d- mycology fungi introduction. fungi are all around us we touch them, we swallow them, we breathe...
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•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
Fungal Fast Facts
Why so few invasive infections?
A. Dumb luckB. Most fungi are wimpsC.Some bugs are meaner than
othersD.Some people are meaner than
othersE. A little of all of these
Host/Pathogen Balance:Normal Circumstances
Host Factors
Anatomical barriers
Adaptive immunity
Innate defenses
Virulence
Fungal Burden
Fungal Factors
Protection Infection
Why so few Invasive Infections?
What are the major fungi I need to worry about?
A. CoccidiomycosisB. HistoplasmosisC.CandidaD.AspergillusE. CryptococcusF. Zygomycetes
Mortality Due to Invasive Mycoses
PathogenOverall
Mortality
Candida 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.
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
Post-Operative Course
• Fever persists, now day 5• Awake and lethargic• Abdominal exam: typical post-op
What tests would you order?
•CT
•Check catheter
•Chest x Ray
•Urine/blood culture
•Percutaneous aspirate
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?
Laboratory Results
• Negative blood cultures• Urine culture positive for Candida
– C. albicans identified by PNA-FISH
• You examine his eyes
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– 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
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
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.
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
Treatment Guidelines for Candidemia:Infectious Disease Society of America 20041,2
Con
ditio
nP
rimar
yth
erap
yA
ltern
ativ
e th
erap
y Amphotericin B +fluconazole 4–7 days then fluconazole
Fluconazole or caspofungin
Fluconazole
Non-neutropenic adults
Chronic disseminated candidiasis
Neutropenic adults
Amphotericin Bor fluconazoleor caspofungin
Amphotericin B (conventional or liposomal)
Amphotericin B (conventional or liposomal) orcaspofungin
1. Pappas PG et al. Clin Infect Dis. 2004;38:161–189.2. Perfect JR. Oncology. 2004;18(suppl):15–22.
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 Solid TransplantTransplant
9%9%
AIDS8%
Other Other ImmuneImmune
6%6%
Pulm9%
Other5%
None2%
BMT/Auto7%
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: ↑size, ↓haloDay 4: ↑size, ↓halo Day 7: air crescentDay 7: air crescent
Halo 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. CerebritisA. Sino-orbital disease C. Cutaneous infection
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
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).
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
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