How Can We Prevent Invasive Fungal Disease?

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1 How Can We Prevent Invasive Fungal Disease? Chris Kibbler Professor of Medical Microbiology University College London And Royal Free Hospital, London, UK

2 Invasive Aspergillosis 2 - Acquisition

3 Preventive Interventions Acquisition -Infection control practices -Environmental controls -Diet Colonisation - Prophylaxis Early invasion -Prophylaxis -Immunomodulation

4 Aspergillus species 4 - Airborne sources Found in air in 9-29% homes in the US, 74% in Scotland Counts may increase 3000x during vacuum cleaning, dusting, door opening, pet entry, vegetable peeling etc. Lehtonen &Reponen, 1993 Seasonal fluctuations - usually higher in autumn and winter? threshold counts for nosocomial IA > 2.0 cfu/m 3 - Alberti 2001 > 0.9 cfu/m 3 - Rhame 1991 > 0.2 cfu/m 3 - Arnow 1991 > cfu/m 3 - Sheretz 1987

5 5 Impact of Air filtration Only 38% IA in BMT patients nosocomial McWhinney et al, Clin Infect Dis 1993; 17: Median time to IA in BMT 78 days in LAF rooms 40 days in non-laf rooms Relative risk of IA <40 days in non-laf room = 5.6 (95% CI, ) Wald et al, J Infect Dis 1997; 175:

6 Which is more important 6 water or air? BMT unit Oslo 15 episodes of IA in BMT recipients Environmental (water: n=54; air: n=21) and clinical (n=21) isolates of Aspergillus fumigatus AFLP used for genotyping Separated isolates into water and air sources Indistinguishable strains 1 patient + lake water supply 1 patient + outside air 8 patients clustered with water isolates 6 patients clustered with air isolates Warris J Clin Microbiol 2003;41:

7 7 Opportunistic Fungal Infections - Main Candidates for Prophylaxis AIDS guidelines IDSA Neutropenic and stem cell transplant patients guidelines IDSA ECIL National e.g. BCSH Solid organ transplant recipients guidelines IDSA ICU patients guidelines IDSA Neonates guidelines IDSA

8 Antifungal prophylactic agents 8 Oral nystatin Oral amphotericin B Miconazole Ketoconazole IV amphotericin B Lipid associated amphotericin B Inhaled amphotericin B/AmBisome Fluconazole Itraconazole Micafungin Posaconazole Voriconazole

9 Azole Prophylaxis in 9 Neutropenia - Meta-analysis RCTs of fluconazole, itraconazole, ketoconazole, miconazole or iv amphotericin B vs. placebo/no treatment or oral polyenes 38 trials 7014 patients Bow et al, Cancer 2002; 94:

10 Azole Prophylaxis in Neutropenia - Meta-analysis - Results 10 IV antifungal therapy use OR 0.57 ( ) Superficial fungal infection OR 0.29 ( ) Invasive fungal infection OR 0.44 ( ) IFI mortality OR 0.58 ( ) No effect on overall mortality and incidence of IA (only 1% in each group) Bow et al, Cancer 2002; 94:

11 Itraconazole prophylaxis - Meta-analysis RCTs Fungal Infection Capsules Oral solution Invasive FI 0.92 ( ) NS 0.51 ( ) p= Invasive yeast Infections 0.63 ( ) NS 0.4 ( ) p=0.005 Invasive Aspergillosis 1.75 ( ) NS 0.52 ( ) p=0.02 Mortality from IFI 1.01 ( ) NS 0.58 ( ) p= Glasmacher et al, J Clin Oncol :

12 Aerosolized Liposomal Amphotericin B plus Fluconazole During Prolonged Neutropenia 12 L-Amb (n=139) Placebo (n=132) P-value Age M/F 77/62 81/51 >0.1 HEPA >0.1 AML-MDS >0.1 Other >0.1 Chemotherapy >0.1 Auto HSCT >0.1 Allo HSCT >0.1 Untreated >0.1 Other >0.1 Rjinders et al, Clin Infect Dis 2008; 46:

13 Aerosolized Liposomal Amphotericin B plus Fluconazole During Prolonged Neutropenia 13 L-Amb (n=139 Placebo (n=134) P-value OR EORTC/MSG IPA Prov/prob MITT 6/139 18/ OT 2/90 13/ Modified EORTC/MSG IPA Prov/prob MITT 11/139 23/ OT 3/90 17/ Rjinders et al, Clin Infect Dis 2008; 46:

14 14 Antifungal Prophylaxis Studies in Allogeneic Hematopoietic Stem Cell Transplant Recipients Voriconazole Posaconazole Micafungin Itraconazole Fluconazole Neutropenia Engraftment GvHD IFI Days post transplant

15 Posaconazole Prophylaxis in Allogeneic HSCT Recipients With GvHD: Incidence of Moulds Fixed Time Period (112 days) Proven/Probable Invasive Fungal Infection All IFI Posaconazole n = (5.3%) Fluconazole n = (9.0%) Aspergillus 7(2.3%) 21(7%) Unspecified Aspergillus 5 (3) 6 (4) P=0.07 P= A fumigatus 2 5 (6) A flavus 0 3 (2) A niger 0 1 A terreus 0 1 (1) Unspecified mould 2 (1) 1 (1) Rhizomucor miehei Scedosporium prolificans (1) 0 Pseudallescheria boydii 1 (1) 0 Numbers in parentheses indicate proven/probable invasive fungal infection while on prophylaxis. Ullmann AJ et al. NEJM 2007;356:335-47

16 Meta-analysis of prophylaxis in Critical Care 16 9 RCTs (3 ketoconazole, 6 fluconazole) 1226 patients Subset selection Central venous catheter TPN Previous antibiotics Previous surgery Colonisation data only reported in 5 trials Variation in inclusion criteria and definition and outcome measures Cruciani Intensive Care Med 2005; 31:

17 17 Cochrane Systematic Review - Prophylaxis in Critical Care 8 trials: fluconazole vs. nil 4 trials: ketoconazole vs. nil or nonabsorbable 1606 patients Invasive Candida infections - fluconazole RR 0.47, 95% CI Superficial fungal infections RR 0.59, 95% CI Total mortality (11 trials) RR 0.76, 95% CI Playford, J Antimicrob Chemother 2006; 57:

18 Prophylaxis in Critical Care - IDSA Recommendations 18 Fluconazole 400mg/day for high risk patients in adult units with a high incidence of candidiasis BI Pappas et al, Clin Infect Dis 2009; 48:503 35

19 Why Do Preventive Measures Fail? Prior colonisation Continued transmission Breakthrough with resistant fungi PK/PD issues Drug Interactions Compliance/tolerance

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