Fungal pneumonia 11
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This document discusses fungal pulmonary infections. It begins by noting that fungi cause a small portion of community-acquired and hospital-acquired pneumonia cases. It then focuses on invasive fungal infections, noting that candidiasis is the fourth most common nosocomial bloodstream infection in the US. Mortality rates for invasive candidiasis and aspergillosis infections are also provided. The document provides information on diagnosing and treating various fungal infections like candidiasis, aspergillosis, and Pneumocystis jirovecii pneumonia. It discusses antifungal drug classes, specific drugs, and treatment guidelines.
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Fungal pneumonia 11
- 1. Fungal Pulmonary infections Islam Ibrahim, M.D., FACP, FCCP, Associate clinical Professor, Pulmonary and critical care medicine, University of California San Diego, USA. imibrahim@ucsd.edu International Medical Center, Jeddah, KSA. iibrahim@imc.med.sa
- 5. • A small portion of CAP and HAP. Fungi • Immunosuppressed Concern
- 7. 7 Invasive Fungal Infections Are a Growing Problem: Focus on Candidiasis Invasive Candida infections – 4th most common nosocomial bloodstream infection in the United States* *In a 3-year (1995–1998) surveillance study of 49 hospitals in the United States. Adapted from Edmond MB et al Clin Infect Dis 1999;29:239–244; Andriole VT J Antimicrob Chemother 1999;44:151–162; Uzun O, Anaissie EJ Ann Oncol 2000;11:1517–1521. Coagulase-negative staphylococci 3908 31.9 Staphylococcus aureus 1928 15.7 Enterococci 1354 11.1 Candida species 934 7.6 Pathogen No. of Isolates Incidence (%)
- 8. IFIs Are a Substantial Source of Mortality in Patients at High Risk Cornely OA et al. Infection. 2008;36:296-313. 0 10 20 30 40 50 60 70 80 90 100 Candida spp Aspergillus spp Mortality Range, % 49 87
- 9. 9 Patients with candidal bloodstream infections Invasive Candidiasis Mortality Associated with Candidemia Adapted from Edmond MB et al Clin Infect Dis 1999;29:239–244. 0 5 10 15 20 25 30 35 40 45 40% 25% PercentofPatients Patients with bacterial (non-candidal) bloodstream infections
- 14. Coccidioides • Soils • Alkaline, salinic, sandy • Extreme temperatures.
- 15. • Sporotrichosis • temperate zones
- 16. Disseminated Fungal Disease • Skin • bone and joints • brain and meninges • Kidneys • Liver and spleen • Muscle (Candida species) • Eye Candida • Nasal passages and sinuses • Bloodstream and bone marrow
- 17. opportunistic
- 25. Diagnosis of IC and candidemia is • Difficult • Uncertain • Delayed Reason • Clinical picture is uncharacteristic • Pathogen detection • Fungi in blood cultures • Limited sensitivity - 50% • Delayed results In the ICU
- 26. Impact of delayed treatment on mortality Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005;49: 3640–5.
- 27. When should I suspect fungal pulmonary infection? High index of suspicion. Immunocompromised patient. Poor response to antibiotics. Persistent fever and illness.
- 28. EORTC/MSG criteria for invasive fungal disease
- 29. Host factors neutropenia allogeneic stem cell transplant Prolonged corticosteroids T cell immunosuppressants Inherited severe immunodeficiency Clinical criteria LRT fungal disease Tracheo-bronchitis Sinonasal infection CNS infection Disseminated candidiasis Mycological criteria antigen in sputum, BAL, PL EFF, BX galactomannan plasma, serum, BAL, or CSF fungus in PL EFF, BX CT: macronodules/ halo sign Air-crescent sign Cavity
- 31. Host factors neutropenia allogeneic stem cell transplant Prolonged corticosteroids T cell immunosuppressants Inherited severe immunodeficiency Clinical criteria LRT fungal disease Tracheo-bronchitis Sinonasal infection CNS infection Disseminated candidiasis Mycological criteria antigen in sputum, BAL, PL EFF, BX galactomannan plasma, serum, BAL, or CSF fungus in PL EFF, BX CT: macronodules/ halo sign Air-crescent sign Cavity
- 33. EORTC/MSG criteria for invasive fungal disease Probable IFD host factor clinical criterion mycological criterion. Possible IFD host factor clinical criterion Confirmed diagnosis Evidence of fungal invasion of tissue. Fungus recovered from a sterile site.
- 35. Dx
- 39. Galactomannan enzyme immunoassay specificity, 97.5% sensitivity, 92.1% (BAL) Galactomannan Sensitivity 90 %. Specificity 94% false-positive piperacillin- tazobactam
- 40. Aspergillus PCR. invasive pulmonary aspergillosis sensitive (100%)40-66% sensitive
- 41. Beta-D-glucan
- 42. Beta-D- glucan • Fungal-derived antibiotics • Pseudomonas aeruginosa infections
- 43. Beta-D-glucan
- 44. Treatment
- 46. (Kathiravan et al., 2012; atsumi et al., 2013).
- 49. (Kathiravan et al., 2012; atsumi et al., 2013).
- 53. Azoles •inhibit lanosterol 14- alpha-demethylase •conversion of lanosterol to ergosterol •cellular membrane .
- 54. Fluconazole •excellent safety profile •Inexpensive •highly bioavailable
- 55. voriconazole • superior to fluconazole • active against C. krusei • cross-resistance • C. glabrata.
- 56. Posaconazole • approved as a prophylactic agent allogeneic hematopoietic cell transplant recipients graft-versus-host disease prolonged neutropenia approved for oropharyngeal candidiasis Not approved for systemic candidiasis
- 57. Itraconazole •mucosal candidiasis •not for systemic infections.
- 58. Isavuconazole •approved for treatment of aspergillosis •not approved for the treatment of candidiasis.
- 59. AnidulafunginCaspofungin Micafungin Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Debono M, Gordee RS. Annu Rev Microbiol. 1994;48:471–497; Debono M et al. J Med Chem. 1995;38:3271–3281. Echinocandins N O O O NH O H H H H O H CH3 O O H2N OH NH HO H2N HO NH H N OH OH HN OH N H HO H3C CH3 CH3 O O O N O O HN N O O O O O N O H3C S O O HO OH HO HO OH H N NH NH H3C H2N HO HO OH NH OH OH CH3 O O N H3C O N O O O O O HO HO HO OH H N NH OH HO HO OH NH HN CH3 OH NH H3C H3C • Side chains are key determinants of lipophilicity, solubility, antifungal activity, and toxicity
- 60. Echinocandins • inhibit synthesis of 1,3-beta-D-glucan of the fungal cell wall • Cidal for most Candida species • favorable toxicity profiles • approved for the treatment of candidemia and other forms of invasive candidiasis. • preferred over azoles for the initial treatment of candidemia • C. glabrata or C. krusei • previously treated with an azole .
- 62. In Vivo Activity in Animal Models of Disseminated Infection *Rat pulmonary infection model. Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information. Caspofungin Micafungin Anidulafungin Candida spp Candidiasis due to: C albicans C glabrata C krusei C lusitaniae C parapsilosis C tropicalis Candidiasis (pathogens not specified) Candidiasis due to: C albicans Aspergillus spp Pulmonary aspergillosis* due to: A fumigatus A Terrus – –
- 63. Candidemia 1. echinocandins 2. azole. 3. amphotericin B - • toxicity.
- 64. Candidemia - Nonneutropenic adults • (caspofungin) is recommended as initial therapy. • Alternative • fluconazole • not critically ill • fluconazole-resistance unlikely • A lipid amphotericin B • resistance to other antifungal agents.
- 65. Candidemia - Nonneutropenic adults Treat for 14 days • after first negative blood culture • resolution of signs and symptoms • Dilated funduscopic examination • within a week of diagnosis • for all patients.
- 66. Candidemia - Neutropenic patients • (caspofungin is recommended as initial therapy. • alternative • A lipid formulation of amphotericin B • less attractive toxicity. • fluconazole 800 • not critically ill • no prior azole exposure • Additional mold coverage -voriconazole 400 mg orally
- 67. Candidemia - Neutropenic patients therapy is 14 days • after documented clearance of Candida from the bloodstream • neutropenia and signs and symptoms have resolved. • Dilated funduscopic examination is recommended for all patients within 7 days after recovery from neutropenia.
- 68. C. glabrata and C. krusei • An echinocandin is preferred over amphotericin B • Voriconazole is approved for this indication • but • cross-resistance between fluconazole and voriconazole
- 69. • usually susceptible to • echinocandins • Voriconazole • resistant to • fluconazole. • high (MICs) to amphotericin B C. krusei
- 70. • 2016, (CDC) • multidrug-resistant • high mortality rates. • initial therapy • echinocandin • resistant to azoles. C. auris
- 71. A. Glockner and M. Karthaus. Current aspects of invasive candidiasis and aspergillosis in adult intensive care patients, Mycosis, Blackwell Verlag GmbH 2010 Early empirical therapy Fungemia Diagnosis Difficult delayed
- 72. Empirical antifungal treatment in ICU Clinical Prediction Rule (CPR) All of mechanical ventilation, day 1–3 of ICU stay broad spectrum antibiotics CVC ONE of • TPN (d1-3) • Dialysis (d1-3) • Major surgery (d-7-0), • Pancreatitis (d-7-0), • Steroids immunosuppressive agents Ostrosky-Zeichner L, et al. 2007. Eur J Clin Microbiol Infect Dis, 26:271–6. Ostrosky-Zeichner L, et al. Mycoses. 2011 Jan;54Ostrosky-Zeichner L, et al. 2007. Eur J Clin Microbiol Infect Dis, 26:271–6. Ostrosky-Zeichner L, et al. Mycoses. 2011 Jan;54
- 73. Empirical antifungal treatment in ICU The Candida Score • Parenteral nutrition.......................................(+1) • Prior surgery..................................................(+1) • Multifocal Candida colonization *................ (+1) • Severe sepsis ............................................... (+2) • 2.5 early antifungal treatment Leon C, et al. 2006. Crit Care Med, 34:730–7.Leon C, et al. 2009 Crit Care Med 37:1624–1633.
- 74. 1- Indication Indications Caspofungin Micafungin Anidulafungin invasive candidiasis adults Neutropenic Neutropenic Neutropenic Non-neutropenic Non-neutropenic Non-neutropenic invasive candidiasis pediatrics Neutropenic Neutropenic Neutropenic Non-neutropenic Non-neutropenic Non-neutropenic Empirical febrile, neutropenic adult or pediatric + X X invasive aspergillosis adult or pediatric refractory to or intolerant + X X
- 79. Caspofungin versus liposomal amphotericin B for treatment of invasive fungal infections in febrile neutropenia. Chin Med J (Engl). 2014;127(4):753-7. meta-analysis 1249 patients intention-to-treat caspofungin equal efficacy safer
- 81. How Should IPA Be Treated? Voriconazole strong recommendation; high-quality evidence). Alternative - liposomal AmB (strong recommendation; moderate-quality evidence) Isavuconazole (strong recommendation; moderate-quality evidence) Early initiation (strong recommendation; high-quality evidence).
- 82. Combination voriconazole + echinocandin may be considered in select patients (weak recommendation; moderate-quality evidence). Primary therapy with an echinocandin is not recommended (strong recommendation; moderate-quality evidence). caspofungin) can be used in settings in which azole and polyene antifungals are contraindicated (weak recommendation; moderate-quality evidence). treatment of IPA -for a minimum of 6– 12 weeks (strong recommendation; low quality evidence).
- 83. Echinocandins Echinocandins are effective in salvage therapy against IA • (either alone or in combination) but we do not recommend their routine use as monotherapy for the primary treatment of IA • (strong recommendation; moderatequality evidence).
- 84. 6- Hepatic Safety Caspofungin significant hepatic dysfunction, hepatitis, and hepatic failure have been reported therapy should be monitored worsening hepatic function risk/benefit of continuing therapy Anidulafungin significant hepatic dysfunction, hepatitis, and hepatic failure were uncommon in clinical trials. should be monitored worsening hepatic function risk/benefit of continuing therapy.