Mycology from the perspective of the Clinician John R

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Mycology from the perspective of the Clinician

• John R. Wingard, MD
• University of Florida
• Gainesville, FL

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Fungal Fast Facts

• Fungi are all around us
• We touch them, we swallow them, we breathe them
• There are more than 1.5 million fungal species in
  nature
• Yet only about 100 cause human disease
• Most cause superficial infections, some cause
  allergic reactions
• Few cause invasive infections

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Why so few invasive infections?

• Dumb luck
• Most fungi are wimps
• Some bugs are meaner than others
• Some people are meaner than others
• A little of all of these

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Why so few Invasive Infections?
Host/Pathogen BalanceNormal Circumstances
Fungal Factors
Anatomical barriers
Virulence
Host Factors
Adaptive immunity
Fungal Burden
Innate defenses
Infection
Protection
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Fungi as Primary Pathogens in Healthy Individuals
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Fungi as Opportunists
Conditions that disrupt immune defenses

• Neutropenia
• Immunosuppression

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What are the major fungi I need to worry about?

• Coccidiomycosis
• Histoplasmosis
• Candida
• Aspergillus
• Cryptococcus
• Zygomycetes

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Mortality Due to Invasive Mycoses
Adults hospitalized in the US Hospitalized
patients with IA HSCT recipients. 1. Pappas PG,
et al. Clin Infect Dis. 200337634-643 2.
Wisplinghoff H, et al. Clin Infect Dis.
200439309-317 3. Perfect J, et al. Clin Infect
Dis. 2001331824-1833 4. Marr KA, et al. Clin
Infect Dis. 200234909-917.
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Risk for Invasive Candidiasis Is a Continuum

• Exposures
• ICU gt7 days
• CVCs
• Antibiotics
• TPN
• Colonization

• High-risk patients
• Surgery
• Leukopenia
• Burns
• Premature infants

• If candidemia develops
• 40 die
• 60 survive

CVCscentral venous catheters TPNtotal
parenteral nutrition. Rex JH, et al. Adv Intern
Med. 199843321-369 Pappas PG, et al. Clin
Infect Dis. 200337634-643.
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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

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What does this patient have?

• Bacterial abscesses
• Spread of leukemia to liver
• Hemangiomas
• Hepatic candidiasis

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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

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Course

• Venous and urinary catheters placed, intubated
• Cefoxitin 1 gram IV en route to OR
• Exploratory laparotomy
• Left nephrectomy
• Sigmoid colectomy and colostomy

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Post-Operative Course

• Fever persists, now day 5
• Awake and lethargic
• Abdominal exam typical post-op

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What tests would you order?

• CT
• Check catheter
• Chest x Ray
• Urine/blood culture
• Percutaneous aspirate

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Findings

• Aspirate grows E. coli
• Antibiotics modified
• Fever persists

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Evaluate for Fungus?

• He has the risk factors
• He has other causes for fever
• Treat presumptively for fungus? (or) Wait for
  positive fungus culture?
• Which drug if you treat?

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Laboratory Results

• Negative blood cultures
• Urine culture positive for Candida
• C. albicans identified by PNA-FISH
• You examine his eyes

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What Is the Diagnosis?
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Key clinical features of Candida infections

• 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
• Microbes virulence factors
• Impairment of host defenses
• Selection of resistant bugs by antimicrobial
  agents used
• Fever often the only clinical manifestation

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CandidiasisSpectrum of Infection
Cutaneous fungemia
Disseminated
Chorioretinitis
Mucosal
Images courtesy of Kenneth V. Rolston, MD, and
John R. Wingard, MD.Walsh et al. Infect Dis Clin
North Am. 199610365-400.
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Who gets Candidemia?
2001
2002
2000
Nguyen, unpublished data from Shands at UF
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Systemic Fungal InfectionsMANAGEMENT

• Remove focus of infection
• Remove/decrease immunosuppression
• Restore Immune Function
• Begin antifungal therapy - EARLY!

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Delaying Antifungal Therapy Until Blood Cultures
are Positive A Risk for Hospital Mortality

• 157 patients with candidemia
• Initiation of antifungal therapy after blood
  culture
• lt12 hours 9 (5.7)
• 12 to 24 hours 10 (6.4)
• 24 to 48 hours 86 (54.8)
• gt 48 hours 52 (33.1)
• Independent determinants of hospital mortality
• APACHE II score (one-point increments) (p lt0.001)
• Prior antibiotics (p 0.028)
• Administration of antifungal therapy 12 hours
  after the first positive blood culture (p
  0.018)

(n86)
(n9)
(n10)
(n52)
Morrell M, et al. Antimicrob Agents Chemother
2005493640-5
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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.

Start Rx
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What are the targets for antifungal therapy?
Cell membrane Fungi use principally ergosterol
instead of cholesterol
DNA Synthesis Some compounds may be selectively
activated by fungi, arresting DNA synthesis.
Cell Wall Unlike mammalian cells, fungi have a
cell wall
Atlas of fungal Infections, Richard Diamond Ed.
1999 Introduction to Medical Mycology. Merck and
Co. 2001
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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)
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Antifungals acting on fungal DNA synthesis
Cell membrane Polyene antibiotics Azole
antifungals
DNA/RNA synthesis Pyrimidine analogues -
Flucytosine
Cell wall Echinocandins
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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.
1999 Introduction to Medical Mycology. Merck and
Co. 2001
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Treatment Guidelines for CandidemiaInfectious
Disease Society of America 20041,2
Condition
Primarytherapy
Alternative therapy
1. Pappas PG et al. Clin Infect Dis.
200438161189. 2. Perfect JR. Oncology.
200418(suppl)1522.
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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

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Invasive AspergillosisUnderlying Diseases
595 Patients
Other Immune6
AIDS8
Solid Transplant9
Other5
Pulm9
None2
Hematologic29
BMT/Auto7
BMT/Allo25
Patterson/ASPERFILE Study Group, MEDICINE, 2000.
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Acute Invasive Aspergillosis
Sequential high-resolution CTs in 25 patients
with neutropenia and IPA at diagnosis median
number of lesions2, bilateral in 48
Baseline halo
Day 4 ?size, ?halo
Day 7 air crescent
Halo transitory lt5 days increased volume for 1
week ? stabilization ? air crescent
IPAinvasive pulmonary aspergillosis. Slide
courtesy of Kieren A. Marr, MD. Caillot et al. J
Clin Oncol. 200119253-259.
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Invasive Aspergillosis
Other Clinical Presentations
B. Cerebritis
C. Cutaneous infection
A. Sino-orbital disease
Images courtesy of Kenneth V. Rolston,
MD. Stevens et al. Clin Infect Dis.
200036696-709 Walsh et al. Infect Dis Clin
North Am. 199610365-400.
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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

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Case 3Radiography
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Case 3Bronchoscopy
Culture Aspergillus fumigatus
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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

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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).

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Early Diagnosis Can Be Helpful
Plt0.001
Greene RE, et al. Clin Infect Dis 200744373-9
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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 (n27) vs IA (n54)
  patients
• Risks among leukemia patients are diabetes,
  malnutrition, and voriconazole prophylaxis

Aspergillus
0.7
0.21
Zygomycetes
0.6
0.18
0.5
0.15
0.4
0.12
Incidence of Zygomycosisper 1,000 Patient-Days
Incidence of IA per 1,000 Patient-Days
0.3
0.09
0.2
0.06
0.1
0.03
0.0
0.00
2000
2001
2002
2003
Year
2000
1800
1600
1400
1200
Total Grams Dispensed to HematologicalMalignancy
and BMT Services
1000
Amphotericin B
Voriconazole
800
600
400
200
0
1. Marty PM et al. N Eng J Med. 2004350950. 2.
Imhof A et al. Clin Infect Dis. 200439743. 3.
Kontoyiannis et al. J Infect Dis. 20051911350.
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Summary (1)

• Invasive fungal infections occur as a result of
  interplay between bug, host, and antimicrobial
  pressures
• Organisms inherent virulence
• Impaired host defenses tips balance in organisms
  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

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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