Liposomal amphotericin B: 20 years of clinical experience The collection of information and recognition of utilization

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Antifungal Therapy: The Last 50 Years. . . . . . . . . . . . . . . . . . . . . . . . . 0. 2. 4. 6. 8. 10. 12. 14. 16. 18. 1950. 1955. 1960. 1965. 1970. 1975. 1980. 1985. 1990. 1995. 2000. 2005.

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Liposomal amphotericin B: 20 years of clinical experience The assortment of information and nature of utilization Malcolm Richardson PhD, FIBiol, FRCPath Associate Professor in Medical Mycology University of Helsinki Finland Malcolm.richardson@helsinki.fi (in light of an introduction given by L. Ostrosky-Zeichner, ISHAM Paris, 2006)

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Echinocandins a work in progress Posaconazole "All medications known to people are toxic substances, just the sum or measurement decide the impacts." Paracelsus, 1490 - 1541. Caspofungin Voriconazole ABCD LAmB ABLC Terbinafine Griseofulvin Amphotericin B Itraconazole Ketoconazole Fluconazole Nystatin Miconazole 5-FC Antifungal Therapy: The Last 50 Years # of medications 18 16 14 12 10 8 6 4 2 0 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2005 2006 2000 Year Slide idea: J. Rex, M.D. what's more, R Lewis

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Candida here, Candida there, Candida wherever George Bernard Shaw, 1903

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Difficult to treat: Candida biofilms

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Difficult to treat: Aspergillus angioinvasion

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Refractory contamination: intrusive aspergillosis

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Amphotericin B Formulations: Safety and Efficacy from Preclinical Data

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Toxicity, however with survival A Classic Example Cr Rise LAmB 5 0 mg/dl LAmB 10 3 mg/dl LAmB 1 cAMB 1 2 mg/dl Control Francis, J Inf Dis 1994; 169:356-68. Aspergillosis in neutropenic rabbits

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Amphotericin B Formulations: Safety from the Clinical Literature

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Nephrotoxicity of cAMB is Notable Average of ~30%  LOS (10d)  Mortality $30,000/scene Bates, CID 2001;32:686

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Lipid Formulations are NOT Problem Free Acute imbuement related responses: Chills, meticulousness, fever, phlebitis, hypotension, and arrhythmia May be compound particular cAMB > ABCD > ABLC > LAMB Cumulative measurements related poisonous quality: K & Mg squandering, arrhythmia, paleness, renal disappointment cAMB > ABCD > ABLC > LAMB Overall, notwithstanding They are unquestionably more secure than AmB-D

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Amphotericin B Formulations: Efficacy from the Clinical Literature

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Data are to some degree scattered Data fall into two huge gatherings Febrile neutropenia: a reasonable piece of information Good randomized information, extraordinary wellbeing information Salvage of demonstrated IFI Although for the most part open-name, there are fairly a ton of cases in the writing

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Open-Label Trials: 575 Proven IFI N=279 24 226 16 30 23 26 31 % Failure 42 51 % Success (CR/PR) 49 74 58 69 77 Mehta 1997 Mills 1994 Ng 19958 Oppenheim 1995 Ringden 1991 Tollemar 1992 Walsh 1998 Walsh 1999 Ostrosky-Zeichner, CID 2003.

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Recent Data for Liposomal Amphotericin B

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Empirical Therapy-Febrile Neutropenia Studies Walsh, et al. NEJM 1999;340:764-71, Walsh, et al. NEJM 2002;346:225-34, Walsh, et al. NEJM 2004;351:1391-402.

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LAmB for Candidaemia Biofilms! Ruhnke et al. ICAAC 2005.

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Characteristics of Drugs That Are Good Candidates for Flexible Dosing History of safe utilize Familiarization Predictable pharmacokinetics Concentration-subordinate pharmacodynamics Slide idea: R. Lewis

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Empirical Antifungal Therapy for Febrile Neutropenia A enter consider choosing an antifungal medication for exact treatment in febrile neutropenic patients is the medication's action against the parasitic pathogens well on the way to be required in these patients.

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The AmBiLoad Study

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Randomized = 339 patients Received > 1 measurements of study medication 331 Probable or Proven Possible 143 188 Upgraded to Proven or Probable 38 Not redesigned = rejected Qualified by examiners 105 Eligibility not affirmed by DRB 226 DRB Confirmed = MITT 25 201

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Underlying Conditions 1. Incorporates intense & perpetual leukemia, lymphoma, myeloma, myelodysplastic disorder 2. Nonattendance of finish reduction at study section 3. Strong organ transplant, HIV, different conditions requiring perpetual corticosteroid treatment 4. Neutropenia: ANC<500 cells/mm3

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AmBiLoad Trial: Endpoints: Overall reaction at agent decided EOT Favorable = Complete + Partial reactions Unfavorable = Stable + Failure + Unevaluable Survival at d14, EOT, 4 wks post-EOT and 12 weeks Safety of 10 mg/kg/day measurements contrasted with standard dosage MITT populace Data Review Board affirmed all IFI cases and general reaction appraisals Cornely OA, et al, CID 2007 (in press)

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Overall Response at EOT No critical distinction in general reaction rates between the treatment arms Duration of treatment, middle (range): 3 mg: 15 days (1-60);

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Survival No huge distinction in general reaction rates between the treatment arms

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Safety No irregular or already unreported wellbeing signs were seen in either treatment arm Higher rates of nephrotoxicity, hypokalemia and medication suspensions (measurably huge) were found in 10 mg/kg/day arm contrasted with 3 mg/kg/day arm Confirms security profile of 3 mg/kg/day measurement in this exceptionally immunocompromised patient populace

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Comparison to Other Studies: Patient Characteristics *Vori: ANC <500 inside 14d of study passage; AmBiLoad: ANC <500 at study section 1. Herbrecht R, et al. N Engl J Med . 2002; 347:408-415 2. Cornely O, et al. CID 2007 (in press)

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Voriconazole versus cAMB AmBisome Putting AmBiLoad in setting Survival at week 12 Survival at week 12

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AmBisome Today Extensive assortment of learning and history of utilization (commonality) Broad range First production: 1990 Number of Medline passages: 481 Number of Google Scholar hits: 3,040 Number of patients treated: >460,000

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Five-year see Main concentration: Invasive aspergillosis and developing molds zygomycosis scedosporiosis fusariosis Rationale noteworthy grimness/mortality generally impervious to existing antifungals Prophylaxis Combination treatment

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