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Η παρουσίαση φορτώνεται. Παρακαλείστε να περιμένετε

ΑΝΤΙΜΥΚΗΤΙΑΣΙΚΑ & ΘΕΡΑΠΕΙΑ ΜΥΚΗΤΙΑΣΙΚΩΝ ΛΟΙΜΩΞΕΩΝ ΓΕΩΡΓΙΟΣ ΠΑΝΟΣ BSc, CEng, MIET, MD, PhD, DTM&H(Lon), FRCP Αν. Καθηγητής Παθολογίας & Λοιμωδών Νοσημάτων.

Παρόμοιες παρουσιάσεις


Παρουσίαση με θέμα: "ΑΝΤΙΜΥΚΗΤΙΑΣΙΚΑ & ΘΕΡΑΠΕΙΑ ΜΥΚΗΤΙΑΣΙΚΩΝ ΛΟΙΜΩΞΕΩΝ ΓΕΩΡΓΙΟΣ ΠΑΝΟΣ BSc, CEng, MIET, MD, PhD, DTM&H(Lon), FRCP Αν. Καθηγητής Παθολογίας & Λοιμωδών Νοσημάτων."— Μεταγράφημα παρουσίασης:

1 ΑΝΤΙΜΥΚΗΤΙΑΣΙΚΑ & ΘΕΡΑΠΕΙΑ ΜΥΚΗΤΙΑΣΙΚΩΝ ΛΟΙΜΩΞΕΩΝ ΓΕΩΡΓΙΟΣ ΠΑΝΟΣ BSc, CEng, MIET, MD, PhD, DTM&H(Lon), FRCP Αν. Καθηγητής Παθολογίας & Λοιμωδών Νοσημάτων Ιατρική Σχολή Παν/μίου Πατρών ΠΓΝΠ

2

3 Η επίδραση της καθυστέρησης της θεραπείας σε ασθενείς με καντιταιμία Mortality (%) Culture day Days to start of fluconazole Garey KW, et al. Clin Infect Dis 2006; 43:25–31; published by the University of Chicago Press Day 1Day 2Day 3

4 Συσχέτιση μεταξύ νοσοκομειακής θνητότητος και χρόνου έναρξης θεραπείας Hospital mortality (%) < 12 Delay in start of antifungal treatment (hours) 12–2424–48> 48 Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–5

5 Θνητότης βακτηριαιμίας ΗΠΑ

6 1- Eggimann P., Garbino J, Pittet D. Management of Candida species infections in critically ill patients. Lancet Infect Dis. 2003;3(12): Azoles: fluconazole, itraconazole, voriconazole, posaconazole Polyenes amphotericin B and lipid formulations of amphotericin B Flucytosine Echinocandinscaspofungin, micafungin, anidulafungin Θεραπευτικές επιλογές 1 amphotericin B fluconazole voriconazole caspofungin anidulafungin

7 Στόχοι αντιμυκητιασικών φαρμάκων Cell membrane Fungi use principally ergosterol instead of cholesterol Cell Wall Unlike mammalian cells, fungi have a cell wall DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis. Atlas of fungal Infections, Richard Diamond Ed Introduction to Medical Mycology. Merck and Co. 2001

8 Στόχοι Cell membrane Polyene antibiotics Polyene antibiotics Azole antifungals Azole antifungals DNA/RNA synthesis Pyrimidine analogues - Flucytosine - Flucytosine Cell wall Echinocandins

9 Γενικά χαρακτηριστικά των αντιμυκητιασικών φαρμάκων Αμφοτερικίνη Β Αμφοτερικίνη Β Ευρύ φάσμα δραστικότητας Ευρύ φάσμα δραστικότητας Κενά στο φάσμα (ανθεκτικά είδη) Κενά στο φάσμα (ανθεκτικά είδη) Δύσκολη φαρμακοκινητική Δύσκολη φαρμακοκινητική Αποτελεσματικότητα όχι μεγαλύτερη σε σύγκριση με την βορικοναζόλη και τις εχινοκανδίνες Αποτελεσματικότητα όχι μεγαλύτερη σε σύγκριση με την βορικοναζόλη και τις εχινοκανδίνες Τοξικότητα από την έγχυση Τοξικότητα από την έγχυση Φαρμακευτική τοξικότης (ηπατική, νεφρική, υποκαλιαιμία) Φαρμακευτική τοξικότης (ηπατική, νεφρική, υποκαλιαιμία) Κόστος Κόστος

10 Amphotericin B deoxycholate Αντιμυκητιασική δράση Αντιμυκητιασική δράση Δυνητικά απειλητικές για την ζωή (ανοσοκατασταλμένοι): Δυνητικά απειλητικές για την ζωή (ανοσοκατασταλμένοι): aspergillosis, cryptococcosis, North American blastomycosis, systemic candidiasis, coccidioidomycosis, histoplasmosis, sporotrichosis, and zygomycosis including mucormycosis aspergillosis, cryptococcosis, North American blastomycosis, systemic candidiasis, coccidioidomycosis, histoplasmosis, sporotrichosis, and zygomycosis including mucormycosis

11 Lipid Amphotericin B Formulations Ribbon-like particles Carrier lipids: DMPC, DMPG Particle size : Particle size (µm): Abelcet ® ABLC Amphotec ® ABCD Amphotec ® ABCD Ambisome ® L-AMB Disk-like particles Carrier lipids: Cholesteryl sulfate Particle size : Particle size (µm): Unilaminar liposome Carrier lipids: HSPC, DSPG, cholesterol Particle size : 0.08 Particle size (µm) : 0.08

12 Reference Pathogen(s) Agent Response Survival Lipid AMB formulations vs. Conventional AMB When Used as First-Line Therapy In Prospective Randomized Trials Wingard. Clin Infect Dis 2002; 35:891-5 Leenders 1998 MixedL-AMBSameSame Leenders1997 Cryptococcus spp. L-AMBSameSame Anaisse1995 Candida spp. ABLCSameSame Bowden 2002 Aspergillus spp. ABCDSameSame Hamill1999 Cryptococcus spp. L-AMBSameSame Johnson2002 H. capsulatum L-AMBGreaterGreater Outcome

13 Lipid AMB Formulations- Summary Efficacy Efficacy – Lipid formulation > AMB-deoxy Nephrotoxicity Nephrotoxicity – L-AMB < ABLC < ABCD << AMB-deoxy Infusion related toxicity Infusion related toxicity – L-AMB < ABLC < ABCD < AMB-deoxy Product cost (AWP) Product cost (AWP) – L-AMB > ABLC > ABCD > AMB-deoxy

14 Γενικά χαρακτηριστικά των αντιμυκητιασικών φαρμάκων Fluconazole Δραστικότης έναντι της Candida albicans Δραστικότης έναντι της Candida albicans Ατοξικότης Ατοξικότης Δοσοεξαρτώμενη δράση Δοσοεξαρτώμενη δράση Συσσωρευμένη κλινική εμπειρία Συσσωρευμένη κλινική εμπειρία Αποτελεσματική στην προφύλαξη Αποτελεσματική στην προφύλαξη Αζόλες Αζόλες Voriconazole Δραστικότης έναντι όλων των ειδών της Candida, Aspergillus, Fusarium, Scedosporium IV, Peros χορήγηση Αδυναμία χορήγησης σε νεφρική ανεπάρκεια (IV) Φαρμακευτικές αλληλεπιδράσεις

15 Global Comparative Candidemia Study In non-neutropenic patients Kullberg BJ et al, Lancet 2005;366:1435

16 Primary and Secondary Analyses (MITT Population)  DRC successes at the last evaluable follow-up study visit Voriconazole (N=248) Amphotericin B  fluconazole (N=122) Success rate (%) P=0.25 GLOBAL COMPARATIVE CANDIDEMIA STUDY Kullberg BJ et al, Lancet 2005;366:1435

17 Success by Baseline Pathogen Voriconazole (N=248) Amphotericin B/fluconazole (N=122) Kullberg BJ et al, Lancet 2005;366:1435

18 Hazard Ratio= % CI: (0.582, 1.161) Note: the hazard ratio is stratified by region Time (weeks) Probability of survival Voriconazole Amphotericin B/fluconazole Kaplan-Meier Survival Curve (MITT Population) Attributable mortality (deaths caused by candidemia) was 10.9% (27/248) in the voriconazole arm compared with 11.5% (14/122) in the amphotericin B/fluconazole arm

19 Γενικά χαρακτηριστικά αντιμυκητιασικών φαρμάκων Flucytosine Περιορισμένο φάσμα Περιορισμένο φάσμα παρενέργειες παρενέργειες Επίκτητη αντοχή Επίκτητη αντοχή > μονοθεραπεία > ταχεία εμφάνιση

20 Flucytosine – Κλινική χρήση Candidiasis Cryptococcosis ?Aspergillosis } Σε συνδυασμό με amphotericin B or fluconazole. μονοθεραπεία : περιορισμένη

21 Eχινοκανδίνες Eχινοκανδίνες – Αντιμυκητιασικό φάσμα έναντι των συνηθεστέρων μυκήτων της καθημερινής κλινικής πράξης – Ατοξικότης – Όχι σημαντικές αλληλεπιδράσεις – Όχι ανάγκη προσαρμογής δοσολογίας Γενικά χαρακτηριστικά των αντιμυκητιασικών φαρμάκων

22 Echinocandins-Spectrum vs. Yeast and Moulds Fungicidal vs. Candida spp. including many fluconazole- resistant species Fungicidal vs. Candida spp. including many fluconazole- resistant species – C. albicans = C. tropicalis = C. glabrata = C. krusei < C. parapsilosis = C. lusitaniae Active against Aspergillus species Active against Aspergillus species No activity against C. neoformans, zygomycetes No activity against C. neoformans, zygomycetes Kuhn et al. Antimicrob Agent Chemother 2002;46:

23 μυκητοκτόνος δράση εναντίον των ειδών Candida - Candida albicans, Candida glabrata, Candida tropicalis, and Candida krusei (MIC 90 ≤ 0.12 µg/mL) - Candida parapsilosis, Candida lusitaniae (MIC 90, 0.5 µg/ml to 2.0 µg/ml) - (Στελέχη ανθεκτικά στη φλουκοναζόλη) In vitro δραστικότης 1- Pfaller M.A., Boyken L., Hollis R.J., Messer S.A., Tendolkar S., Diekema D.J. In vitro activities of anidulafungin against more than 2,500 clinical isolates of Candida spp., including 315 isolates resistant to fluconazole. J Clin Microbiol. 2005;43:

24 Caspofungin vs. Amphotericin B Deoxycholate in the Treatment of Invasive Candidiasis in Neutropenic and Non-Neutropenic Patients CAS [95% CI] AMB Difference adjusted for stratification MITT 71/115 (74%) [65-82] 71/115 (62%) [53-71]12.7%[ ] End of Therapy response * 71/88 (81%) [72-89] 63/97 (65%) [55-75]15.4%[ ] Mora-Duarte et al. NEJM Volume 348: * P < 0.05, secondary analysis Caspofungin 70 mg day #1, then 50 mg QD vs. AMB-D mg/kg/q24h

25 Νεότερα αντιμυκητιασικά φάρμακα Αζόλες itraconazole (i.v.) voriconazole posaconazole ravuconazole BAL 8557/4815 Εχινοκανδίνες caspofungin micafungin anidulafungin Aminocandin Πολυένια ABLC, ABCD, AmBisome liposomal nystatin inhaled amphotericin B

26 Copyright restrictions may apply. Pasqualotto, A. C. et al. J. Antimicrob. Chemother :i19-30i; Chemical structures of the licensed and new azoles and echinocandins

27 Posaconazole

28 Προφύλαξη Προφύλαξη In vitro δραστικότης παρόμοια με voriconazole Όχι ένδειξη για συστηματική καντιντίαση Μόνο στοματοφαρυγγική καντιντίαση 200 mg X4 400 mg X2 Posaconazole

29 Posaconazole Salvage Therapy for Invasive Aspergillosis Open, salvage therapy; historical controls refractory or intolerant of standard therapy Open, salvage therapy; historical controls refractory or intolerant of standard therapy Posaconazole: Oral solution (200mg qid X 2 wk/400mg bid) Posaconazole: Oral solution (200mg qid X 2 wk/400mg bid) Adverse events: 4-10% (Headache, abdominal pain, nausea, liver enzyme elevations) Aspergillus speciesPosaconazole (n)Historical Controls (n) All Aspergillus42% (107)26% (86) A. fumigatus41% (29)35% (34) A. flavus53% (19)19% (16) A. terreus29% (14)18% (11) Raad I, et al. ICAAC 2004 (Abstract M-669)

30 In vitro activity 1 1- Cappelletty D. et al. Reviews of therapeutics : the echinocandins Pharmacotherapy 2007, 27(3): Anidulafungin Micafungin* Caspofungin Candida species MIC 50 (µg/ml) MIC 90 (µg/ml) MIC 50 (µg/ml) MIC 90 (µg/ml) MIC 50 (µg/ml) MIC 90 (µg/ml) albicans glabrata tropicalis dubliniensis krusei lusitaniae parapsilosis guilliermondiiND1ND > 8 Minimum inhibitory concentrations of the echinocandins against Candida species * Micafungin has not yet been approved in the EU.

31 Θεραπεία της εν τω βάθει Καντιντίασης Aνιντουλαφουνγκίνη

32 1- Ecalta SPC. 2-Reboli A.C., Rotstein C., Pappas P.G., Chapman S.W., Kett D.H., Kumar D., Betts R., Wible M., Goldstein B.P., Schranz J., Krause D.S., Walsh T.J. Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356(24): Το νεώτερο αντιμυκητιασικό Επιθυμητή φαρμακοκινητική Δραστικό εναντίον της Candida albicans και ειδών non- albicans 1 Όχι ηπατικός ή νεφρικός μεταβολισμός 1 Όχι προσαρμογή δοσολογίας σε ηπατική ή νεφρική ανεπάρκεια 1 Δεν αναφέρονται φαρμακευτικές αλληλεπιδράσεις 1 Anidulafungin – Χαρακτηριστικά

33 Μηχανισμός δράσης ECALTA ® SPC. 2- Odds F.C., Brown A.J.P., Gow N.A.R. Antifungal agents: mechanism of action. Trends Microbiol. 2003;11: Debono M., Turner W.W., LaGrandeur L. et al. Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB. J Med Chem. 1995;38(17): Raasch R.H. Anidulafungin: review of a new echinocandin antifungal agent. Expert Rev Anti Infect Ther. 2004;2: Anidulafungin: Αναστολή της σύνθεσης της 1,3-β-D – γλυκάνης 4 Glucan is essential to fungal cell wall integrity 2-4 Without it, fungal cells are osmotically fragile and easily lysed 4

34 Anidulafungin : μυκητοκτόνος δράση εναντίον των ειδών Candida - Candida albicans, Candida glabrata, Candida tropicalis, and Candida krusei (MIC 90 ≤ 0.12 µg/mL) - Candida parapsilosis, Candida lusitaniae (MIC 90, 0.5 µg/ml to 2.0 µg/ml) - Candida parapsilosis, Candida lusitaniae (MIC 90, 0.5 µg/ml to 2.0 µg/ml) - (Στελέχη ανθεκτικά στη φλουκοναζόλη) - (Στελέχη ανθεκτικά στη φλουκοναζόλη) In vitro δραστικότης 1- Pfaller M.A., Boyken L., Hollis R.J., Messer S.A., Tendolkar S., Diekema D.J. In vitro activities of anidulafungin against more than 2,500 clinical isolates of Candida spp., including 315 isolates resistant to fluconazole. J Clin Microbiol. 2005;43:

35

36 Global success at the end of IV therapy Anidulafungin demonstrated superiority vs fluconazole: Significantly greater response rate in the anidulafungin group Difference: 15.4% (95% CI: 3.9% to 27.0%) Mean (median) duration of IV therapy: fluconazole: 12.1 (11) days anidulafungin: 13.5 (14) days Primary endpoint 1 1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:

37 Global per-pathogen success at the end of IV therapy Secondary endpoint 1 (2) 1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:

38 At the end of intravenous therapy, persistent infection was documented in: 8 patients (6.3%) in the anidulafungin group 17 patients (14.4%) in the fluconazole group (P = 0.06) Kaplan–Meier estimates of survival The median time to death was 21 days in the anidulafungin group 14 days in the fluconazole group More patients died in the fluconazole group (37 of 118: 31.4%) than in the anidulafungin group (29 of 127: 22.8% (P = 0.13) Secondary endpoint 1 (3) 1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:

39 Μικαφουνγκίνη REVIEWS OF ANTI-INFECTIVE AGENTS CID 2006:42 (15 April) 1171

40 Micafungin MYCAMINE ® (micafungin sodium)

41 Mechanism of action Micafungin inhibits 1,3-β-D-glucan synthesis – 1,3-β-D-glucan forms helically intertwined chains that are essential to cell wall rigidity – Inhibition of 1,3-β-D-glucan synthesis results in destabilisation of the cell wall, eventually causing cell lysis Micafungin Inhibition of 1,3-β-D-glucan synthase Depletion of 1,3-β-D-glucan resulting in cell wall destabilisation

42 Structure of the 1,3-β-D-glucan synthase enzyme, revealing the site of action of micafungin Kurtz MB & Douglas CM. J Med Vet Mycology 1997; 35:79–86 UDP Catalytic subunit (Fks) 1,3-β-D-glucan Soluble regulatory subunit (Rho1) Exoplasm Plasma membrane Cytoplasm Micafungin blocks this reaction UDP = uridine diphosphate

43 In vitro activity of micafungin against Candida spp. Organism Study 1*Study 2 † No. of isolates MIC 50 (µg/ml) MIC 90 (µg/ml) No. of isolates MIC 50 (µg/ml) MIC 90 (µg/ml) C. albicans2, C. glabrata C. tropicalis C. parapsilosis C. krusei C. kefyr C. guilliermondii C. lusitaniae C. famata240.51––– C. haemulonii––– C. fermentati–––1011 Candida spp Total5, –– *Pfaller MA, et al. J Clin Microbiol 2008; 46:150–6; † Dannaoui E, et al. Antimicrob Agents Chemother 2008; 52:778–81

44 In vitro activity of micafungin against Candida spp. – comparison with other echinocandins Organism MIC 90 (µg/ml) Number of isolates MicafunginCaspofunginAnidulafungin C. albicans2, C. parapsilosis C. glabrata C. tropicalis C. krusei C. guilliermondii61112 C. lusitaniae C. kefyr C. famata24112 Candida spp Total5, Pfaller MA, et al. J Clin Microbiol 2008; 46:150–6

45 Micafungin licensed indications The indications of micafungin can be summarised as follows: In adults and children (including infants < 12 months of age and premature neonates) for: – the treatment of invasive candidiasis – prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem cell transplantation or patients who are expected to have neutropenia (absolute neutrophil count < 500 cells/µl) for ≥ 10 days It is also approved for the treatment of oesophageal candidiasis in adult patients (including adolescents ≥ 16 years of age and the elderly) for whom intravenous therapy is appropriate MYCAMINE ® (micafungin sodium) for injection SmPC. Astellas Pharma Europe Ltd., September 2008

46 Comparison of approved indications in Europe for the echinocandins 1. MYCAMINE ® (micafungin sodium) for injection SmPC. Astellas Pharma Europe Ltd., September 2008; 2. CANCIDAS (caspofungin) SmPC. Merck Sharp & Dohme Ltd, November 2008; 3. ECALTA ® (anidulafungin) SmPC. Pfizer Ltd., October 2007 Micafungin 1 *Caspofungin 2 Anidulafungin 3 Invasive candidiasisYes Yes † Neutropenic patientsYes No Paediatric patientsYes ‡ ≥ 12 monthsNo NeonatesYesNo Prophylaxis in HSCT patients or expected neutropenic patients AdultsYesNo Paediatric patientsYesNo NeonatesYesNo Oesophageal candidiasis in adult patientsYesNo Invasive aspergillosis SalvageNoYesNo Empiric therapy in febrile neutropeniaNoYesNo *The decision to use micafungin should take into account a potential risk for the development of liver tumours (rat finding). Micafungin should therefore only be used if other antifungals are not appropriate. 1 † Anidulafungin was studied primarily in patients with candidaemia and only in a limited number of patients with deep tissue Candida infections or abscess-forming disease. ‡ Including infants < 12 months of age and premature neonates.

47 Πλεονεκτήματα του φαρμάκου

48 Cateau E, et al. J Antimicrob Chemother 2008; 62:153–5 Biofilm growth inhibition (%) (a) C. albicans ATCC h48h72h24h48h 12 h old biofilm Biofilm growth inhibition (%) (b) C. albicans ATCC day old biofilm12 h old biofilm5 day old biofilm Caspofungin 2 mg/l Micafungin 5 mg/l h48h72h24h48h Micafungin activity against biofilms Micafungin showed excellent activity against both intermediate- and mature-phase biofilms of two separate Candida albicans strains: – ATCC 3153 – ATCC 66396

49 In vivo drug–drug interaction studies with micafungin in healthy subjects DrugClass Effect of micafungin on metabolism of co-administered drug Effect of co-administered drug on metabolism of micafungin Mycophenolate mofetil 1 Cyclosporin 1 Tacrolimus 2 Immunosuppressant None Prednisolone 1 Corticosteroid Ritonavir 1 Antiviral Rifampicin 1 Antibacterial Amphotericin B 3 Voriconazole 4 Fluconazole 1 Antifungals Nifedipine 1 Calcium channel blocker When co-administered with micafungin:  monitor for toxicity  reduce dose (if necessary) Sirolimus 1 Immunosuppressant Itraconazole 5 Antifungal 1. Astellas Pharma US, Inc. MYCAMINE ® (micafungin sodium) for injection US Prescribing Information Available at: (accessed February 2009); 2. Hebert MF, et al. J Clin Pharmacol 2005; 45:1018–24; 3. Undre N, et al. 17th ECCMID. Munich, Germany, 31 Mar–3 Apr 2007; Poster P971; 4. Keirns J, et al. Antimicrob Agents Chemother 2007; 51:787–90; 5. Undre N, et al. 17th ECCMID. Munich, Germany, 31 Mar–3 Apr 2007; Poster P970

50 Administration to special populations There is no requirement for micafungin dose adjustments in special populations – Age – Gender – Renal impairment – Mild-to-moderate hepatic impairment 1–3 Micafungin has not been studied in patients with severe hepatic impairment 2,4 1. Groll AH, et al. Expert Opin Investig Drugs 2005; 14:489–509; 2. Astellas Pharma US, Inc. MYCAMINE ® (micafungin sodium) for injection US Prescribing Information Available at: (accessed February 2009); 3. Hebert MF, et al. J Clin Pharmacol 2005; 45:1018–24; MYCAMINE ® (micafungin sodium) for injection SmPC. Astellas Pharma Europe Ltd., September 2008

51 Oesophageal candidiasis

52 Summary of micafungin clinical data in oesophageal candidiasis Study designComparatorPatientsDoses Key efficacy results Open-label, dose-finding 1 –120 patients with endoscopically proven oesophagitis 12.5–100 mg/dayClear dose– response pattern with improved efficacy at higher doses Randomised, double-blind, dose–response 2 Fluconazole (IV) 245 patients; 185 treated with micafungin and 60 treated with fluconazole Micafungin: 50 mg/day (n = 64); 100 mg/day (n = 62); 150 mg/day (n = 59) Fluconazole: 200 mg/day (n = 60) Endoscopic cure rate: micafungin (pooled 100 mg/day mg/day) 83.5%; fluconazole 86.7% Randomised, double-blind, comparative, non-inferiority, Phase III 3 Fluconazole (IV) 518 patients; 260 treated with micafungin and 258 treated with fluconazole Micafungin: 150 mg/day Fluconazole: 200 mg/day Endoscopic cure rate: micafungin 87.7%; fluconazole 88.0% 1. Pettengell K, et al. Aliment Pharmacol Ther 2004; 20:475–81; 2. de Wet N, et al. Clin Infect Dis 2004; 39:842–9; 3. de Wet NT, et al. Aliment Pharmacol Ther 2005; 21:899–907

53 Systemic Candida infections

54 Phase II micafungin study: global response rate Ostrosky-Zeichner L, et al. Eur J Clin Microbiol Infect Dis 2005; 24:654–61 De novo patients Micafungin MicafunginTotal in combinationalone Efficacy failure patients Response rate (%) PP population

55 Phase III study micafungin vs. L- AmB: overall treatment success by infection site Kuse ER, et al. Lancet 2007; 369:1519–27 Treatment success rate (%) Candidaemia n = 170n = 32 Invasive candidiasis MicafunginL-AmB n = PP population

56 92.3 Phase III study micafungin vs. L- AmB: overall treatment success by Candida species PP population Kuse ER, et al. Lancet 2007; 369:1519–27 L-AmB C. krusei Treatment success rate (%) Non-albicans Candida spp. n = C. albicansAny non- albicans C. glabrataC. tropicalisC. parapsilosis Micafungin

57 n = 247 Micafungin 25 Phase III study micafungin vs. L- AmB: treatment success by neutropenic status Treatment success rate (%) MicafunginL-AmB OverallNon-neutropenicNeutropenic Kuse ER, et al. Lancet 2007; 369:1519– L-AmB mITTPP mITT = modified intent-to-treat; PP = per-protocol set

58 Phase III study micafungin vs. caspofungin: treatment success Pappas PG, et al. Clin Infect Dis 2007; 45:883–93 n = 191n = 188n = 199 Caspofungin 50 mg/day* Treatment success rate (%) n = Micafungin 100 mg/day Micafungin 150 mg/day *Loading dose 70 mg; mITT population

59 Phase III study micafungin vs. caspofungin: treatment success by Candida species C. albicansAny non-C. glabrataC. tropicalisC. parapsilosisC. krusei albicans Pappas PG, et al. Clin Infect Dis 2007; 45:883–93 Non-albicans Candida spp. *Loading dose 70 mg; mITT population Micafungin 100 mg/day (n = 191) Treatment success rate (%) p = NS p = 0.07 (NS) Micafungin 150 mg/day (n = 199) Caspofungin 50 mg/day* (n = 188) p = NS n =

60 Phase III study micafungin vs. caspofungin: treatment success by neutropenic status Overall Non-neutropenic Pappas PG, et al. Clin Infect Dis 2007; 45:883  93 n =199 Micafungin 100 mg/day 17 Treatment success rate (%) Micafungin 150 mg/day Caspofungin 50 mg/day* Neutropenic *Loading dose 70 mg; mITT population

61 Paediatric sub-study micafungin vs. L-AmB: treatment success by primary infection site Adapted from Queiroz-Telles F, et al. Pediatr Infect Dis J 2008; 27:820– Invasive candidiasis Candidaemia Micafungin L-AmB mITT population n = Treatment success rate (%)

62 Paediatric sub-study micafungin vs. L-AmB: treatment success by neutropenic status Treatment success rate (%) n = L-AmB Micafungin Overall Queiroz-Telles F, et al. Pediatr Infect Dis J 2008; 27:820–6 mITT population Non-neutropenicNeutropenic

63 Paediatric subset of Phase III trial micafungin vs. fluconazole: treatment success van Burik JA, et al. Clin Infect Dis 2004; 39:1407–16 80 MicafunginFluconazole Treatment success rate (%) MicafunginFluconazole n = 3945

64 Θεραπευτικές προσεγγίσεις μυκητιασικών λοιμώξεων Θεραπευτικές προσεγγίσεις μυκητιασικών λοιμώξεων

65 Θεραπευτικές προσεγγίσεις μυκητιασικών λοιμώξεων candida spp Polyenes – Amphotericin B, including lipid formulations Azoles – Older agents: fluconazole, itraconazole – Newer agents: voriconazole, posaconazole Echinocandins – Micafungin – Caspofungin – Anidulafungin

66 Micafungin

67 Guidelines for the treatment of patients with SCIs: Europe 2007 Several groups within Europe have published individual recommendations for the treatment of SCIs, including FUNGINOS, DGHO, SAEI and ECIL 1–6 Patient typeFirst choiceAlternatives Non-neutropenicFluconazole (800 mg/d loading, then 400 mg/d)* 1,2 Amphotericin B deoxycholate (AmB-d) or caspofungin †1 AmB-d or caspofungin or voriconazole* 1,2 Liposomal amphotericin B (L ‑ AmB) †1 NeutropenicAmB-d 1,2 Caspofungin or L-AmB 1 Fluconazole or L-AmB 2 Severe sepsis/ septic shock Caspofungin 1,2 or AmB-d 2 L-AmB 1,2 or voriconazole 1 Haemato-oncologyEchinocandin or L-AmB or, if patient is non- neutropenic, voriconazole 3 Fluconazole is reserved for patients who are stable, non-neutropenic, with no prior azole exposure and with a susceptible Candida species 3 Caspofungin or L-AmB 4 L-AmB or ABLC 3 1. Fluckiger U. Swiss Med Wkly 2006; 136:447–63; 2. Pachon J, et al. Enferm Infecc Microbiol Clin 2006; 24:254–63; 3. Böhme A, et al. Ann Hematol 2009; 88:97–110; 4. Prentice AG, et al. British Committee for Standards in Haematology. London; British Society for Haematology; 5. Marchetti O, et al. Eur J Cancer Suppl 2007; 5:32–42; 6. Herbrecht R, et al. Eur J Cancer Suppl 2007; 5:49–59 *No prior azole exposure; † Prior azole exposure; ABLC = amphotericin B lipid complex

68 Guidelines for the treatment of invasive candidiasis: IDSA Pappas PG, et al. Clin Infect Dis 2009; 48:503–35 Condition or treatment group Therapy PrimaryAlternative RecommendationRank*RecommendationRank* Non-neutropenic patients Candidaemia (targeted therapy) Fluconazole or an echinocandin † A-ILipid formulation of AmB (LFAmB) or AmB-d or voriconazole A-I Suspected candidiasis (empirical therapy ‡ ) As for candidaemia; echinocandin or fluconazole preferred † B-IIILFAmB or AmB-dB-III Neutropenic patients Candidaemia (targeted therapy) Echinocandin or LFAmBA-IIFluconazole § or voriconazole B-III Suspected candidiasis (empirical therapy ‡ ) LFAmB or caspofungin or voriconazole A-I (B-I for voriconazole) Fluconazole ¶ or itraconazole ¶ B-I *See following slide for definitions. † An echinocandin is favoured for moderately severe to severe illness and in patients with recent azole exposure, and as initial therapy in patients with or suspected to have C. glabrata infection; fluconazole is preferred as initial therapy in patients with or suspected to have C. parapsilosis infection, if no prior azole exposure. ‡ Empirical therapy should be initiated following ≥ 4 days’ fever despite antibiotics. § Fluconazole should be reserved for patients without prior azole exposure who are not critically ill. ¶ Azoles should not be used for empirical therapy in patients who have received an azole for prophylaxis

69 ΠΡΟΦΥΛΑΞΗ ΜΥΚΗΤΙΑΣΕΩΝ ΠΟΥ ΚΑΙ ΠΟΤΕ

70 ΔΙΟΤΙ : – Υπάρχουν καλά καθορισμένοι πληθυσμοί ασθενών που διατρέχουν ψηλό κίνδυνο να παρουσιάσουν Διηθητικές Μυκητιασικές Λοιμώξεις (ΔΜΛ) ΠΟΙΕΣ ΛΟΙΜΩΞΕΙΣ; – 1. Από ζυμομύκητες (Yeast infections) ΚΑΙ κυρίως από Candida spp (Candida albicans αποτελεί κύριο εκπρόσωπο) – 2. Σε δεύτερο χρόνο, από υφομύκητες (Mould infections) ΚΑΙ κυρίως από Aspergillus spp ΓΙΑΤΙ;

71 ΠΛΗΘΥΣΜΟΙ: – Α. ΧΑΜΗΛΟΥ ΚΙΝΔΥΝΟΥ – Β. ΥΨΗΛΟΥ ΚΙΝΔΥΝΟΥ

72 Πληθυσμοί χαμηλού κινδύνου: Ασθενείς με λέμφωμα που λαμβάνουν ‘standard’ χημειοθεραπεία Ασθενείς που υπόκεινται σε αυτόλογη μεταμόσχευση αρχέγονων κυττάρων μετά από χημειοθεραπεία υψηλών δόσεων ΚΑΙ ΔΕΝ έχουν λάβει πρόσφατα πουρινικά ανάλογα που καταστέλλουν τα Τ κύτταρα Ασθενείς που υπόκεινται σε μεταμόσχευση παγκρέατος (χωρίς χαρακτηριστικά υψηλού κινδύνου) Ασθενείς που υπόκεινται σε μεταμόσχευση ήπατος και ΔΕΝ χαρακτηρίζονται ως υψηλού κινδύνου Ασθενείς που υπόκεινται σε μεταμόσχευση νεφρού ή καρδίας (θεωρούνται ΠΟΛΥ Χαμηλού κινδύνου)

73 Πληθυσμοί υψηλού κινδύνου Ουδετεροπενία επι κακοήθων αιματολογικών νόσων (Neutropenia in malignant haematological diseases) Δέκτες αλλογενούς μεταμόσχευσης αρχέγονων κυττάρων (Allogenic stem cell transplant recipients) Δέκτες συμπαγών οργάνων μετά μεταμόσχευση (Solid organ transplant recipients) Ορισμένοι ασθενείς σε ΜΕΘ (Intensive care patients) Ασθενείς με AIDS και CD4 <50 κύτ/μl ??? ???

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Κατέβασμα ppt "ΑΝΤΙΜΥΚΗΤΙΑΣΙΚΑ & ΘΕΡΑΠΕΙΑ ΜΥΚΗΤΙΑΣΙΚΩΝ ΛΟΙΜΩΞΕΩΝ ΓΕΩΡΓΙΟΣ ΠΑΝΟΣ BSc, CEng, MIET, MD, PhD, DTM&H(Lon), FRCP Αν. Καθηγητής Παθολογίας & Λοιμωδών Νοσημάτων."

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