Guidelines for Antifungal Therapy for Invasive Fungal Infection. National Comprehensive Cancer Care Network

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1 Guidelines for Antifungal Therapy for Invasive Fungal Infection Guidelines for Antifungal Therapy for Invasive Fungal Infection ew Antifungals Dr Rosemary Barnes Infectious Diseases Society of America Australasian Society for Infectious Diseases University of Manitoba Canadian Mycoses Group European Conference on Infections in Leuaemia (EL) Groupe de travail de CRU de Lille Japanese Society for Medical Mycology ational Comprehensive Cancer Care etwork Guidelines of the ew South Wales Infectious Diseases Group Infectious Diseases working party of the German Society of ematology and ncology Fungal Infection network of Switzerland (FUGIS) Grupos de Estudio infeccion fungica Antifungals Significant properties of fungal cells ew antifungal therapies fungi have eukaryotic cells which have few differences from human cells fungi have relatively few unique and essential targets for anti-fungal agents unique cell wall using chitin as the main structural polymer cell membrane contains unique fungal sterols some unique cytoplasmic membrane enzymes in some species Evolution Revolution formulations/devlivery systems classes Lipid based amphotericin, Echinocandins ew drugs in existing class voriconazole, posaconazole, micofungin isavuconazole anidulafungin indications for old drugs Sordarins terbinifine combinations terbinafine + azole Echinocandin + azole/amphotericin Immunomodulators 1

2 Amphotericin B deoxy Broad spectrum Active against wide variety of moulds and yeasts Bind also to cholesterol and human lipoproteins and cause host damage Particularly nephrotoxicity which is dose limiting Immediate side-effects Shakes and bakes Lipid preparations Increases selectivity for fungal cell Uptake into phagocytes delivers drug to sites of infection Markedly reduces toxicity igher dosages possible Better therapeutic index Very expensive Renal impact of amphotericin B therapy =707 Median duration 10 days Median total dose 0.6 g ARF in 30% 13% severe 2x S. creatinine, peak 3 17% significant 1.5x S. creatinine, peak 2 igher mortality 54% vs 16% (P=0.001) Increased hospital stay Mean 8 days Increased cost Bates et al (D 2001) Mean $29,823 ephrotoxity (T) by AmB Formulation (patients with normal RF at outset) ew azoles: voriconazole voriconazole Total ( = 390) AmBd L-AmB ABLC & ABCD on-t 169 (43.3) 80 (32.5) 70 (69.3) 19 (44.2) T 221 (56.7) 166 (67.5) 31 (30.7) 24 (55.8) 1.5-2x baseline SCr 108 (27.7) 77 (31.3) 22 (21.8) 9 (20.9) 2-3x baseline SCr 81 (20.8) 65 (26.4) 6 (5.9) 10 (23.3) > 3x baseline SCr 32 (8.2) 24 (9.8) 3 (3.0) 5 (11.6) T resulted in a doubling in mortality and increased LS Ullmann AJ, Sanz M, Tramarin A. Clin infect Dis 2006 Active against yeasts and moulds Including fluconazole resistant ral and iv preparations Well absorbed 96% bioavailability Given A1 recommendation for aspergillosis by IDSA and EL fluoropyrimidine & methyl group Extensive hepatic metabolism interacts with C-14 - demethylase Potential for interaction with inducers/inhibiters of P 450 (CYP3A4) Case reports of success with fluconazole resistant strains C krusei Also.posaconazole, isavuconazole etc 2

3 Posaconazole (oxafil) Broad spectrum Some clinical evidence for activity against zygomycosis ral formulation only Indicated for prophylaxis Reduced incidence of IFI from 8% to 2% verall survival benefit Cornely at al Engl J Med. 2007;356: Cost effectiveness depends on prevalence Refractory aspergilllosis Echinocandins Mechanism of Action Ergosterol Inhibitors of glucan synthesis in the fungal cell wall Cell wall target absent from mammalian cells 2 Chemical Structures Glarea lozoyensis 2 C 3 3C C 3 C 3 S 2 Micafungin Coleophoma empetri 3C All large molecules ral preparations T a viable option C 3 3C 3C 3C Anidulafungin Aspergillus nidulans C 3 3C Systemic candidosis Response rates from RCTs 3 RCTs of echinocandins published to date: versus Ampho B deoxy Micafungin versus Anidulafungin versus fluconazole Any comparison must take into account differences in study design ampho B AmB Flucon Echino All echinocandins show non-inferiority. All non toxic with low incidence of S/E Easy to use in critically ill patients All appear to be better than fluconazole ow do we decide which one to use? 3

4 Ease of use Cost Factors to concentrate on o dosage adjustment required for renal insufficiency IV Age, weight, gender ethnicity Liver Echinocandins spontaneously degraded Caspo and mica have some liver metabolism caspofungin micafungin anidulafungin epatic Insufficiency -Mild o dosage change o dosage change o dosage change - Moderate 35 mg dose (70 mg LD) o dosage change o dosage change - Severe o data o data o dosage change per day 14 days 5days Activity against particular Candida species eg C. parapsilosis Data in different sub populations eg paediatrics particularly neonates Biofilm activity Impact of line removal Endocarditis, prosthetic infection MICology and correlation with clinical outcomes MICology CMR Pfaller and Diekema 2007 More than 2500 candida isolates tested Correlation with clinical outcome Place in treatment Systemic candiosis Invasive aspergillosis Empirical treatment of neutropenic fever Pre-emptive treatment Primary prophylaxis Secondary prophylaxis Combination therapy of relapsed /refractory fungal infection caspofungin anidulafungin micafungin Antimicrob Agents Chemother 2005; 49:

5 Aspergillosis: Key recommendations IDSA BCS EL Prophylaxis SCT and allogenic SCT A1a Allogeneic SCT AML/MDS and AL BIIa Fluconazole BI Intermittant Posaconazole* Amphotericin Remission induction AL Fluconazole Posaconazole* Empiric therapy Therapy of proven /probable aspergillosis AmB, LFAB,, or caspofungin A1 Empiric therapy discouraged A1b ot specified ABLC Amphotericin B deoxycholate Fluconazole ABLC ABCD Amphotericin B deoxycholat B1 BI BI BI** A1 BI BII DI DI II II (n=144) vs amphob (n=133) Drug Success at 12 weeks Full Compliance 53% 73% c Ampho B 32% 20% ot a RCT of vori vs ampo Vori +LAT vs Ampho + LAT camphotericin B (38%) Lipid Amphotericin (27%) intolerance n=52 (36%) (33%) Combination (2%) Lipid Amphotericin B (44%) camphoterin B intolerance n=107 (96%) (36%) ther (20%) erbrecht R, et al: Vori v amp B for primary therapy of invasive aspergillosis. ew Eng J Med :408 vs. AmB-d Ampho B-d Responses at week 12 32% 71% L-AmB 10 mg/kg/day L-AmB 3 mg/kg/day AmBiLoad Responses at ET 46% L-AmB 3 53% mg/kg/day 50% Survival at week 12 Survival at week 12 72% Risk group stratification Combination therapy: Possible pharmacodynamic outcomes Multicenter, open, phase II study activity and safety of caspofungin as first-line therapy of probable and proven invasive aspergillosis In patients with hematological malignances or SCT Trial abandoned after preliminary analysis showed failure to reach specified objective of response rate >35% Viscoli et al TIMM 2007 Response rate ET 20/61 (33%) Day 84 19/61 (31%) 95 % (21% - 46%) (20% - 44%) Vori L-AmB Caspo Age (y) % haem malig % true proven/prob IA (not just halo) % uncontrolled malignancy? % baseline neutropenia Antagonism Drug interactions increased toxicity Increased cost Synergism Increased spectrum Minimal toxicity Decreased resistance 5

6 Summary of in vivo testing Ampho B + flucytosine = indifferent Ampho B + azoles = antagonism Azole + flucytosine = indiffent /synergistic thers = insufficent data Echinocandins + azoles = probable synergy Biological response modifiers Adjuvant therapy in fungal infection Cytokines Gamma interferon Growth factors GCSF;GMCSF Antibodies Mycograb antibody against fungal heat shock protein 90 Clin Infect Dis : Likely to act synergistically with antifungal drugs Summary Treatment of candidosis Echinocandins in critically ill and azole pre-treated Treatment of aspergillosis or Treatment of unknown fungal nfection ; (posaconazole) Empirical treatment To be avoided combination therapy nly in desperation (apart from crypto) Problems with fungal trials Relatively few well-designed RCTs nly posaconazole studies used CSRT criteria Use of historical controls Complex and biased end-points Underpowering to reduce number of patients needed and noninferiority based on intention to treat The unequal reorganisation of subgroups after the trial results are known Results analysed at too early a time point Concentration on empirical antifungal trials Empiric therapy o evidence base to support this practice Improvement in diagnosis render this obsolete Radiological Biomarkers Antigen PCR ow replaced with targeted/pre-emptive therapy Biomarkers to select early treatment at risk infection disease 6

7 Biomarkers to select early treatment at risk infection disease Finally In the post genomic era, what contribution has the identification of potential target made to antifungal drug development? Absolutely nothing yet Prophylaxis Pre-emptiveemptive Targetted 7

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