clinical mycology u f medical students 12 05 07 final2
TRANSCRIPT
Mycology from the perspective of the Clinician
John R. Wingard, MD
University of Florida
Gainesville, FL
• Fungi are all around us
• We touch them, we swallow them, we breathe them
• There are more than 100.000 fungi in nature
• Yet only about 100 cause human disease
• Most cause superficial infections, some cause allergic reactions
• Few cause invasive infections
Fungal Fast Facts
Why so few invasive infections?
A. Dumb luck
B. Most fungi are wimps
C. Some bugs are meaner than others
D. Some people are meaner than others
E. A little of all of these
What are the major fungi I need to worry about?
A.Coccidiomycosis
B.Histoplasmosis
C.Candida
D.Aspergillus
E.Zygomycetes
Top 10 fungi you need to worry about in clinical medicine
1) 2) 3) 4) 5) 6) 7) 8) 9) 10)
CandidaCandidaCandidaCandidaCandidaCandidaCandidaAspergillusAspergillusEverything else
Nosocomial Bloodstream Infections in US Hospitals: Nosocomial Bloodstream Infections in US Hospitals: 1995-20021995-2002
% BSI % Crude Mortality
Rank Pathogen
BSI per 10,000
admissionsTotal
(n=20,978)ICU
(n=10,515)Non-ICU (n=10,515) Total ICU Non-ICU
1. CoNS 15.8 31.3 35.9 26.6 20.7 25.7 13.8
2. S aureus 10.3 20.2 16.8 23.7 25.4 34.4 18.9
3. Enterococcus spp 4.8 9.4 9.8 9.0 33.9 43.0 24.0
4. Candida spp 4.6 9.0 10.1 7.9 39.2 47.1 29.0
5. E coli 2.8 5.6 3.7 7.6 22.4 33.9 16.9
6. Klebsiella spp 2.4 4.8 4.0 5.5 27.6 37.4 20.3
7. P aeruginosa 2.1 4.3 4.7 3.8 38.7 47.9 27.6
8. Enterobacter spp 1.9 3.9 4.7 3.1 26.7 32.5 18.0
9. Serratia spp 0.9 1.7 2.1 1.3 27.4 33.9 17.1
10. A baumannii 0.6 1.3 1.6 0.9 34.0 43.4 16.3
BSI=blood stream infection; CoNS=coagulase-negative staphylococci. Surveillance and Control of Pathogens of Epidemiologic Importance (SCOPE) study.Wisplinghoff H, et al. Clin Infect Dis. 2004;39:309-317.
Mortality Due to Invasive Mycoses
PathogenOverall
MortalityCandida spp 40%
Aspergillus spp 62%
Other Invasive moulds (Fusarium spp., Zygomycetes)
~80%
Scedosporium spp. 100%
*Adults hospitalized in the US; †Hospitalized patients with IA; ‡HSCT recipients.1. Pappas PG, et al. Clin Infect Dis. 2003;37:634-643; 2. Wisplinghoff H, et al. Clin Infect Dis. 2004;39:309-317; 3. Perfect J, et al. Clin Infect Dis. 2001;33:1824-1833; 4. Marr KA, et al. Clin Infect Dis. 2002;34:909-917.
Increased Hospital Costs Associated Increased Hospital Costs Associated With CandidemiaWith Candidemia
Total cost of candidemia: $44,536*
Adverse drug reactions$610 (1.4%)
Diagnostic procedures$1513 (3.4%)
Hospital stay$37,681 (84.6%)
Antifungal therapy$4710 (10.5%)
*1997 dollars.Rentz AM, et al. Clin Infect Dis. 1998;27:781-788.
Estimated Annual Costs to US Economy
• Candida $3 billion
• Aspergillus $1 billion
Candida
• Yeasts
• Pseudohyphae
• Part of the endogenous flora• Skin
• Gut
• Mucosal surfaces
• Portal of entry: breach in skin or mucosa
• Most infections are due to person’s own flora
Risk for Invasive Candidiasis Risk for Invasive Candidiasis Is a ContinuumIs a Continuum
High-risk patients
• Surgery
• Leukopenia
• Burns
• Premature infants
Exposures
• ICU >7 days
• CVCs
• Antibiotics
• TPN
• Colonization
If candidemia develops…• ~40% die
• ~60% survive
CVCs=central venous catheters; TPN=total parenteral nutrition.Rex JH, et al. Adv Intern Med. 1998;43:321-369; Pappas PG, et al. Clin Infect Dis. 2003;37:634-643.
Case 1Patient with Acute Leukemia
• 36 yo woman with AML in CR1 given HDAC to mobilize for stem cell collection & consolidation
• Discharged on ciprofloxacin, no fluconazole
• Day 15 admitted for sepsis; blood cultures grew ESBL E. coli (sensitive only to imipenem, meropenem, gentamycin)
• She received imipenem + vancomycin
• Fever persists
• CT scan done 7 days later
What does this patient have?
• Bacterial abscesses
• Spread of leukemia to liver
• Hemangiomas
• Hepatic candidiasis
Case 2
• 43 years old male, GSW to abdomen
• Arrives in shock
• 1.5 liter combined blood loss from trauma and surgery
• Sigmoid colon injury with fecal contamination
• Renal laceration
• Hypothermia and acidosis
Course
• Venous and urinary catheters placed, intubated
• Cefoxitin 1 gram IV en route to OR
• Exploratory laparotomy
• Left nephrectomy
• Sigmoid colectomy and colostomy
• 6u PRBC, 4u FFP, 10u PLTS intraoperatively
Post-Operative Course
• Fever persists, now day 5
• Awake and lethargic
• Abdominal exam: typical post-op
How Would You Evaluate?
• CT
• Check catheter
• Chest x Ray
• Urine/blood culture
• Percutaneous aspirate
Findings
• Aspirate grows E. coli
• Antibiotics modified
• Fever persists
Evaluate for Fungus?
• He has the risk factors
• He has other causes for fever
• Treat “presumptively” for fungus? Wait for positive fungus culture?
• Which drug if you treat?
Laboratory Results
• Negative blood cultures
• Urine culture positive for Candida • C. albicans identified by PNA-FISH
• You examine his eyes
What Is the Diagnosis?
• Line-associated candidemia
Key clinical features in common
• Invasive Candida infections rarely are the first infection, more commonly “superinfections”
• They are opportunists• Breach in host barriers by catheters, trauma, surgery• Impaired immune defenses• Antimicrobial agents
• Bacterial flora suppressed by antibiotics• Certain fungi are suppressed by specific antifungal agents
• Risk for infection determined by interplay of bug, host, and environmental pressures
• Microbe’s virulence factors• Impairment of host defenses• Selection of resistant bugs by antimicrobial agents used
• Fever often the only clinical manifestation
CandidiasisSpectrum of Infection
Images courtesy of Kenneth V. Rolston, MD, and John R. Wingard, MD.Images courtesy of Kenneth V. Rolston, MD, and John R. Wingard, MD.Walsh et al. Walsh et al. Infect Dis Clin North AmInfect Dis Clin North Am. 1996;10:365-400.. 1996;10:365-400.
Cutaneous fungemia
Chorioretinitis
Disseminated
Mucosal
Who gets Candidemia?
0
10
20
30
40
50
60N
um
be
r o
f c
an
did
em
ia
ca
se
s a
t S
HU
F
SICU Surgery Organ transplant
Medicine MICU Hem/BMT
Pediatric
2000 2001 2002
Nguyen, unpublished data from Shands at UF
Systemic Fungal InfectionsMANAGEMENT
Remove focus of infection
Remove/decrease immunosuppression
Restore Immune Function
Begin antifungal therapy - EARLY!
Delaying Antifungal Therapy Until Blood Cultures are Positive: A Risk for Hospital Mortality
Hospital Mortality Associated with Delayed Antifungal Therapy for
Candidemia
0
5
10
15
20
25
30
35
<12 12 to 24 24 to 48 >48
Hos
pita
l Mor
talit
y (%
)
Morrell M, et al. Antimicrob Agents Chemother 2005;49:3640-5
• 157 patients with candidemia
• Initiation of antifungal therapy after blood culture
<12 hours: 9 (5.7%) 12 to 24 hours: 10 (6.4%) 24 to 48 hours: 86 (54.8%) > 48 hours: 52 (33.1%)
• Independent determinants of hospital mortality
APACHE II score (one-point increments) (p <0.001)
Prior antibiotics (p = 0.028) Administration of antifungal therapy 12
hours after the first positive blood culture (p = 0.018)
(n=9) (n=10) (n=86) (n=52)
Catheters & Candidemia
• Non-neutropenic• #1 source!
• Cancer patients• Tunneled lines are less often sources
• The gut is probably a frequent source in neutropenic patients with mucositis
Consider changing lines. May help some pts.
0
50
100
150
-10 0 10 20
Day of Last +BC
% C
and
idem
ic All new by day 0
No change by d0
Start Rx
What are the targets for antifungal therapy?
Cell membraneFungi use principally ergosterol instead of cholesterol
Cell WallUnlike mammalian cells, fungi have a cell wall
DNA SynthesisSome compounds may be selectively activated by fungi, arresting DNA synthesis.
Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
Cell Membrane Active Antifungals
Cell membrane • Polyene antibiotics - Amphotericin B, lipid formulations - Nystatin (topical)
• Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Posaconazole - Miconazole, clotrimazole (and other topicals)
Antifungals acting on fungal DNA synthesis
Cell membrane • Polyene antibiotics • Azole antifungals
DNA/RNA synthesis • Pyrimidine analogues - Flucytosine
Cell wall • Echinocandins
Cell Wall Active Antifungals
Cell membrane • Polyene antibiotics • Azole antifungals
DNA/RNA synthesis • Pyrimidine analogues - Flucytosine
Cell wall • Echinocandins -Caspofungin -Micafungin -Anidulafungin
Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
Candidemia: Current Treatment Guidelines
• Amphotericin 0.6-1.0 mg/kg/day IV
• Fluconazole 400-800 mg/kg/day IV or PO
• Caspofungin 70 mg LD, then 50 mg/day IV
• Treat for 14 days after last positive culture and resolution of signs and symptoms
• Remove all intravascular catheters, if possible
Pappas, Clin Infect Dis 2004; 38: 161
Typical Epidemiology of Candidemia & In Vitro Susceptibility of Candida spp.
NOTE: Mixed species/others ~5%
S=Susceptible S-DD=Susceptible-Dose Dependent I=Intermediate R=Resistant
Species Frequency %
Flu Itra AmB Vori Posa Candins
C. albicans 46 S S S S S S
C. glabrata 20 S-DD/R S-DD/R S/I S/I S/I S
C. parapsilosis 14 S S S S S S/I
C. tropicalis 12 S S S S S S
C. krusei 2 R S-DD/R S S S S
C. dubliniensis <1 S/S-DD S S/I S/I S/I S
C. lusitaniae <1 S S S/R S S S
Pappas PG et al, Clin Infect Dis 2004;38:161-89; Bartizal K et al, Antimicrob Agents Chemother 1997;41:2326-32; Patterson TF. J Chemother 1999;11:504-12; Pfaller MA et al, Antimicrob Agents Chemother 2002;46:1723-7; Pfaller MA et al, J Clin Microbiol 2002;40:852-6
United States, 1980-1997
AspergillusAspergillus
Rate
per
100,0
00 P
op
ula
tion
Rate
per
100,0
00 P
op
ula
tion
YearYear
0.60.6
0.40.4
0.20.2
0.00.019811981 19861986 19911991 19961996
McNeil et al. Clin Infect Dis. 2001;33:641-647.
CandidaCandida
Trends in US Mortality Due to Mycotic Infections
Epidemiology of Candidemia:Impact of Prior Antifungal Therapy
Uzun O et al. Clin Infect Dis 2001;32:1713-17
Breakthrough (n=49)
C. albicans21%
C. tropicalis6%
Others8%
C. krusei14%
C. parapsilosis20%
C. glabrata25%
C. albicans44%
C. tropicalis19%
Others8%
C. krusei3%
C. parapsilosis17%
C. glabrata10%
Non-Breakthrough (n=430)
Mortality: 50% vs Mortality: 50% vs 76%76%
Before we leave Candida: Clouds on the Horizon
Mechanisms of antifungal resistance
• Target enzyme modification
• Ergosterol biosynthetic pathway
• Efflux pumps
• Drug import
White TC, Marr KA, Bowden RA. Clin Microbiol Review 1998;11:382-402
Aspergillus• Moulds
• True hyphae
• Exogenous, airborne• Soil
• Water / storage tanks in hospitals etc
• Food
• Compost and decaying vegetation
• Fire proofing materials
• Bedding, pillows
• Ventilation and air conditioning systems
• Computer fans
• Portal of entry: nasal passages, respiratory tract
• Potential for hospital outbreaks
Patterson/ASPERFILE Study Group, MEDICINE, 2000.Patterson/ASPERFILE Study Group, MEDICINE, 2000.
595 Patients595 Patients
Hematologic29%
BMT/Allo25%
Solid TransplantSolid Transplant9%9%
AIDSAIDS8%8%
Other Other ImmuneImmune
6%6%
Pulm9%
OtherOther5%5%
NoneNone2%2%
BMT/AutoBMT/Auto7%7%
Invasive AspergillosisUnderlying Diseases
Acute Invasive Aspergillosis
Sequential high-resolution CTs in 25 patients with neutropenia and IPA at diagnosis: median number of lesions=2, bilateral in
48%
Baseline: haloBaseline: halo Day 4: Day 4: size, size, halohalo Day 7: air crescentDay 7: air crescentHalo transitory: <5 days; increased volume for 1 week stabilization air
crescentIPA=invasive pulmonary aspergillosis.IPA=invasive pulmonary aspergillosis.Slide courtesy of Kieren A. Marr, MD.
Caillot et al. J Clin Oncol. 2001:19:253-259..
Invasive AspergillosisOther Clinical Presentations
Images courtesy of Kenneth V. Rolston, MD..Stevens et al. Clin Infect Dis. 2000;36:696-709;
Walsh et al. Infect Dis Clin North Am. 1996;10:365-400..
B. CerebritisB. CerebritisA. Sino-orbital diseaseA. Sino-orbital disease C. Cutaneous infection
Case ContinuedCase Continued
Case 3Patient with acute leukemia
• 51 yo man with AML
• Cytogenetics: intermediate risk category
• Induced with 3 + 7 (Idarubicin + cytarabine)
• Pneumonia at time of count recovery
• Bone marrow shows pt to be in CR1
Case 3Radiography
Case 3Bronchoscopy
Culture: Aspergillus fumigatus
Treatment principles
• Reduce immunosuppresion, restore immunity if possible
• Start antifungal therapy promptly• Polyenes
• Mould-active azoles
• Echinocandins
• Consider surgical resection of infarcted tissue in certain situations
IDSA Aspergillus Treatment Guidelines for Primary Therapy of Invasive Aspergillosis
• Preferred therapy:•Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients
•Alternative Agents:•Liposomal therapy could be considered as alternative primary therapy in some patients (AI).
Early Diagnosis Can Be Helpful
52
32
0
10
20
30
40
50
60
Halo Sign No Halo Sign
% R
esp
on
se
P<0.001
Greene RE, et al. Clin Infect Dis 2007;44:373-9
Zygomycetes
• Resistant to voriconazole• Increased infections in
setting of voriconazole prophylaxis1,2
• Frequent cause of breakthrough infection in patients receiving voriconazole1,2
• Increased incidence of Zygo infections at MDACC3
• Case-control study of Zygo (n=27) vs IA (n=54) patients
• Risks among leukemia patients are diabetes, malnutrition, and voriconazole prophylaxis
1. Marty PM et al. N Eng J Med. 2004;350:950.2. Imhof A et al. Clin Infect Dis. 2004;39:743.3. Kontoyiannis et al. J Infect Dis. 2005;191:1350.
0.70.60.50.40.30.20.10.0In
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Inc
ide
nc
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tien
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ys
Year
AspergillusZygomycetes
Amphotericin BVoriconazole
0
1000
800
600
400
200
1800
1600
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1200
2000
To
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May
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-04
Feb
-04
Mar
-04
Ap
r-04
Summary (1)
• Invasive fungal infections occur as a result of interplay between bug, host, and antimicrobial pressures
• Organism’s inherent virulence
• Impaired host defenses tips balance in organism’s favor
• Ecological advantage offered by suppression of other microbes in the host environment
• Invasive fungal infections are mostly opportunistic
• Take advantage of breach in host defense
Summary (2)
• Candida is the most common invasive fungal pathogen in hospitalized patients
• Part of endogenous flora• Portal of entry: skin, mucosa• Fever is often the only manifestation• Usually disseminates via bloodstream• Early recognition and treatment is key to successful treatment
• Aspergillus is much less common but even more deadly
• Airborne• Portal of entry: nasal passages, respiratory tract• Pneumonia, sinusitis usual presentation