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

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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

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35

<12 12 to 24 24 to 48 >48

Hos

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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

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150

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Day of Last +BC

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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

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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

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% R

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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.

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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