Transcript The Evolution of Fungal Infections in the Surgical Patient

The Evolution of Fungal Infections
in the Surgical Patient
Bradley J. Phillips, MD
Burn-Trauma-ICU
Adults & Pediatrics
PROHIBITED
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Kaplan-Meier curves
Too many n = ___, p values
Multivariate analysis
finger pointing
Overview
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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
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Candida
Aspergillus
Cryptococcus
Histoplasma
Coccidioides
Blastomyces
Candida Subtypes
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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 invasivenot 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
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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 tubingmanufacturing 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
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Surgery
Trauma
Burns
Malignancy
Bacterial sepsis
hypoperfusion
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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
phagocytosisburnspecific 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
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Candiduria
Abdominal abscess
Endocarditis
Endophthalmitis
Myocarditis
Skin lesions
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Esophagitis
Pharyngitis
Pneumonia
Peritonitis
Suppurative
thrombophlebitis
• Meningitis
SICU length of stay
Total
No broad
Spec Abx
Br.Sp.Abx
“High risk”
Patients
117
40%
ICULOS
7
3
HospLOS
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17
60%
17%
10
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26
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) positiveColonization? 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
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Toxicity:
Hypokalemia, hypomagnesemia, renal failure
Fever, rigors
Mild anemia, thrombocytopenia
Full drug course: 12-14 days
Antimetabolite
• 5-Fluorocytosine
Fluoronated cytosine- enters celldeaminated 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 lipophilicthree 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
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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
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
“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…?