Alle Echinocandine sind gleich?

Transcription

1 Alle Echinocandine sind gleich? Giftiger Donnerstag Hospital Innsbruck, Cornelia Lass-Flörl Division of Hygiene and Medical Microbiology Innsbruck Medical University

2 Indications Caspofungin - Candicas Invasive candidiasis in adults and pediatrics. Invasive aspergillosis with failure of AmB, L-AmB and/or Itraconazol treatment or in patients incl. peadiatric pts unable to tolerate these substances. For empirical therapy in case of suspected fungal infections in adult and pediatric patients with fever and neutropenia. Anidulafungin - Ecalta Invasive candidiasis. Micafungin - Mycamine Invasive candidasis, oesophageal candidasis. Prophylaxis of Candida infections in patients undergoing allogeneic, hematopoietic stem cell transplantation or in case neutropenia of at least 10 days is to be expected. In children and juveniles < 16 years for treatment of invasive candidasis, prophylaxis of candidiasis in patients undergoing allogeneic, hematopietic stem cell transplantation or in case neutropenia of at least 10 days is to be expected.

3 Are echinocandins equal? All three echinocandins inhibit fungal growth through a non-competitive inhibition of 1,3-β-D-glucan synthase share a similar structural chemical backbone IDSA and ESCMID guidelines do not differentiate between the three available echinocandins all iv

4 Are echinocandins equal? indication dosing pharmacokinetics and pharmacodynamics MICs and resistance tissue penetration drug interactions outcome fungal breakthrough (selection of C. parapsilosis) mortality in vitro in vivo amount of data avialable differs

5 Echinocandins Anidulafungin Caspofungin Micafungin Pharmacodynamics Concentrationdependent killing Prolonged postantifungal effects AUC/MIC and C max /MIC predictive indices Candida pharmacodynamic targets similar among echinocandins and Candida species AUC/MIC target = C max /MIC target = 1-3 Pharmacokinetics Loading dose ANID: 200 mg CASPO: 70 mg MICA: non required Dosing is daily via IV infusion ANID: 100 mg CASPO: 50 mg MICA: 50/100 mg Tissue penetration No active drug in urinary tract, CSF, vitreous

6 Echinocandine Mannoproteine b1,3 b1,6 Glucane AfFKS1p (IntF) PPL- bilayer b1,3 Glucan Synthase Ergosterol Chitin Anilin-Blau Echinocandine hemmen Glucan-Synthase-Komplex : Hemmung der Verlängerung der wachsenden Enden der (aktiven) Aspergillus Hyphen. Beauvais et al. J. Bacteriol 2001;183:

7 In vivo data

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9 Echinocandins invasive candidiasis studies (End points and success rates) Study Design Efficacy end point Success rate (cured + improved) Mora- Duarte et al. (2002) Kuse et al. (2007) Pappas et al. (2007) Reboli et al. (2007) * p < 0.05 Caspofungin vs. amphotericin B Micafungin vs. liposomal amphotericin B Micafungin (100, 150 mg) vs. caspofungin Anidulafungin vs. fluconazole Primary: Favourable response at end of IV therapy only (MITT) Primary: favourable response at end of therapy (per protocol) MITT Primary: favourable response at end of IV therapy (MITT) Primary: favourable response at end of IV therapy (MITT) Overall mortality 73% vs. 62% 34% vs. 30% 87% vs. 90% 69% vs. 74% 40% vs. 40% 76% vs. 71% vs. 72% 29% vs. 33% vs. 26% 76% vs. 60%* 23% vs. 33%

10 Micafungin vs. Caspofungin: invasive candidiasis 100% 80% ,3 Mica 100 Mica 150 Caspo 70/50 60% 191 pts micafungin 100 mg 199 pts micafungin pts caspofungin 70/50 mg (10 days iv) 40% 20% % Pappas PG et al. CID 2007;45:883

11 Defining success Favorable clinical response Complete resolution of signs and symptoms attributable to the invasive mycoses Favorable microbiological response Eradication from follow-up cultures ( presumptive eradication permitted for non-blood cases if there was no apparent evidence of residual infection from symptoms, physical exam, or radiographic studies)

12 Survival distribution function Combination therapy for invasive aspergillosis Prospective, randomized, doubleblind trial in allo-hsct recipients and patients with haematological malignancies with proven or probable IA. Patients were randomized 1:1 to receive either voriconazole (monotherapy or voriconazole plus anidulafungin (combination therapy). Combination therapy for 2-4 weeks; after 2 weeks, the investogator could switch to voriconazole monotherapy, to complete at least 6 weeks of antifungal treatment. a) b) Mortality at Week % Vori/anid MITT population Results showed that combination therapy was associated with a substantial, but not statistically significant, reduction in overall mortality. P= P= % CL 19.0, % CL 19.0, 1.5 Time to death (days) Voriconazole/anidulafungin (n=135) Voriconazole/placebo (n=135) 27.5% Vori/placebo

13 The post-vori-echinocandin Era the mucormycetes? 27% of proven infections are due to zygomycetes Lass-Flörl et al, CID 2008

14 Fungal isolates with species reported in echinocandin recipients with breakthrough invasive mycosis Case report/series Prophylactic use Therapeutic use Breakthrough mycosis (no. of cases) Aspergillosis (13) Candidiasis (10) Candidiasis (26) Species (no of isolates with species A. fumigatus (5) C. glabrata (4) C. albicans (1) reported) A. ustus (2) C. albicans (3) C. parapsilosis (1) A. nidulans (1) C. parapsilosis (2) C. lusitaniae (1) Candidiasis (9) C. lipolytica (1) C. glabrata (1) C. tropicalis (4) C. lusitaniae (1) Aspergillosis (12) C. parapsilosis (3) C. tropicalis (1) N/A C. guilliermondii (1) Aspergillosis (7) Fusariosis (2) Trichosporonosis (8) A. terreus (2) N/A T. asahii (6) A. fumigatus (1) Zygomycosis (2) Zygomycosis (3) A. versicolor (1) N/A Rhizomucor (1) Trichosporonosis (3) Cryptococcosis (1) Mucor (1) N/A N/A Cryptococcosis (2) Zygomycosis (3) Trichosporonosis (1) C. neoformans (2) Rhizopus (1) N/A Fusariosis (1) Mucor (1) Unidentified mould (1) N/A Fusariosis (2) N/A Scedosporiosis (1) N/A Pseudallescheria boydii (1) Cryptococcosis (1) N/A Others (2) Exserohilum (1) N/A: not available Sun H.-Y., Singh N. Int J Antimicrob Agents 2010; 35: 211-8

15 Antifungal drug exposure influences the epidemiology! C. albicans C. glabrata C. parapsilosis C. tropicalis C. krusei Lortholary et al. Antimicrob Agents Chemother 2011,55: 532; Blanchard et al. Antimicrob Agents Chemother 2011,55:5358; Forrest et al. J Infection, 2015

16 In vitro data

17 MICs ETest versus Sensititre YeastOne versus EUCAST Aigner et al, AAC, in press 2017

18 Aures, 2015 EUCAST Recommendation: not do test caspofugin (instable) instead anidulafungin (2017)

19 Paradoxical growth effects of the echinocandins: eagle effect Eagle effect or paradoxical growth effect: When Candida spp. are grown in media containing high concentrations of antifungal agents, the result can be reduced activity of these agents against organisms. Candida species (no. of isolates) Paradoxical effect (%) CASPO MICA ANID C. albicans (20) C. parapsilosis (10) C. tropicalis (10) C. krusei (10) C. glabrata (10) Drug Paradoxical effect (%) ANID None of the isolates CASPO C. dubliniensis isolates (90%) C. albicans isolates (14%) MICA C. dubliniensis isolates (63%) Chamolis G et al. AAC 2007;51:2257 Fleischhacker M et al. Eur J Clin Microbiol Infect Dis 2008;27:127

20 Catheters and biofilms Lines and foreign bodies Remove if possible better outcomes Biofilms are important Fluconazole and voriconazole were ineffective against biofilms of all five Candida species, with none of the isolates showing an azole SMIC of <128 µg/ml Echinocandins and amphotericin much better penetration L-AMB and echinocandins FLUC Anaissie et al. Am J Med 1998;104:238 Cole et al. CID 196;22:S73 Nucci et al. CID 2002;34:591 Schinabeck et al. AAC 2004;48:1727 Fiori B et al. AAC 2011;55:3031

21 PD data

22 Anidulafungin undergoes spontaneous chemical degradation and physiologic conditions active molecule Chain breaks at physiologic 37 C and ph 7.4 Inactive peptide converted to peptidic degradants and eliminiated in feces Anidulafungin is the only echinocandin not hepatically metabolized or renally excreted Because anidulafungin elimination is not dependent on hepatic/renal function there are no known drug interactions of clinical significance there are no required dose adjustments

23 Anidulafungin Clearance differs from other echinocandins

24 Metabolism and interaction profile of the available echinocandins Caspofungin Micafungin Anidulafungin Hepatic metabolism? CYP3A4 inhibitor? Drug interactions? Dose adjustments? Yes (N-acetylation) Yes (Acrylsulfatase and catechol-omethyltransferase; Some CYP3A hydroxylation) No Weak No Cyclosporine; Tacrolismus Rifampin; Efavirenz; Nevirapine; Phenytoin; Dexamethasone; Carbamazepine Yes Moderate hepatic dysfunction with CYP inducers Sirolismus Nifedipine No No No known interactions No

25 Half-life of the available echinocandins Beta Half-life (hours) Comparisons do not imply interchangeability or comparable efficacy and safety. Eraxis [package insert]. New York, NY: Pfizer Inc; Mycamine for Injection [package insert]. Tokyo, Japan: Astellas Pharma, Inc; 2006 Cancidas for Injection [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; Stone JA et al. AAC 2002;46:739

26 Volume of distribution of the echinocandins Vd (L) Comparisons do not imply interchangeability or comparable efficacy and safety. Eraxis [package insert]. New York, NY: Pfizer Inc; Dowell JA et al. J Clin Pharmacol 2004;44:590 Mycamine for Injection [package insert]. Tokyo, Japan: Astellas Pharma, Inc; 2006 Stone JA et al. AAC 2002;46:739

27 Distribution into tissue: Fisher 344 rats following a single IV bolus 5 mg/kg dose of 14C-anidulafungin Organ Tissue/plasma AUC ratio for parent drug* Liver 12.4 Kidney 10.7 Spleen 9.2 Lung 10.4 Tissue levels were 9- to 12-fold higher than plasma * Following a single IV bolus 5mg/kg dose of 14 C-anidulafungin Data on file. Pfizer Inc, New York, NY.

28 In vitro & in vivo data

29 Presentation of the clinical features (CMC) of the female 27-year-old patient. Lackner M et al. Antimicrob. Agents Chemother. 2014;58:

30 Mutant isolates ANI MICA CAS FKS SS WT SC5314 wild typ (S) <0.008 (S) 0.19 (S) wild typ RR MH2 R647R/G and P649P/L heterozygous double mutation RS MH1 R647R/G heterozygous single mutations 0.06 (R) 0.03 (R) 0.75 (R) (S) 0.03 (R) 0.25 (S) heterocygot SR MH1 P649P/L heterozygous single mutations (S) (S) 0.25 (S) RR MHO2 R647G and P649L homozygous double mutation 0.06 (R) 1 (R) 1 (R) homocygot Positions and Numbers of FKS Mutations in Candida albicans Selectively Influence In Vitro and In Vivo Susceptibility to Echinocandins Homo-versus heterozygous mutations display different MICs The three sisters act different MIC shifting due to mutations? Lackner M et al. Positions and Numbers of FKS Mutations in Candida albicans Selectively Influence In Vitro and In Vivo Susceptibilities to Echinocandin Treatment. AAC 2014;58:

31 Mouse model: In vivo susceptibilities of isogenic mutants derived from parental strain Anidulafungin Caspofungin Micafungin Point mutations of the FKS HS do not explain the different outcome Dosisescalation improved outcome of heterozygous single mutations Different outcome of the various echinocandins despite using the same strains Isolates carrying homozygous double mutations are difficult to treat

32 Was gibt es Neues? Orales Echinocandin C. auris

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35 Conclusions: Are echinocandins equal? There are differences between the echinocandins dosing pharmacokinetics and pharmacodynamics MICs and resistance tissue penetration drug interactions How or whether these differences impact patient care is unknown!