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Is azole prophylaxis a double-edged sword?

Is azole prophylaxis a double-edged sword?. Malcolm Richardson PhD, FRCPath Senior Lecturer in Medical Mycology University of Helsinki Finland. Who is at risk?. Prolonged/severe neutropenia AML: MO-2, MO FAB subtypes Corticosteroid use Indwelling catheters GvHD/gaft rejection in BMT

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Is azole prophylaxis a double-edged sword?

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  1. Is azole prophylaxis a double-edged sword? Malcolm Richardson PhD, FRCPath Senior Lecturer in Medical Mycology University of Helsinki Finland

  2. Who is at risk? • Prolonged/severe neutropenia • AML: MO-2, MO FAB subtypes • Corticosteroid use • Indwelling catheters • GvHD/gaft rejection in BMT • Total body irradiation and GI toxicity • Colonisation • Bacteraemia • Broad spectrum antibiotics • CMV • Chemotherapy with HD Ara-C/Fludarabine

  3. International consensus conference • BMT recipients: 400 mg/day fluconazole p.o. of i.v. • Lung or heart-lung transplants: fluconazole 10-14 days post-transplantation • Liver treansplantation: 100 mg/day fluconazole at time of admission • Recommendation: • neutropenia • only during periods of highest risk

  4. IDSA practice guidelinesCandidosis Prophylaxis – neutropenic patients • fluconazole 400 mg/d • amphotericin B 10-20 mg/d • AmBisome 1 mg/kg/d

  5. IDSA Practice guidelines Aspergillosis • IPA • amphotericin B: response: 14-83% • AmBisome 66% • iv itraconazole • switching therapy • Prophylaxis • itraconazole oral solution • ampho ’lite’ 0.15-0.25 mg/kg/d • ampho B aerosol

  6. Meta-analysis studies • Gotzche et al. BMJ 1997; 314: 1238-1244 • Bow et al. 37th ICAAC 1997; azole and polyenes: endpoints: • rates of superficial infection • use of empirical therapy • definite SFI • fungal death Conclusion: statistically significant benefit in azole prophylaxis but very low number of fungal deaths

  7. Prophylaxis – Current situation • Fluconazole: 200-400 mg daily • Itraconazole (capsules, oral solution): 400 mg/day • Low-dose amphotericin B: 0.1 to 0.25 mg/kg/day • Amphotericin B solution, sprays or inhalants • AmBisome: 2 mg/kg, 3 x weekly • Full dose AmBisome to protect patients with previous aspergillosis

  8. Prophylaxis: Key issues 1 • Which patients should benefit from prophylaxis? • What is the best drug and what is the appropriate dose? • What is the impact of prophylaxis on clinical practice re the use of empirical amphotericin B/AmBisome?

  9. Prophylaxis: Key issues 2 • Is prior prophylaxis a risk factor for subsequent IFI caused by resistant pathogens? • What is the approach for those patients with a previously documented fungal infection who need to undergo BMT? • What is the indication for growth factors?

  10. Prophylactic Therapy • Data on the efficacy of prophylaxis are not definitive. • There is no clear benefit of prophylaxis in many cases.

  11. Fluconazole for prophylaxis against rectal colonisation in the very LBWN • fluconazole 6 mg/kg or placebo • rectal colonisation • C. albicans most common species • 15.1% FLU • 46% placebo BUT: no difference in rate of invasive candidosis Kicklighter et al. Pediatrics 2001; 107: 293-298

  12. Serum levels of fluconazole in patients after cytoxicchemotherapy for hematological malignancy • 19 patients: samples d7 and d15 • HPLC detection • Max serum levels: • 200 mg/d: 7.9 mg/l • 400 mg/d: 15.6 mg/l • Min serum levels: • 200 mg/d: 5.0 mg/l • 400 mg/d: 10.3 mg/l • Considerable variation between patients Conclusion: ”These variations may be associated with prophylactic failures for patients with unsufficient fluconazole concentrations” Kami et al. Amer J Hematol 2001; 66: 85-91.

  13. Effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in BMT recipients withspecial attention to hepatic candidiasis • Autopsy study: 355 patients • 50% prophylaxis: 400 mg/kg • 40% fungal infection (any site) • Decrease in Candida infections: 27% to 8% • Increase in Aspergillus infections: 18%-29% • Fungal liver infection: 9% • Conclusions: • significant reduction in Candida • increase in aspergillosis van Burk Medicine (Baltimore) 1998; 77: 246-254

  14. Fluconazole prophylaxis prevents intra-abdominal candidiasis in high risk surgical patients • 49 patients: recurrent gastrointestinal perforations or anastomatic leakages • Fluconazole 400 mg/day intervention, or placebo 15 days • Primary end-point: intra abdominal Candida infection • Colonisation: • 15% fluconazole group • 62% placebo group • Infection: • 2/23 fluconazole • 7/20 placebo • 87% C. albicans • All strains susceptible to fluconazole Eggimann et al. Crit Care Med 1999; 27: 1066-1072

  15. Adverse consequences of azole prophylaxis • Increase in bacteraemia • Greater use of amphotericin B • No impact on survival • Advere effect on neutrophil recovery • Higher rate of GvHD • Increased mortality • Risk of hepatitis • Emergence and colonisation by FLU-resistant strains

  16. Stable phenotypic resistance of Candida species to amphotericin B conferred by preexposure to subinhibitory levels of azoles 1. “Inadvertant clinical selection for resistance to AmB may be more likely due to prolonged azole use than to AmB therapy” • Candida species differ in their response to AmB • Preexposure to azoles decreased the susceptibilities of all Candida species that were otherwise found to be susceptible to AmB Vazquez et al. J Clin iMicrobiol 1998; 36: 2690-2695

  17. Stable phenotypic resistance of Candida species to amphotericin B conferred by preexposure to subinhibitory levels of azoles 2 • C. albicans was unique: preexposure to azolesallowed growth, not just survival, in the presence of AmB • fluconazole-mediated AmB tolerance established by only a few hours exposure to fluconazole • protection lasts a few days Vazquez et al. J Clin Microbiol 1998; 36: 2690-2695

  18. Stable phenotypic resistance of Candida species to amphotericin B conferred by preexposure to subinhibitory levels of azoles 3 “Clinicial implications of this study are apparent. If patients fail to respond to fluconazole, they are frequently switched to amphotericin B” “Our in vitro data suggess that these sequential treatments may be counterproductive” Vazquez et al. J Clin Microbiol 1998; 36: 2690-2695.

  19. Isolation and characteristics of fluconazole-and amphotericin B-resistant Candida albicans from blood of two patients with leukemia • Fungaemia • Fluconazole prophylaxis 400 mg/day, 2 weeks • Empiric amphotericin B 0.5 mg/kg/day • Fluconazole MICs >64 mg/l, no history of previous exposure • Isolates resistant to amphotericin B • Successful treatment with amphotericin B 1-1.25 mg/kg/day + 5FC 150 mg/kg/day Nolte et al. Antimicrob Agents Chemother 1997; 44: 196-199

  20. Isolation and characteristics of fluconazole-and amphotericin B-resistant Candida albicans from blood of two patients with leukemia Conclusion “The emergence of fluconazole- and amphotericin B-resistant strains of C. albicans is a troubling new development” Nolte et al. Antimicrob Agents Chemother 1997; 44: 196-199

  21. Polyene resistance Myth or reality? “Polyene resistance has not been a major clincial problem to date” White et al. Clin Microbiol Rev 1998; 11: 382-402 “Despite more than 30 years of clinical use, resistance to polyene antifungals is rare” Ghannoum & Rice Clin Microbiol Rev 1999; 12: 501-517

  22. Fitness of azole-resistant clinical isolates • Exposure to azole antifungals selects azole-resistant isolates • Does persistence of azole-resistant strains require continuing presence of azole antifungals? • Maintenance of azole-resistant isolates will depend on their fitness (virulence) compared to azole-susceptible isolates • Conclusion: azole resistance acquired by genetic alterations is not necessarily linked with a decrease in virulence

  23. Alteration in cell type • Morphological forms of C. albicans differ in susceptibility to azoles • Azole drugs interfer with hyphal elongation • Do resistant yeasts form hyphae? • Are resistant strains with the ability to form hyphae, even in the presence of azoles, more pathogenic than a sensitive strain unable to form hyphae?

  24. Are azole-resistant yeasts more resistant to phagocytic killing? • Candida albicans/C. glabrata • virulent strains more resistant to phagocytosis and intracellular killing • azole-resistant strains more resistant to phagocytosis and killing • ?alterations in complement/opsonin receptors • Aspergillus fumigatus ???

  25. Is there a relationship between resistance development and virulence? • Animal models: resistance appears to correlate with diminished virulence • azole-resistant C. albicans: CMC • C. albicans strains defective in sterol 5,6 desaturase • AIDS patients with OPC: sequential isoaltes: azole resistant: no decrease in virulence Conclusion: azole resistance and decrease in virulence Sanglard. Drug Resistance Updates 1998; 1: 255-265

  26. Conclusions - Fluconazole • Fluconazole prophylaxis is a double-edged sword • Use should not be trivalized • Fluconazole attractive: • low toxicity • proven efficacy in systemic candidosis • Selection of fluconazole-resistant isolates and species will occur if used broadly and injudiciously

  27. Conclusions - Itraconazole • Oral solution potentially useful where Aspergillus anticipated: risk assessment • Steady state rapidly achieved • Topical effect – benefit in OPC • Breakthrough infections associated with plasma levels <0.25 mg/l • Cross-resistance to ITR 30% of 96 FLU-resistant Candida isolates • No ITR resistance in FLU-sensitive isolates

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