, 33% mortality Fluconazole IV- 0% dissemination, 5% mortality

44 Recommendations 1997-consensus statement- ID For Candidemia and/ or dissemination: 1. Patient stable, no hx of Diflucan, C kruzei unlikely--- Fluconazole 800mg, the 400mg qd 2. Patient stable, + Diflucan for 2d or more--- Amphotericin B 0.7mg/ kg 3. Patient unstable, no hx Diflucan, C kruzei unlikely---Fluconazole or AmphoB

45 Recommendations 1997-consensus statement- ID Empiric treatment: Fluconazole for non-neutropenic + risk factors Central line TPN >14d antibiotics Complex intraabd surgery Candida isolated from 2 or more sites Fluconazole for neutropenic if fever > 3d w/ appropriate Abx and no identifiable source

46 Recommendations 1997-consensus statement- ID If Then Candiduria, no DM or No treatment immunosuppression Candida cystitis (pyuria) Diflucan Candida peritonitis Diflucan Candida in liver or spleen Diflucan Endophthalmitis-stable Diflucan Endophthalmitis- worsening AmphoB

47 “Newer” Options… Voriconazole- azole like fluconazole, similar spectrum of activity but gets Aspergillus (Fall 2001) Antibiotics vs bacteria- drop of a hat Antifungals vs Candida, etc.- use responsibly but think about it

48 Questions…?


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