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Lecture on Prevention of Fungal Infections by Dr. Gamini Kumarasinghe during the 6th International Infection Control Conference 2006

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  1. 1. PREVENTION OF FUNGAL INFECTIONS Gamini Kumarasinghe Division of Microbiology National University Hospital, Singapore
  2. 2. Fungi range in size C. albicans chlamydospores Polyporus sulphureus Amanita muscaria Mycelia inside potato Black bread mold Mycelia on various foods
  3. 3. <ul><li>Found in virtually every habitat on the earth where organic materials exist , including the Antartica </li></ul><ul><li>salt, sugar etc </li></ul><ul><li>leather, wax, jet fuel, plastics etc </li></ul><ul><li>thermal pools, volcanic craters </li></ul>Fungal Habitats
  4. 4. <ul><li>Advancements in modern medicine has left </li></ul><ul><li>many individuals with impaired immune </li></ul><ul><li>systems </li></ul><ul><li>These individuals are the most vulnerable to </li></ul><ul><li>the fungal diseases </li></ul>Prevention Of Fungal Infections
  5. 5. The usual reservoir - not an infected human or animal - a site in nature where the fungus is growing as a saprophyte Prevention Of Fungal Infections Chung & Bennett, 1992
  6. 6. Because human mycoses are poorly communicable from person to person, mycoses are often endemic but rarely epidemic. Prevention Of Fungal Infections Chung & Bennett, 1992
  7. 7. Prevention Of Fungal Infections mopping the floor e.g. diving boards & floor mats periodically with a fungicidal solution
  9. 9. <ul><li>Respiratory isolation </li></ul><ul><li>not indicated </li></ul><ul><li>even when the patient in the adjacent bed is </li></ul><ul><li>immunosuppressed </li></ul><ul><li>Outside of neonatal candidiasis, transmission of a deep mycosis has been extraordinarily rare </li></ul><ul><li>( C & B; Garner, 1996 ) </li></ul>Isolation Precautions
  10. 10. INFECTION IN THE HOSPITAL Immuno-compromised patients
  11. 11. Aspergillosis Infection In The Hospital
  12. 12. <ul><li>Aspergillosis </li></ul><ul><li>Patients susceptible to invasive aspergillosis are particularly congregated in </li></ul><ul><li>oncology </li></ul><ul><li>transplantation </li></ul><ul><li>intensive care units </li></ul>Infection In The Hospital
  13. 13. Nosocomial Aspergillosis <ul><li>“ safety levels” for bio-aerosols ? </li></ul><ul><li>Rural outdoor air – 10,000 CFU/cm </li></ul><ul><li>Threshold limit in indoor environment unknown </li></ul><ul><li>Positive correlation – increased spore count & IA </li></ul><ul><li>(Iwen et al, 1994; Hay et al, 1995) </li></ul>
  14. 14. <ul><li>Positive Pressure Ventilation (PPV) </li></ul><ul><li>sealed room </li></ul><ul><li>with an anteroom </li></ul><ul><li>air-floor at least 12 ACH </li></ul><ul><li>HEPA filter (99.97% efficient at 0.3 µ g particles) </li></ul><ul><li>(ASHRAE, 1998; Humphreys, 2003) </li></ul>Protective Isolation
  15. 15. <ul><li>Laminar air-flow (LAF) </li></ul><ul><li>much greater ACH </li></ul><ul><li>expensive </li></ul><ul><li>noise </li></ul><ul><li>drafts </li></ul><ul><li>Uncomfortable to the patient </li></ul><ul><li>(ASHRAE, 1998; Humphreys, 2003) </li></ul>Protective Isolation
  16. 16. Anteroom Patient’s Room Bed Exhaust PPV : 12 ACH LAF : 400 ACH Positive Pressure Ventilation Room Adapted from HPAC, 2000
  17. 17. Aspergillosis Keeping patients in such special rooms - considerable cost - nursing care, medical attention - emotional stress on the patient Infection In The Hospital
  18. 18. Nosocomial Aspergillosis <ul><li>Most institutions rely on PPV filtration & not on LAF </li></ul><ul><li>Important risk factor </li></ul><ul><li>immunosuppressive condition </li></ul><ul><li>High risk patients may develop IA even with </li></ul><ul><li>low spore count </li></ul><ul><li>(Hay et al, 1995) </li></ul>
  19. 19. HEPA filters Haematological malignancies - protective for highly IC patients - effective at controlling outbreaks due to Aspergillus conidia (Hahn et al., 2002) Protective Isolation
  20. 20. HEPA filters Bone marrow transplant recipients - tenfold greater incidence than other IC patients - risk could be eliminated by using HEPA with LAF (Sheretz et al., 1987) Protective Isolation
  21. 21. Portable HEPA filters ? Protective Isolation
  22. 22. Portable HEPA filters - costly preventive strategy of questionable value 1 - under field conditions portable units not recommended 2 1. Mantadakis & Samonis, 2006 2. Engelhart et al., 2003 Protective Isolation
  23. 23. Nosocomial infections: other moulds Fusarium, Trichosporon spp., dematiaceous moulds, Zygomycetes etc may affect immunocompromised patients (Walter EA, 1995)
  24. 24. <ul><li>“ other moulds” </li></ul><ul><li>IC individuals risk infections by more than 270 species </li></ul><ul><li>contaminated skin lotions, twigs, medications etc </li></ul><ul><li>gain access: through GI tract </li></ul><ul><li>normally a sign of contamination </li></ul><ul><li>(but in neutropaenic might indicate disseminated disease) </li></ul>Fungal Infections Perfect JR, 2005
  25. 25. IC individuals risk infections by more than 270 species Fungal Infections Perfect JR, 2005 Good housekeeping
  26. 26. Candidiasis Infection In The Hospital
  27. 27. Candidiasis The usual reservoir is the patient's own body Infection In The Hospital
  28. 28. Candidiasis Patients with severe and prolonged neutropenia Prone to develop disseminated candidiasis from numerous small ulcers caused by Candida species in the stomach, oesophagus, and intestine Infection In The Hospital
  29. 29. Prevention of candidiasis Despite massive oral doses of nystatin , to reduce Candida in stools prevention of disseminated candidiasis has not been convincingly demonstrated Infection In The Hospital
  30. 30. <ul><li>Topical / Non-absorbable antifungal agents </li></ul><ul><li>clotrimazole </li></ul><ul><li>nystatin </li></ul><ul><li>amphotericin B </li></ul><ul><li>- decrease colonizing burden </li></ul><ul><li>- mucosal manifestations </li></ul><ul><li>However, does not reduce invasive candidiasis or mould infection </li></ul><ul><li>(Tollemar, 1997; Boeckh & Marr, 2001) </li></ul>Infection In The Hospital
  31. 31. <ul><li>Candidiasis in Neonatal Units </li></ul><ul><li>Low birth weight more susceptible </li></ul><ul><li>blood stream infection following IV </li></ul><ul><li>catheters </li></ul>Infection In The Hospital
  32. 32. <ul><li>Candidiasis in Neonatal Units </li></ul><ul><li>candidaemia in low birth weight – high mortality </li></ul><ul><li>preliminary data – fluconazole reduces infections </li></ul><ul><li>this practice is not used widely </li></ul><ul><li>criteria for initiation prophylaxis is unknown </li></ul>Prophylaxis Burwell, 2006 Aseptic techniques, care of umbilical catheters
  34. 34. <ul><li>Ubiquitous fungi, such as Candida and Aspergillus, can </li></ul><ul><li>be handled with BSL 1 precautions </li></ul><ul><li>Standard microbiologic technique is all that is required </li></ul>Infection In The Laboratory
  35. 35. <ul><li>H. capsulatum or C. immitis </li></ul><ul><li>for opening culture dishes </li></ul><ul><li>pipetting, vortexing, </li></ul><ul><li>any other activity that might generate an aerosol </li></ul><ul><li>handling ‘ mould forms ’ </li></ul><ul><li>Class 1 or class 2 biologic safety cabinet </li></ul>Infection In The Laboratory
  36. 36. <ul><li>Most other procedures with pathogenic </li></ul><ul><li>fungi can be done at biosafety level 2 </li></ul><ul><li>This includes processing clinical specimens and </li></ul><ul><li>working with the ‘ yeast form’ of H. capsulatum or </li></ul><ul><li>spherules of C. immitis </li></ul>Infection In The Laboratory
  37. 37. <ul><li>Risk group 1 ubiquitous </li></ul><ul><li>Risk group 2 hepatitis B, HIV </li></ul><ul><li>Risk group 3 TB, Fungi* </li></ul><ul><li>Risk group 4 African h’gic fevers </li></ul><ul><li>– aerosol generating procedures* </li></ul><ul><li>– ‘ mould forms’ </li></ul>Classification of Microorganisms
  39. 39. <ul><li>Biosafety level 2 precautions are adequate for </li></ul><ul><li>all mycoses </li></ul><ul><li>Urine of animals may contain </li></ul><ul><li>C neoformans, H capsulatum & C immitis & </li></ul><ul><li>contaminate cage bedding </li></ul><ul><li>Animal bedding contaminated with the tissue forms </li></ul><ul><li>might convert and grow the mould during prolonged </li></ul><ul><li>storage </li></ul>Precautions With Infected Laboratory Animals
  40. 40. Environmental control
  41. 41. <ul><li>Candida is present in the subject's endogenous </li></ul><ul><li>reservoir (Odds, 1998) </li></ul><ul><li>However, exogenous sources such as </li></ul><ul><li>another person, food, intravenous catheters, and parenteral </li></ul><ul><li>fluids—have also been reported (Meunier, 1987) </li></ul><ul><li>Reduction in risk factors, aseptic practices & reducing </li></ul><ul><li>Candida colonization </li></ul>Environmental control Yeasts
  42. 42. Outbreaks of infections after construction work in hospitals (Bodey & Vartivarian, 1989) Environmental control Aspergillus spp. & other molds
  43. 43. <ul><li>Construction & renovation associated with IA </li></ul><ul><li>( Weems et al, 1987 ) </li></ul><ul><li>HEPA significantly reduces the incidence of lA </li></ul><ul><li>( Humphreys, 2004 ) </li></ul><ul><li>Enhanced cleaning & the sealing of windows </li></ul><ul><li>the use of prophylactic anti-fungal agents ??? </li></ul>
  44. 44. <ul><li>Endemic areas of histoplasmosis / coccidiomycosis </li></ul><ul><li>Preventing inhalation of infected dust </li></ul><ul><li>- more difficult </li></ul><ul><li>control measures appear prudent around </li></ul><ul><li>desert military training areas , airports and helicopter landing </li></ul><ul><li>areas, construction sites etc </li></ul><ul><li>e.g. water sprays, disinfectants </li></ul><ul><li>(DHHS, 1997) </li></ul>Prevention Of Fungal Infections
  45. 45. <ul><li>Cryptococcosis is an exogenous infection </li></ul><ul><li>usually acquired prior to hospitalization by inhalation </li></ul><ul><li>of fungal spores found in soil, vegetable matter, and </li></ul><ul><li>bird excrement. </li></ul>Environmental control
  46. 46. <ul><li>proper cooking of food </li></ul><ul><li>avoidance of raw vegetables & pepper </li></ul><ul><li>no potted plants or flowers should be allowed on the </li></ul><ul><li>ward </li></ul>Environmental control (Tollemar, 1997)
  47. 47. One year old study in a major tertiary care hospital About 200 bone marrow and organ transplants / yr Dept of Environmental and Occupational Health Science, University of Illinois at Chicago Fungi in the environment Curtis et al, 2005
  48. 48. <ul><li>One year old study: monitor fungi in the hospital </li></ul><ul><li>extensive indoor renovations </li></ul><ul><li>several large demolition & building projects within 1 km </li></ul>Fungi in the environment Curtis et al, 2005
  49. 49. <ul><li>One year old study </li></ul><ul><li>Aspergillus propagules in all parts of the hospital </li></ul><ul><li>Aspergillus concentrations higher indoors cf to outside </li></ul><ul><li>Total fungi were significantly higher outside </li></ul><ul><li>Therefore, infiltration of outside air cannot be the primary </li></ul><ul><li>mechanism for producing airborne aspergillus levels </li></ul>Fungi in the environment Curtis et al, 2005
  50. 50. <ul><li>One year old study </li></ul><ul><li>Aspergillus sources in the hospital </li></ul><ul><li>dust from duct cleaning </li></ul><ul><li>renovation </li></ul><ul><li>sites of water damage </li></ul><ul><li>moisture condensation </li></ul>Fungi in the environment Curtis et al, 2005
  51. 51. <ul><li>One year old study </li></ul><ul><li>Approaches to controlling aspergillus infections in hospitals </li></ul><ul><li>moisture / water control </li></ul><ul><li>HEPA filters </li></ul><ul><li>sealed positive pressure rooms </li></ul><ul><li>environmental monitoring of aspergillus </li></ul>Fungi in the environment Curtis et al, 2005
  52. 52. <ul><li>differences in opinion </li></ul><ul><li>current guidance, in favour of their removal from clinical </li></ul><ul><li>areas </li></ul><ul><li>not in the vicinity of IC patients </li></ul>Potted plants & Flowers CDC, MMWR 2000;49(RR10):1-128
  53. 53. Routine measures – not the ideal solution Fungal Infection Prevention
  54. 54. <ul><li>Environmental fungi </li></ul><ul><li>- preventing exposure, not effective </li></ul><ul><li>Endogenous flora </li></ul><ul><li>- difficult </li></ul><ul><li>Improving host defences </li></ul><ul><li>- not always possible </li></ul>Fungal Infection Prevention
  55. 55. Prevention <ul><li>Prophylactic </li></ul><ul><li>Empirical & </li></ul><ul><li>Pre-emptive therapy </li></ul>Resort to Antifungal Agents
  56. 56. Antimicrobials administered to patients at high risk of developing the disease, who are not infected and not manifesting symptomatic disease. Prophylaxis Goodman et al., 1992
  57. 57. <ul><li>commencement of Rx at the first clinical suspicion </li></ul><ul><li>still results in about 10% break through infections </li></ul>Empiric therapy De Pauw, 2005
  58. 58. Toxicity & cost are major shortcomings of such therapy Hence, “preemptive” approach Emperic therapy Maertens clin inf dis 2005 Nov 1
  59. 59. Preemptive Therapy
  60. 60. The administration of antimicrobials to patients already infected , but who do not yet manifest symptomatic disease in whom there are markers of pathogen invasion Synonymous with secondary prophylaxis or preventive therapy Preemptive Therapy Singh N., 2001
  61. 61. <ul><li>conventional microbiological </li></ul><ul><li>histological </li></ul><ul><li>radiological techniques </li></ul><ul><li>were the cornerstone of diagnosis </li></ul>Diagnosis of fungal infections
  62. 62. <ul><li>Limited impact on clinical decision making </li></ul><ul><li>too insensitive </li></ul><ul><li>time consuming </li></ul><ul><li>lacked general accessibility </li></ul><ul><li>So P-E therapy depends on microbiological markers </li></ul><ul><li>i.e. non-culture techniques </li></ul>Diagnosis of fungal infections Hope et al., 2005
  63. 63. Microbiologic markers Non culture based assays
  64. 64. <ul><li>Non culture based assays </li></ul><ul><li>galactomannan </li></ul><ul><li>beta-D-glucon (accuracy, role in diagnosis remains </li></ul><ul><li>unclear, Wheat 2006 ) </li></ul><ul><li>fungal DNA by PCR (validation & standardization needed) </li></ul>Preemptive therapy Maertens et al, 2006
  65. 65. <ul><li>Galactomannan </li></ul><ul><li>multicentre study; 61% sensitivity & 93% specificity </li></ul><ul><li>(Pfeiffer et al., 2005) </li></ul><ul><li>clinical issues unanswered </li></ul><ul><li>does the assay correlates with fungal burden ? </li></ul><ul><li>impact of antifungals on test performance ? </li></ul><ul><li>cut-off value ? </li></ul><ul><li>false-positives and false-negative values etc etc ? </li></ul><ul><li>In conjunction with imaging techniques </li></ul>Preemptive therapy Maertens et al., December 2006
  66. 66. <ul><li>Galactomannan and computed tomography </li></ul><ul><li>Galactomannan </li></ul><ul><li>thoraxic computed tomography scanning </li></ul><ul><li>bronchoscopy with lavage </li></ul><ul><li>Conclusion: Reduce the exposure to expensive and potentially toxic </li></ul><ul><li> drugs & offer effective antifungal control </li></ul><ul><li> Failed to detect non-Aspergillus IFI </li></ul>preemptive therapy Maertens et al., 2005
  67. 67. Candida markers Mannan is a major component of the Candida cell wall Platelia Ag/Ab; Bio-Rad Lab 93% specificity & 80% sensitivity (Sendid et al., 1999 & 2002, Year et al., 2001)
  69. 69. <ul><li>Invasive Yeast Infection </li></ul><ul><li>Oral fluconazole </li></ul><ul><li>At a dose of 400 mg/day </li></ul><ul><li>provides protection against invasive yeasts </li></ul><ul><li>if infection occurs despite fluconazole </li></ul><ul><li>- assume the isolate is resistant </li></ul><ul><li>- moulds universally resistant </li></ul><ul><li>Emergence of non-albicans resistant strains </li></ul><ul><li>C krusei, C glabrata – naturally resistant </li></ul><ul><li>(MMWR, 2000; Goodman et al, 1992) </li></ul>Antifungal prophylaxis
  70. 70. <ul><li>Invasive Mould Infection </li></ul><ul><li>regimens studied </li></ul><ul><li>- moderate dose amphotericin B </li></ul><ul><li>- low dose amphotericin B </li></ul><ul><li>- aerosolized amphotericin B </li></ul><ul><li>- intranasal amphotericin B </li></ul><ul><li>- lipid formulations of amphotericin B </li></ul><ul><li>- itraconazole </li></ul><ul><li>no regimen shown to be effective </li></ul><ul><li>Hence, environmental protection strategies </li></ul><ul><li>Boeckh & Marr, 2001; MMWR 2000; 49:1-125 </li></ul>Antifungal prophylaxis
  71. 71. <ul><li>Solid Organ Transplant (SOT) </li></ul><ul><li>A more controversial issue </li></ul><ul><li>primary antifungal chemoprophylaxis, because </li></ul><ul><li>only a few trials have been done </li></ul><ul><li>( Tollemar et al, 1995; Lumbreras, 1996 ) </li></ul>Prophylaxis
  72. 72. Pneumocystis jirovecii <ul><li>Autologous and allogenic transplantation </li></ul><ul><li>Prophylaxis with TMP-SMX – negligible rates </li></ul><ul><li>Dapsone, atovaquone or inhaled pentamidine </li></ul>(Espinel-Ingroff et al., 1997, 2000)
  73. 73. <ul><li>Adults </li></ul><ul><li>ALL </li></ul><ul><li>CNS tumours </li></ul><ul><li>receiving high-dose corticosteroid therapy </li></ul><ul><li>patients receiving combination </li></ul><ul><li>corticosteroid therapy with either myelotoxic </li></ul><ul><li>agents or fludarabine </li></ul><ul><li>prophylaxis should be considered </li></ul><ul><li>(Sullivan et al, 2001) </li></ul>Pneumocystis jirovecii
  74. 74. Pneumocystis jirovecii Children acute lymphoblastic leukemia allogeneic BMT SCT recipients - are known high-risk groups that should be offered prophylaxis. Momin & Chandrasekar, 1995: Link et al, 1993
  75. 75. New antifungal agents
  76. 76. <ul><li>Less toxic formulations of amp B </li></ul><ul><li>Improved azoles: Itraconazole, Voriconazole </li></ul><ul><li>Posaconazole </li></ul><ul><li>Echinocandin: micafungin </li></ul><ul><li>Despite these advances, mortality rates for IFI is about 90% </li></ul>New antifungal agents Denning et al., 1998
  77. 77. Summary and Conclusions
  78. 78. Summary of major recommendation for prevention of invasive fungal infection (Sullivan et al, 2001) Handwashing to prevent spread of exogenous Candida species Fungal surveillance cultures are not indicated in asymptomatic patients Topical antifungal agents are not recommended for prevention of invasive fungal infection Fluconazole (400 mg/day) is recommended to prevent invasive yeast Patients are to avoid hospital construction or renovation areas Alll Dll Dll All Alll Type of Prevention Rating
  79. 79. <ul><li>Pre-emptive approach for the prevention </li></ul><ul><li>Methods to monitor aspergillus in hospitals & other environments </li></ul><ul><li>- use of ELISA* </li></ul><ul><li>- DNA hybridization** </li></ul><ul><li>- PCR** </li></ul><ul><li>* Arruda et al., 1992 </li></ul><ul><li>** Rath & Ansorg, 2000 </li></ul>Future
  80. 80. <ul><li>The prevention an important goal of IC patients </li></ul><ul><li>Non-culture microbiologic assays </li></ul><ul><li>Prophylactic fluconazole at a dose of 400 mg/day decrease both </li></ul><ul><li>the rate of invasive yeast infection and mortality </li></ul><ul><li>Thus far, no prophylactic strategy has been shown to decrease the </li></ul><ul><li>incidence of invasive mould infection </li></ul><ul><li>Enhanced cleaning of the environment </li></ul>Conclusions