Janin on Fungal Infections


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Pierre Janin is an intensivist with many interests. For example you may have seen his fantastic echo guide or his talk on transcranial doppler. One of his other passions is microbiology, and at BCC last year he gave this talk on Fungal infections. He often proudly shows pictures of his fungal balls on ward rounds.

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  • What’s about fungal infections? … it’s quite a fascinating kingdom, different to what we are used to, with fascinating names, impossible and always changing classification. I have the privilege to work with an ID/Micro department at the moment, so I had the privilege to be asked to tell more about it … of course I felt really lucky about it … thinking it’s a bit of a mess, it’s never clear, the treatment is difficult …
  • In fact, taking the risk of being disappointing, there is not much fun about it except that they can look very pretty in the lab … but looking into more details, there are certainly a few simple points that can be isolated. Fungus is a very broad kingdom. Very small subset are medically relevant. Represent an important problem. Importance is increasing. Many in fact are disease of modern medicine, as the emergence accompanies profound immunodeficient states (haematology, transplant, cancer, prosthesis, …).
  • As a general view, fungi are present in very different types of disease. Superficial infections, which are of limited interest in the ICU, except that they represent an entry point for more severe infection such as cellulitis. Endemic mycoses, which we almost never see in Australia, and opportunistic infections, which is the relevant category to ICU.
  • Where do they come from ?Saprohyte: role in ecosystem. Not in conflict with a host. No toxins.
  • Problem with the culture is that it takes a very long time, while we know that delaying treatment probably has a negative impact on mortality.
  • Since beginning of this talk, we have emphasized the problem of diagnostic. So is there any test to improve that ?
  • As a general view, fungi are present in very different types of disease. Superficial infections, which are of limited interest in the ICU, except that they represent an entry point for more severe infection such as cellulitis. Endemic mycoses
  • Janin on Fungal Infections

    1. 1. Dr P. Janin RNSH
    2. 2. • Complex names, description, and classification• Difficult diagnosis• Difficult treatment strategy
    3. 3. • More than 100 000 species • Small subset can cause human disease• Increasing incidence • Disease of modern Medicine • Aspergillosis: 10 000 hospitalization /year (USA) 20% increase compared with previous 2 decades.• Mortality ~100% if left untreated.• Substantial financial burden • Annual cost for candidemia: $44-320 million (USA) • Hospitalization for Aspergillosis: >$60 000
    4. 4. • Subcutaneous, Cutaneous, Superficial mycosis• Endemic mycoses • Histoplasma, Bastomyces, Coccidioides • Restricted to specific areas. Less relevant in Australia. • Wide variety of syndromes• Opportunistic fungal infections • The most relevant category in ICU patients • Both yeasts and moulds • Associated with many difficulties
    5. 5. • Many species are free living in the environment (moulds), or are part of the normal flora (candida) • Continuous exposure • Normally well controlled in immunocompetent host• Many fungi are saprohytes • Disease when tissue becomes “inert”: profound immunosuppression • Direct inoculation• Diagnostic problem • Colonization vs Invasive infection
    6. 6. • Protagonists in ICU : • Invasive Candidiasis • Represents over 10% of infections in ICU • Rates in the ICU >10-fold those on the wards • Probably underestimated • Invasive Aspergillosis and other mould pathogens • Transplant patients, haematological conditions, immunosuppressed • Other patients (lung disease, liver failure). Uncommon. • Fusarium, Scedosporium, Zygomycetes • Pneumocystis • Cryptococcus
    7. 7. • Emergence : • Normal colonizer of GI tract. Most infections are endogenous. • GI tract surgery • Immunosuppression, including : • Broad spectrum antibiotics • Neutropenia and Decreased T-cell immunity • Invasive devices (CVC, Dialysis, TPN) • Extensive candidiasis develops early when integrity of natural barriers is compromised • Risk assessment
    8. 8. • Invasive Candidiasis : • May affect virtually every organ (micro-abscesses) • Vulnerable sites : endophtalmitis, meningitis, vertebral osteomyelitis, hepatosplenic abscesses, endocarditis (prosthetic valves)• Culture from normally sterile sites, including blood cultures • Newer techniques not sufficiently validated• High mortality rate (25-38% for candidemia, at least in part due to the infection itself)• Many species • Different susceptibility profiles • No prediction model shown accurate
    9. 9. • Echinocandin (Caspofungin, Anidulafungin, Micafungin) as initial choice• Many patients have prior Azole exposure. Selection of resistant organism • C. glabrata • C. krusei (intrinsic)• Clinical superiority compared to Azoles? • Theoretical fungicidal benefit • Anidulafungin vs Fluconazole C. Reboli & Al. – NEJM 2007;356:2472-2482 Non inferiority trial D. R. Andes & Al. - Clinical Infectious Disease 2012;54(8):1110-1122
    10. 10. • Echinocandin (Caspofungin, Anidulafungin, Micafungin) as initial choice• Other considerations: • Bypasses the problem of drug interactions • Caspofungin: agent with extensive data in Neutropenic patients • Amphotericin B still preferred ? • C. parapsilosis: higher MIC ; no outcome implication?
    11. 11. • Echinocandin (Caspofungin, Anidulafungin, Micafungin) as initial choice • Other considerations: • Only Fluconazole can achieve sufficient concentrations in urine • Problem of fungal balls • Eye/CNS diffusion: Flucytosine, Fluconazole, Amphotericine B • Hepatotoxicity … • Removal of CVC: associated with decreased mortality • Mortality benefit of early treatment implementation • Days rather than hours
    12. 12. • Combination therapy ?• CNS infections• Prosthesis (prosthetic joints, …) • Flucytosine better than Fluconazole on biofilms• Endocarditis
    13. 13. • Aspergillus • Zygomycetes (Mucor, Rhizopus) • Other (Scedosporium, Fusarium)• Diagnostic problem • Infect areas in direct contact with the environment • Culture and examination of superficial specimen : contaminants • Biopsy• Treatment problem • Resistant organism • Empirical treatment: risk of inadequacy • Conservative treatment: often insufficient
    14. 14. • By far the most common opportunistic mould • Invasive pulmonary Aspergillosis • Aspergilloma• Haematology patients: 2 waves • Neutropenia • Post-acute phase: Steroids (GVHD)• Epidemiology • Important data to identify patients at risk • Derives the required pre-test probability • Very difficult
    15. 15. • Strategy • Empirical approach • Diagnostic approach • No very satisfying guideline• Diagnostic issues • Halo sign only if neutropenic • Sputum production is minimal if neutropenic • Poor performance of testing• Limitations of empirical approach • Selection of rare pathogens (underlying condition, antifungal prophylaxis) • No satisfying broad empirical coverage • Interfere with future diagnostic attempts
    16. 16. • Serologic tests • ß-D-Glucan: fungus (non Cryptococcus, Zygomycetes) • Galactomannan: Aspergillus • PCR: not validated• ß-D-Glucan • Attempt to solve issue of slow growth of Candida from BC • False positive common. Moderate performance (PPV ~55%). • May exclude Pneumocystis if negative?• Galactomannan • Proposed as screening test for high risk patients • Interference with ß-Lactams (Tazocin), and fungal prophylaxis • Non reproducible results on Australian samples • Role when used on BAL samples ? • Highly standardized technique (120mL, Centrifugation) • Cut-off? 1.0? • Good negative predictive value
    17. 17. • Difficult use • Spectrum inadequate for empirical use • Which end-points? (fever not reliable, …) • Side effects • Drug interactions • Pharmacodynamics/Pharmacokinetics • Diffusion problem • Dose adjustment• 3 major classes • Triazoles • Fluconazole, Itraconazole, Voriconazole, Posaconazole • Echinocandins • Caspofungin, Anidulafungin, Micafungin • Amphotericin B • Flucytosine
    18. 18. • Linear pharmacokinetics. Predictable levels.• Loading dose• Tubular reabsorption • Increased clearance in CVVH• Non optimized dosing accounts for treatment failure ?
    19. 19. • Itraconazole • Concominant use of PPI: major impingement on absorption • Cyclodextrine • Increased absorption • Increased nausea/diarrhea • Accumulation in renal failure• Voriconazole • Complex pharmacokinetics • No impact of PPI • Large individual variations (CYP2C19): • Poor (Chinese) vs high metabolizers • Highly variable concentrations • Very often under-dosed • 4 mg/Kg q12h, after loading dose • Saturable excretion: risk of overdosing! • Interactions: Phenytoin, Rifampicin, Corticosteroids
    20. 20. • Posaconazole • IV formulation available in the future • Interference by PPI, mucositis, fatty meal • Limited benefit in acute setting • 100h for steady state
    21. 21. • An expanding problem of modern medicine• Vulnerable host • predisposing holes in the normal barrier • Holes in the prophylactic “immune system replacement therapy”• True impact on outcome • more than just the effect of the underlying advanced disease• Difficult diagnosis. Host is predisposed to a wide array of injuries. • Value of tissue / deep specimen collection• Inconvenient empirical treatment• Difficult drugs. Difficult endpoints.• Role of TDM