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. Where did it come from?
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 117 7 22
No broad %
Spec Abx
Br.Sp.Abx %
“High risk” %

26. Fungal Infection
How do I fix it?

27. How do I fix it? 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…?