The Evolution of Fungal Infections in the Surgical Patient

Bradley J. Phillips, MD

Burn-Trauma-ICUAdults & Pediatrics

PROHIBITED

• Kaplan-Meier curves

• Too many n = ___, p values

• Multivariate analysis

• finger pointing

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?

Fungal Infection

•What is it?

The players

• Candida

• Aspergillus

• Cryptococcus

• Histoplasma

• Coccidioides

• Blastomyces

Candida Subtypes

• C. albicans

• C. tropicalis

• C. parapsilosis

• C. kruzei

• Torulopsis glabrata

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

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

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% +

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

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

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

Fungal Infection

• Where did it come from?

Where did it come from?

• The patient

Where did it come from?

• The patient

• Thirty years ago, yeast was a contaminant or a nuisance

• Increasing ICU stays, increasing risk factors

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

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, 1974- Candida translocation

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

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

Immunosuppression

• Surgery• Trauma• Burns• Malignancy• Bacterial sepsis• hypoperfusion

• Corticosteroids• Chemotherapy• Diabetes• Post-transplant

medications• Congenital (SCID,

etc.)

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

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

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)

Morbidity of Fungal infection

• Candiduria• Abdominal abscess• Endocarditis• Endophthalmitis• Myocarditis• Skin lesions

• Esophagitis• Pharyngitis• Pneumonia• Peritonitis• Suppurative

thrombophlebitis• Meningitis

SICU length of stay

Patients ICULOS HospLOS

Total 117 7 22No broad 40% 3 17Spec Abx

Br.Sp.Abx 60% 10 26

“High risk” 17% 20 39

Fungal Infection

•How do I fix it?

How do I fix it?

• Diagnose (find it)

• Treat (kill it)

• Prevention (keep it away)

Diagnosis

• Not so easy to do

• Colonization vs. infection/disseminated disease

• Can’t find Candida if you don’t look

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

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

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

Physical exam

• Patient doesn’t look good

• Endophthalmitis- 30%

• Skin lesions associated with progressive myalgias

Treatment

• Remove infected central lines and prosthetic devices

• Drainage/ debridement

• Pharmacotherapy:

Polyenes

Antimetabolites

Azoles

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

Amphotericin B

• Effective against Candida and Torulopsis

• Route: IV, intrathecal, intravesical

• Different products:

Liposomal (AmBiosome)

Colloidal dispersion (Amphotec)

Lipid complex (Abelcet)

Amphotericin B

• Toxicity:

• Hypokalemia, hypomagnesemia, renal failure

• Fever, rigors

• Mild anemia, thrombocytopenia

• Full drug course: 12-14 days

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

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

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

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

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

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?

Pharmaceutical prophylaxis

• Slotman, 1994- patient w/ candiduria equal risk of death as fungemia

• Nassoura, 1993- candiduria:

AmphoB bladder irrigation- 63% dissemination, 33% mortality

Fluconazole IV- 0% dissemination, 5% mortality

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

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

Recommendations• 1997-consensus statement- ID

If ThenCandiduria, no DM or No treatment immunosuppressionCandida cystitis (pyuria) Diflucan

Candida peritonitis Diflucan

Candida in liver or spleen Diflucan

Endophthalmitis-stable Diflucan

Endophthalmitis- worsening AmphoB

“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

Questions…?