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Opportunistic Fungal Infections

Opportunistic Fungal Infections. Candida Susan Richardson January 11, 2010. Opportunistic Fungal Infections. Require impairment of host immunity to cause serious infection Clinical infection - localized to severe systemic infection Yeasts :

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Opportunistic Fungal Infections

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  1. Opportunistic Fungal Infections Candida Susan Richardson January 11, 2010

  2. Opportunistic Fungal Infections • Require impairment of host immunity to cause serious infection • Clinical infection - localized to severe systemic infection • Yeasts: • Candida spp. (albicans, tropicalis, parapsilosis, krusei, glabrata, lusitaniae, kefyr, guilliermondii etc.) • Cryptococcus neoformans • Filamentous fungi: • Aspergillus spp. (fumigatus, niger, flavus) • Zygomycetes (Rhizopus, Mucor, Rhizomucor, Absidia) • Fusarium spp. • Penicillium spp. (marneffei) • Pseudallescheria boydii (Scedosporium apiospermium) • Curvularia spp.

  3. Predisposing Factors (Immunologic) • Cancer (esp. hematological malignancy) • Key defect: Neutropenia • Organ Transplantation (bone marrow, liver, lung, kidney) • Key defect: Neutropenia, Impaired T cell function • Cellular Immune Dysfunction(AIDS, lymphoma, CMC) • Key defect: Impaired T cell function

  4. Predisposing Factors (Non-Immunologic) • Chemotherapy (cytotoxic) - mucosal damage of GI, respiratory, GU tracts • Antibiotics - Broad spectrum; loss of normal flora, esp. anaerobic • Invasive devices - breach skin/mucosal defences, i.e. intravenous lines, urinary catheters, tracheostomies • Invasive procedures - surgery, diagnostic biopsies

  5. Transmission of Opportunistic Fungi • Candida, Trichosporon, Malassezia • ENDOGENOUS • unique strain • colonization precedes infection • antibiotic suppression of normal flora, fungal overgrowth • EXOGENOUS • hand carriage health care worker

  6. Transmission of Opportunistic Fungi • Aspergillus, Zygomycetes, other filamentous fungi, Cryptococcus • EXOGENOUS • inhaled conidia • ventilation systems, construction, heliports, plants, environment • direct contact - dressings, arm boards, burns, wounds

  7. Candida • MOST COMMON invasive fungal infection in immunocompromised patients • 4th most common cause of nosocomial blood stream infection • Species implicated in human disease most often: • C. albicans • C. tropicalis • C. parapsilosis • C. krusei(fluconazole resistant) • C. glabrata • C. lusitaniae(amphotericin B resistant)

  8. Candida • Thick cell wall of mannan and glucan polysaccharides • Unicellular, budding (asexual) reproduction (blastospores) • Filament formation • Pseudohyphae (buds stay attached, constricted, chains of elongated blastospores) • Hyphae (buds germinate)

  9. Cell wall Candida albicans

  10. Candida - Pathogenicity / Virulence Factors • C. albicans >>> virulent than other Candida species • Rapid switching of expressed phenotype • Enhanced ability to reassort and regulate genetic expression by chromosomal rearrangement and recombination • phenotypic - nutrient stress produces different colony forms • virulence factors (including antifungal resistance, e.g. C. lusitaniae vs. amphotericin B)

  11. Candida - Pathogenicity / Virulence Factors • Hyphal formation • Hyphal formation is associated with tissue invasion ( yeast forms associated with epithelial colonization) • spontaneous C.albicans non-hyphae-forming mutant shows decreased pathogenicity in a rat Candida vaginitis model • Experimental renal infection - yeast and hyphae initiate renal lesions, but hyphae are essential for invasion of the renal pelvis. • Hyphae adhere more readily to host epithelial surfaces than do yeast cells (50x more adherent)

  12. Candida - Pathogenicity / Virulence Factors • Contact sensing - growth of hyphae on filters or membranes (thigmotropism) • When placed on agar medium grow through pores and along grooves. Tissue penetration may be aided by following surface discontinuities and microscopic breaks • Surface hydrophobicity • Hydrophobic C. albicans at 25 C >>virulent than more hydrophilic C. albicans at 37 C • Hydrophobic CA show increased adherence and more rapid hyphal germ tube formation

  13. Candida - Pathogenicity / Virulence Factors • Surface virulence molecules(receptors, adhesins, pyrogens, and immunomodulators) • Candida adhere to: • epithelial cells (buccal, cervical, corneal, urinary, gastrointestinal mucosa), vascular endothelial cells, spermatozoa, plastics • Candida form ligands to host components - C3d, iC3b, fibrinogen, laminin, fibronectin, fucose receptors, N-acetylglucosamine receptors

  14. Candida Pathogenicity / Virulence Factors • Molecular mimicry • Surface coat of molecules that mimics host components (decreases recognizability) • C. albicans cells in the bloodstream become rapidly coated with host platelets via the fibrinogen-binding ligand. • Lytic enzymes • Hydrolases with broad substrate specificities (proteinase, phospholipase(s), lipase(s), acid phosphomonoesterase). • Aspartyl proteinase - most potent or thoroughly studied.

  15. Candida Pathogenicity / Virulence Factors • Growth rate and undemanding nutrient requirements • Virulent strains have shorter doubling times than attenuated strains • C. albicans not fastidious, but nutritionally deprived mutants (auxotrophs for adenine, lysine, serine, uracil and heme) show decreased virulence

  16. Candida • Human commensal (endogenous) • skin, gastrointestinal, genitourinary tracts • 5 - 15% carriage rate in normal people • increased carriage with use of antibiotics • Environmental (exogenous) • much less common • food, animals, soil hospital environment • outbreaks have occurred

  17. Candida - Clinical • Mucous membrane infections • Thrush (oropharyngeal) • Esophagitis • Vaginitis • Cutaneous infections • Paronychia (skin around nail bed) • Onychomycosis (nails) • Diaper rash • Balanitis • Chronic mucotaneous candidiasis • children with T-cell abnormality

  18. Mucosal candidiasis Oral thrush Vaginal candidiasis

  19. Cutaneous candidiasis Diaper dermatitis Balanitis

  20. Cutaneous candidiasis Onychomycosis and paronychia Chronic mucocutaneous candidiasis

  21. Candida - Clinical • Urinary tract infection • Fungemia • Disseminated (systemic, invasive) infection • Immunocompromised patients • Cancer/chemotherapy • Neonatal candidiasis • Endophthalmitis (eye) • Liver and spleen • Kidneys • Skin • Brain • Lungs • Bone

  22. Clinical profile Central catheter Parenteral nutrition Broad-spectrum antibiotics Neutropenia Very low birth weight

  23. Disseminated candidiasis Endophthalmitis Disseminated skin lesion

  24. Disseminated candidiasis Hypo-echoic splenic lesions

  25. Candida - Laboratory Diagnosis 1 • Specimens - Blood, tissue (biopsy or autopsy), sterile fluid, urine, CSF, skin, respiratory secretions • Microscopy (direct on specimen - except blood and urine) • Gram stain, Calcofluor • Histopathology (tissues) • H & E - stain poorly • GMS, PMS - stain well

  26. Candida species Top: Calcofluor White x400: Yeast and pseudohyphae Bottom: Gram stain x1000: Yeast and pseudohyphae

  27. Pathology of disseminated candidiasis Yeast-like cells and septate hyphae GMS

  28. Pathology of disseminated candidiasis Esophagus, vascular invasion, blastoconidia and pseudohyphae, PAS

  29. Pathology of disseminated candidiasis Hematogenous renal candidiasis. Disseminated miliary abscesses, cortex and medulla. Necrotic papillae.

  30. Candida - Laboratory Diagnosis 2 • Culture (all specimens) • Colony morphology • White, smooth, creamy, sometimes wrinkled • Laboratory identification • Unique color on chromagar • Chlamydospore production (terminal vesicle) • Germ tube production (in horse serum) • beginning of true hypha (no constriction) • C. albicans - Germ tube positive • Other Candida - Germ tube negative • Carbohydrate assimilation and fermentation (API 20C, Vitek2, RapID and reference) • Urea and nitrate • Microscopic morphology on Cornmeal Tween 80

  31. Yeast Identification

  32. Candida species Candida albicans Sabouraud Agar Morphology: Creamy white yeast, may be dull, dry irregular and heaped up, glabrous and tough Chromagar producing green pigmented colonies on specially designed medium to speciate certain yeasts based on color they produce

  33. Candida species Germ tube: inoculation of yeast in horse serum incubated at 370C for 2 to 3 hours Germ Tube: Positive Germ tube is a continuous filament germinating from the yeast cell without constriction at the point of attachment. e.g. C. albicans, C. dubliniensis Germ Tube: Negative Shows constriction at the attachment site e.g. other Candida species, esp. C. tropicalis

  34. Candida species Candida albicans Oxgall Agar large round and thick walled chlamydospores Cornmeal Agar clusters of blastospores along pseudohyphae at regular intervals x400 x1000 x400 x1000

  35. Yeast identification C. lusitaniae Slender, branched, curved pseudohyphae short chains of blastoconidia C. parapsilosis Short, curved pseudohyphae C. guilliermondii Few, short pseudohyphae Clusters of blastoconidia at septae C. lipolytica Elongated blastoconidia in short chains arthroconidia

  36. Yeast identification C. tropicalis Graceful long pseudohyphae Single/small groups blastoconidia along pseudohyphae C. dubliniensis Terminal chlamydospores C. krusei Elongate blastoconidia Cross-matchsticks, tree-like C. glabrata No pseudohyphae, small blastoconidia

  37. Candida - Laboratory Diagnosis 3 • Candida antigen, antibody and metabolite detection • NOT useful in routine practice • Low sensitivity and specificity • Polymerase chain reaction • No more sensitive than blood culture in studies to date

  38. Candida - Treatment • Remove infected intravenous lines • Antifungal therapy for systemic infection • Amphotericin B IV • Azoles (fluconazole, itraconazole, voriconazole, posaconazole) orally, intravenous • Flucytosine (only with Ampho B because of resistance) • Echinocandins (caspofungin, micafungin)

  39. Candida antifungal resistance • Primary (inherent) resistance • C. lusitaniae (amphotericin B) • C. glabrata (fluconazole) • C. krusei (fluconazole) • Secondary (acquired) resistance • Fluconazole, other azoles • Amphotericin B • 5-FC

  40. Candida antifungal susceptibility testing • Testing methodology • Reference broth microdilution (CLSI) • Commercial broth microdilution with alamar blue (Sensititre, YeastOne) • E-test • Disk diffusion (CLSI • Vitek 2

  41. Candida antifungal susceptibility testing

  42. Candida antifungal susceptibility testing

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