fungal management

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fungal management

  1. 1. MANAGEMENT OF INVASIVEFUNGAL INFECTIONS IN THENIGERIA SETTING DR RITA OLADELE CLINICAL MYCOLOGIST CMUL/LUTH
  2. 2. Direct microscopy
  3. 3. TRENDS IN FUNGAL DISEASES • Increasing cases of invasive fungal infections • Poor diagnostic tools • Replacement of sensitive species by resistant ones
  4. 4. Invasive fungal infections• Candida Endogenous (mostly)• Aspergillus Exogenous• Cryptococcus• Zygomycetes• Rare filamentous species •Histoplasmosis Reactivation •Blastomycosis •Coccidioidomycosis •Paracoccidioidomycosis
  5. 5.  Chamilos et al (2006) reported autopsy-proven IFI in patients with HM from a single institute during three separate four year periods, 1989-93, 1994-98 and 1999-2003. There was a declining rate of autopsies (67%-34%-26%) but IFI were found in 314 of 1017 autopsies and most were not diagnosed in life (75%).
  6. 6. Incidence of invasive fungal infections inneutropenic patients with haematological malignancies 25% Proven Proven / suspected Rate of invasive fungal infections 16% Incidence in autopsies 20% 14% 12% 15% 1978-82 10% 1983-87 8% 10% 1988-92 6% 5% 4% 2% 0% 0% Invasive mycoses: Polyenes/no prophylaxis • 76% responsible for death Data from the control arms of RCTs on antifungal prophylaxis, n=3597 (Glasmacher et •19% of patients with AIDS al., JCO 2003) Frankfurt (Germany), Groll et al. 1996 25% of patients with AML Candida spp. 49%, Aspergillus spp. 51%
  7. 7. Mortality from invasiveAspergillus infections %100 90 Lin et al., CID 2001; 32: 358 80 70 60 50 40 30 20 10 0 Leuk./Lymph. alloSCT Kidney-Tx Lung/Heart-Tx Liver-Tx AIDS/HIV
  8. 8. Mortality from invasiveCandida infections % 100 Tortorano et al., EJCMID 2004; 23: 317 90 80 70 60 50 40 30 20 10 0 Surgery ICU Solid tumor Haem. Malig. HIV Premature birth
  9. 9. Development of antifungals Polyenes Polyene Pyrimidinanaloga Azoles Azole Echinocandins Echinocandine Nystatin Amphotericin B 5-Flucytosin Ketoconazol Fluconazol Itraconazol AmBisome Abelcet Abelcet Amphotec Voriconazol Caspofunginliposomales Nystatin Anidulafungin Ravuconazol Posaconazol Posaconazol Micafungin mod. nach R. Lewis, ICAAC 200
  10. 10. The (small) world ofantifungals Membrane function: Cellwall synthesis: Amphotericin B Echinocandins Ergosterol synthesis: Azoles
  11. 11. Antifungal Activity(█ > 75% sensible, █ 50%, █ < 5%; mixed colours: differing results; modified after OBrien et al., ASH Edu 2003) Erreger AmB Fluco Itra Vori Caspo Flucyt. C. albicans C. parapsilosis C. tropicalis C. glabrata C. krusei A. fumigatus A. flavus A. terreus Zygomycetes Fusarium spp.
  12. 12. Presentation overview Risk stratification Antifungal prophylaxis Empirical antifungal therapy Therapy of proven invasive mycoses
  13. 13. Table 1. Infectious Diseases Society of America, United States Public Health Service Grading System for ranking recommendations Cornely, O. A. et al. Haematologica 2009;94:113-122Copyright ©2009 Ferrata Storti Foundation
  14. 14. Evidence based Chamilos et al (2006) reported autopsy-proven IFI in patients with HM from a single institute during three separate four year periods, 1989-93, 1994-98 and 1999-2003. There was a declining rate of autopsies (67%-34%-26%) but IFI were found in 314 of 1017 autopsies and most were not diagnosed in life (75%).
  15. 15. Evidence based fungal infection and the decrease of IFI attributable mortality. In a longitudinal observation survival benefit extended beyond the period of fluconazole treatment (75 days) and was accompanied by a lower incidence of intestinal graft versus host disease.19 Moreover, fluconazole has been reported to protect from cyclophosphamide toxicityUpton A, McCune JS, Kirby KA, Leisenring W, McDonald G, Batchelder A, et al. Fluconazole coadministration concurrent with cyclophosphamide conditioning may reduce regimen- related toxicity postmyeloablative hematopoietic cell transplantation. Biol Blood Marrow Transplant 2007;13:760-4
  16. 16. Evidences still The clinical relevance of the development of resistance during fluconazole prophylaxis is still a matter of debate, while a general shift towards higher rates of strains exhibiting primary resistance have been clearly shown in the intensive care setting. favorable safety profile and patient compliance rate of fluconazole resulted in discontinuation rates of less than 8%. There is good evidence (Level A I) that primary prophylaxis with fluconazole 400 mg/d reduces the incidence of invasive candidiasis and the mortality rate after allogeneic hematopoietic stem cell transplant. For patients with acute leukemia prophylaxis with fluconazole 400 mg/d cannot be recommended with similar strength (Level C I). Doses less than 400 mg/d have not been effective in well designed trials (Level E I).
  17. 17. Risk groups for invasive fungalinfections in cancer patients rentice HG, Kibbler CC, Prentice AG, BJH 2000; 110: 273 Autologous bone marrow /stem cell transplant (SCT) Low risk Childhood ALL (except for P. jirovecii) Lymphoma Moderate neutropenia 0.1-0.5 G/l < 3 weeks Intermediate Lymphocytes < 0.5 G/l + antibiotics – low – risk Older age  Central venous catheter Colonized > 1 site OR heavy at one site Intermediate Neutropenia < 0.5 to > 0.1 G/l >3 to <5 weeks – high – risk AML  TBI  Allogeneic matched sibling donor SCT Neutrophils <0.1 G/l > 3 weeks OR <0.5 G/l > 5 weeks Colonized by Candida tropicalis Unrelated or mismatched donor SCT  GVHD High risk Corticosteroids: > 1mg/kg & neutroph. < 1 G/l >1 week Corticosteroids: > 2mg/kg > 2 weeks High-dose cytarabine  Fludarabine?
  18. 18. Why do we need empiricalantifungal therapy? High incidence and fatality rates for invasive fungal infections Insufficient diagnostics  Culture-based methods  Helpful only with Candida, but even then 10% false negative  Almost never diagnostic for invasive Aspergillus infections  Non-culture based methods (GM, PCR)  Still high false negative rate Many invasive fungal infections are diagnosed too late or only at autopsy Late treatment greatly reduces success rates
  19. 19. The options available Four classes of drugs for the treatment of invasive fungal infections exist: polyenes, triazoles,echinocandins and nucleoside analogues. Conventional amphotericin B (CAB), liposomal amphotericin B, amphotericin B lipid complex (ABLC),B colloidal dispersion (ABCD) , fluconazole, itraconazole, voriconazole, posaconazole, caspofungin , anidofulgins flucytosine
  20. 20. Predicting who willbecomeinfected……...
  21. 21. Evidences Fluconazole has activity against many yeasts but limited activity against moulds.19 Reduced susceptibility to fluconazole is also seen with C. krusei and C. glabrata. C. tropicalis has been reported to have reduced susceptibility to fluconazole in international studies but this is rarely seen in Australia. Itraconazole has anti-Aspergillus activity and variable activity against other moulds. Voriconazole has activity against most yeasts and moulds; zygomycetes and Scedosporium prolificans are important exceptions. Zygomycetes are susceptible to posaconazole. S. prolificans is resistant in vitro to all available Caspofungin has poor activity against Cryptococcus neoformans, Scedosporium species, Fusarium species and zygomycetes.antifungal drugs.
  22. 22. Development of empirical antimycotic therapy Period I (1982-1988)  Conventional amphotericin B vs. no therapy / placebo  Pizzo et al. 1982, EORTC 1988  Significant reduction of breakthrough infections if both studies combined Period II (1993-1998)  Conventional amphotericin B vs. fluconazole or liposomal AmB  Defervescence as main outcome, mostly no statistically signif. differences  Only one study (Prentice 1997) with a significant difference Period III (1998-2001)  Introduction of the composite outcome score (Walsh et al., COS)  Conventional AmB vs. liposomal AmB, fluconazole, itraconazole, ABCD  No significant differences Period IV (2000-today)  Continued use of the composite outcome score (COS)  Liposomal AmB vs. ABLC, voriconazole, caspofungin
  23. 23. Definition of proveninfectionsEORTC/MSG criteria: Proven: Culture / histology from a normally sterile body site Probable: Requires host, clinical AND microbiological factors E.g.: Neutropenic patient with a typical lesion in HR-CT AND two positive galactomannan antigen results Possible: Requires host, clinical OR microbiological factors E.g.: Same patient without two positive GM antigen resultsThese criteria are made for clinical trials and should not be used for clinical decision making Of 22 patients with IPA at autopsy only 2 were classified as proven, 6 as probable, 13 as possible. 64% had no microbiological or major clinical criteria before death (Subira et al., AH 2003).
  24. 24. Treatment indication according torisk groups for invasive fungalinfections No primary antifungal prophylaxis Low risk Empirical antimycotic therapy rarely necessary Treat proven / probable infections Intermediate No primary antifungal prophylaxis (in most circumstances) – low – risk Empirical antimycotic therapy usually indicated Intermediate – high – risk Antifungal prophylaxis recommended Empirical antimycotic therapy recommended High risk
  25. 25. Prophylaxis Patients receiving chemotherapy for acute leukaemia may have the same risk of IFI as allogeneic haematopoietic stem cell transplant patients. Prophylaxis of IFI should be confined to high risk patients The two most common organisms in all studies are Candida and Aspergillus spp
  26. 26. Bob Dylan hospitalized with chest infectionMay 28, 1997 Web posted at: 10:07 p.m. EDTNEW YORK (CNN) -- Singer Bob Dylan has been hospitalized with a"potentially fatal" chest infection, according to a statement from hisrecord label.The rock/folk legend, who turned 56 on Saturday, was admittedover the weekend with severe chest pains, the Columbia Recordsstatement said Wednesday.He was diagnosed with histoplasmosis, which causes swelling of thesac that surrounds the heart, the statement said. Columbia did notsay where he contracted it or whether the disease was associatedwith an underlying disorder such as HIV positivity.
  27. 27. ASPERGILLOSIS AT AUTOPSY - RISK GROUPS Vogeser et al Eur J Clin Microbiol Infect Dis 1999;18; 42-45 1187 autopsies 1993 - 1996aspergillosis 48 (4%) aspergillosis Steroids unknown Hematologic malignancy Solid tumor Hematopoietic stem cell transplant Solid organ transplant
  28. 28. The final advice that I can give ya,Whether your name is Lester or Lydia,Or whether you live in L.A. or Moskovia,Try to watch out for all those fungal conidia.Adapted from:Barranco C.P. J Med Vet Mycol, 1994, 32, 477-479
  29. 29. Community-acquired pneumonia
  30. 30. Male, 45 year-old farmer, no relevant historySince 1 month “malaise”Admission to another hospital with pneumoniaTransfer due to respiratory insufficiencyHigh fever, CRP 307, LC 1.8Chest X-ray: bilateral infiltrates
  31. 31. 11 September• Laboratory: ASAT 852, ALAT 514, creatinin 394, WBC 8.5 (left shift)• gram negative rods (E. coli) in bloodcultures and bronchial secretions• Rx/ ciprofloxacin
  32. 32. 11 September• Laboratory: ASAT 852, ALAT 514, creatinin 394, WBC 8.5 (left shift)• gram negative rods (E. coli) in bloodcultures and bronchial secretions• Rx/ ciprofloxacin
  33. 33. 16 September• Persistently febrile (40 oC)• bloodcultures 14 Sept: Candida• more bloodcultures 15 Sept: C. albicans Fluconazole• liver function improved• abnormalities chest X -ray better• respiratory failure improved
  34. 34. 22 September• Persistent febrile;fundoscopy normal• CRP 163, WBC 15.2: 86% neutrophils• No more clinical or radiological improvement (Cipro d. 11;Fluco d. 6) Bronchoalveolar lavage E. faecalis 4+ A. fumigatus + HSV +
  35. 35. 23/9Neurological signs & symptomsCT cerebrum: multiple abscesses24/9Biopsy…………….A. fumigatusR/ AmB Amoxicillin Aciclovir
  36. 36. 23/9HIV-No apparent host defence defects29/9No improvement -interferon, donor granulocytes, steroids30/9R/ Ambisome + rifampin
  37. 37. 03/10Neurological and clinical deteriorationCT cerebrum: no improvement07/10DiedDisseminated aspergillosis
  38. 38. Voriconazole Adult >40 kg Dosing Regimen• Intravenous formulation:– Loading dose (first 24 hours) = 6 mg/kg q12h.– Maintenance doses serious Candida = 3 mg/kgq12h. Aspergillus, Scedosporium, Fusarium, other moulds= 4 mg/kg q12h• Oral formulation:– Loading dose (first 24 hours) = 400 mg or 10 mL q12h– Maintenance doses. serious Candida = 200 mg or 5 mLbd Aspergillus, Scedosporium, Fusarium, other moulds. = 200mg or 5 mL bdPaediatric dosing 2 to <12 years (EU)• No oral or IV loading dose recommended• Intravenous formulation:– Maintenance doses 7 mg/kg q12h (up to 12 mg/kgq12h have been used) ? dosing intervals.• Oral formulation:– Maintenance doses = 200 mg bd• Adolescents
  39. 39. Treatment of adult patients withcandidemia or invasive candidiasisThursky et al. 2008. Internal Medicine Journal 38:496-520.(1) Unknown or yet to be identified Candida species, not haemodynamicallyunstable, not neutropenic, and no risk factors associated with azoleresistantCandida spp.(2) Candida species known (or likely) to be susceptibility for fluconazole.Fluconazole (A)Caspofungin (B) ORVoriconazole (B) ORLipid-AmB B (C) OR AmB-D (A).(1) Unknown or yet to be identified Candida species, haemodynamically unstable,neutropenic, or risk factors associated with azole-resistant Candida spp.(2) Candida species known (or likely) to be resistant to fluconazole.Caspofungin (B) ORLipid-AmB (C)Voriconazole (B) ORAmB-D (B)
  40. 40. Treatment of definite, probable andpossible invasive AspergillosisThursky et al. 2008. Internal Medicine Journal 38:496-520.(1) Invasive pulmonary aspergillosis(2) Infection with Aspergillus isolates known to be resistant to AmBVoriconazole IV 6 mg/kg bdfor 24 hours (loading dose)then 4 mg/kg IV bd or 200-300 mg po bd (maintenance)(B)Liposomal AmB 3 mg/kg/day (B)ORAmB-D 1.0-1.5 mg/kg/day (C).Caution with voriconazole if concomitant use of a cytochrome P450 inducers, vincaalkaloids, tacrolimus or significant hepatic dysfunction.Conventional AmB should be avoided in patients at risk of nephrotoxicity, or withpre-existing renal impairment.AmB resistant isolates include A. terreus, A. nidulans and A. ustus
  41. 41. Treatment of definite, probable andpossible invasive AspergillosisThursky et al. 2008. Internal Medicine Journal 38:496-520.CNS or disseminated diseaseVoriconazole IV 6 mg/kg bd for 24hours (loading dose) then 4 mg/kgIV bd or 200-300 mg po bd(maintenance (D)An intra-vitreal injection of AmB(10 μg) is recommended forendopthmalmitis.Liposomal AmB3 mg/kg/day (D)L-AmB is preferred due its ability to achieve higher concentrations in the blood andbrain than AmB and other lipid formulations.

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