Invasive Fungal Infections: Controversies and Lessons from Clinical Practice, ESCMID Postgraduate Education Course Saint Petersburg 23-24 June 2011 Azole derivatives and other antifungal drugs Francesco Barchiesi Dipartimento ©di Scienze by author Biomediche Università Politecnica della Marche Ancona - Italy ESCMID Online Lecture Library Polyenes: Pyrimidines: amphotericin B 5-FC Allylamines: terbinafine squalen 5-FC DNA/RNA lanosterol 5-FU synthesis Cell wall 5-FUMP zymosterol -(1-3)-D-glucan Cell ergosterol Azoles: membrane ketoconazole © by author fluconazole Echinocandins: itraconazole caspofungin voriconazole anidulafungin posaconazole micafungin ESCMID Online Lecture Library © by author ESCMID Online Lecture Library Antifungal spectrum of activity against common fungi Ashley et al., Clin. Infect. Dis. 2006;43:S28–S39 In Vitro Methods for Determining Fungicidal Activity for Antifungal Agents against Yeasts and Molds 1. Time-Kill Studies 2. Minimal Fungicidal Concentration © by author ESCMID Online Lecture Library “cidal definition….” Control 1/8 1/4 1/2 1 2 © by author Fungicidal 99.9% or 3-log10 -unit decrease in CFU/ml 4 8, 16, 32 ESCMID Online Lecture Library © by author ESCMID Online Lecture Library neutropenic mice Pharmacodynamic properties of antifungal agents as determined by in vitro time-kill studies (I) Drugs Pharmacodynamic Comments caractheristics Ampho. B Conc.-dependent Confirmed by in fungicidal activity in vivo studies; PAFE >12 h optimal peak/MIC is 4 Echinocandins Conc.-dependent© by author Not “cidal” against (caspofungin, fungicidal activity all strains; optimal anidulafungin, PAFE >12 h peak/MIC is 3-4 micafungin) ESCMID Online Lecture Library Pfaller et al., CMR, 17:268-280; 2004 Pharmacodynamic properties of antifungal agents as determined by in vitro time-kill studies (II) Drugs Pharmacodynamic Comments caractheristics Fluconazole Conc.-independent Concentrations > 4x MIC fungistatic activity not associated with no PAFE additional antifungal activity Vori/Posa Conc.-independent Maximal effects at fungistatic activity 2-3 x MIC no PAFE © by author Flucytosine Conc.-independent Maximal effects at fungistatic activity 1-4 x MIC ESCMIDPAFE 2-4Online h Lecture Library Pfaller et al., CMR, 17:268-280; 2004 AMB vs C. guilliermondii AMB vs C. lusitaniae CAS vs C. kefyr VORI vs C. kefyr © by author ESCMID Online Lecture Library Di Bonaventura, et al., AAC 2004, 48:4453-4456 Comparative pharmacokinetics of the antifungal agents AmB ABLC L-AmB FLU VORI POSA ITRA CAS MICA ANID 5-FC Parameters Oral bioavailability % <5 <5 <5 95 96 ND 50 <5 <5 <5 80 Cmax (mcg/ml) 0.5-2 131 0.1 0.7 4.6 7.8 11 0.27 0.24 0.83 80 AUC (mg x h/L) 17 14 555 400 20.3 8.9 29.2 119 158 99 62 Protein binding % >95 >95 >95 10 58 99 99.8 97 99 84 4 CSF penetration % 0-4 <5 <5 >60 60 NR <10 <5 <5 <5 75 Vitreal penetration % 0-38 0-38 0-38 28-75 38 26 10 0 <1 0 49 Urine penetration % 3-20 <5 4.5 90 <2 <2 1-10 <2 <2 <2 90 Metabolism Minor Unk Unk Minor Hep Hep Hep Hep Hep None Minor Hep Hep intest Elimination Feces Unk Unk Urine© byRenal authorFeces Hep Urine Feces Feces Renal Half-life, h 50 173 100-153 31 6 25 24 30 15 26 3-6 Ashley et al., Clinical InfectESCMIDious Diseases 2006; 43:S28–39 Online Lecture Library Drugs that significantly decrease the serum levels of antifungal agents Drugs Concomitant drug(s) Action ITRA H-2 antagonists and proton pump Monitor ITRA serum levels and considering inhibitors, rifampin increase the dose of ITRA or choosing alternate drug(s) FLUCO Rifampin Consider increasing the dose of FLU VORI Rifampin, rifabutin, efavirenz, Controindicated coadministration with ritonavir, carbamazepine, long- carbamazepine, long-acting barbiturates, rifampin and rifabutin; with phenytoin and efavirenz, acting barbiturates, and phenytoin double VORI dosage and monitor for the increase of the concomitant drugs POSA Cimetidine, rifabutin, and phenytoin© by authorAvoid concomitant use CASPO Rifampin, efavirenz, nevirapine, Increase maintenance dose of CAS to 70 mg/day dexamethasone, phenytoin, and carbamazepineESCMID Online Lecture Library Nucci and Perfect, Clin. Infect. Dis. 2008;46:1426-1433 Antifungal therapeutic drug monitoring: established and emerging indications Indication Time of first Efficacy (mcg/ml) Safety (mcg/ml) measurement 5FC Routine during first 3-5 days Peak > 20 Peak < 50 week therapy, renal insuff., poor response ITRA Routine during first 4-7 days Prophylaxis > 0.5; NA week therapy, GI therapy through > disfunction, co- 1-2 medication VORI Lacking response, 4-7 days Prophylaxis > 0.5; Through <6 GI dysfunction, co- therapy through > medication, 1-2 children, IV to oral switch, unexplained neurological symptoms/signs © by author POSA Lacking response, 4-7 days Prophylaxis > 0.5; NA GI dysfunction, co- therapy through > medication, PPI 0.5-1.5 therapy ESCMID Online Lecture Library Andes et al., AAC, 2009, 53: 24-34 DEFINITION • Microbiological R Nonsusceptibility of a fungus to an antifungal agent by in vitro susceptibilty testing, in which Primary R (intrinsic): the MIC of the drug exceeds the susceptibility i.e.: Candida krusei to FLU, breakpoint for that organism Cryptococcus neoformans to echinocandins Secondary R (acquired): • Clinical R i.e.: development of FLU R in Candida albicans or Cryptoccoccus Failure to eradicate a fungal infection neoformans despite the administration of an antifungal agent with in vitro activity against the Clinical R can be attributed to a organism combination of factors related to host, the antifungal agent, or the © by author pathogen Espinel‐Ingroff A, Rev. Iberoam.ESCMID Micol., 25:101‐106, 2008Online Lecture Library Kanafani ZR and Perfect JR, Clin. Infect. Dis., 46:120‐8, 2008 Development of azole resistance in C. albicans 128 g/ml FLU 4.0 g/ml ITRA 0.25 g/ml 0.06 g/ml © by author White, AAC – 1997, ESCMID1482-1487 Online Lecture Library White, AAC – 1997, 1488-1494 Antifungal • CLSI Susceptibilty Document M27-A Testing Document M38-A Document M44-A Technical differences: medium, inoculum size, time of incubation, readings • EUCAST CLSI breakpoints (µg/ml): Document EDef. 7.1 FLU S ≤8FLU R ≥64 ITRA S ≤0.125 ITRA R >1 Document EDef. 9.1 VORI S ≤ 1 VORI R >4 ECHINOCANDINS “NS” ≤2 µ/ml • Commercial methods are available that display good correlation with the EUCAST breakpoints (µg/ml): FLU S ≤ 2FLU R > 4 methods© by author of reference such as E-test, VORI S ≤0.125 VORI R >0.125 Sensititre and Vitek2 Arikan S, Med. Mycol., 45:569‐87, 2007 Johnson E, J. Antimicrob. ESCMIDChemother., 61:Suppl1:i13 ‐8,Online 2008 Lecture Library Cuenca‐Estrella M and Rodriguez‐Tudela JL, 8:267‐76, 2010 Resistance to Azoles 256882 isolates of Candida spp. tested for FLU % 197619 isolates of Candida spp. tested for VORI 30% of FLU-R isolates remained S to VORI An increase in FLU R over time was seen with C. parapsilosis, C. guilliermondii, C. lusitaniae, and % C. pelliculosa © by author Pfaller MA et al., J. Clin. Microbiol.,ESCMID 48:1366‐77, 2010 Online Lecture Library Susceptibility to one azole predicts susceptibility to all? There is a good correlation There is enough differences that testing each agent is worthwhile * * Especially vori and posa As FLU MICs rise, so do these but – Not always so much and not always to “untreatable” levels – E.g., vori data suggests © by author at least some activity vs. C. krusei - 7/10 (70%) salvage response rate Kanafani ZR and Perfect JR,ESCMID Clin. Infect. Dis., 46:120‐ 8,Online 2008 Lecture Library * Spreghini et al., Antimicrob. Agents Chemother., 52:1929‐33, 2008 48h NCCLS M27-A2 MIC, 2000 bloodstream isolates VORI MIC mcg/ml 0.06 0.13 0.25 0.5 1 2 4 > 8 0.13 196 1 1 1 1 0.25 383 3 2 2 2 1 5 0.5 346 9 3 3 2 1 1 5 1 228 26 5 3 2 8 2872053115 444432544 14 8 215566355 4 1 FLU MIC 16 5 8 25 48 35 2 1 32 5 4 21© by15 author 27 5 1 3 > 64 21 2 5 16 12 16 18 31 1. Ostrosky-Zeichner et al. Antifungal susceptibility survey of 2,000 bloodstream Candida isolates in the United States. Antimicrob Agents Chemother 2003;47:3149- 3154. ESCMID Online Lecture Library 2. Ostrosky-Zeichner et al. Voriconazole salvage treatment of invasive candidiasis. Eur J Clin Microbiol Infect Dis 2003;22:651-655. Geographic variation in the frequency of isolation and fluconazole and voriconazole susceptibilities of Candida glabrata: ARTEMIS DISK 12439 2470 45‐88 % 75‐92 % 5629 50‐100% 728 48‐87 % 2039 43‐92 % © by author ESCMID Online Lecture Library Pfaller MA et al., Diagn. Microbiol. Infect. Dis., 67:162‐71, 2010 Resistance to Azoles Clinical breakpoints have not been established for mold testing Proposed for Aspergillus spp: ITRA and VORI R > 2.0 μg/ml POSA R > 0.5 μg/ml Although ECVs do not predict therapy outcome, they may aid in detection of azole resistance (non- WT MIC) Cross-resistance between azole drugs depends on specific % mutations in cyp51A: © by author 1. gly 54 ITRA/POSA 2. meth 220 ITRA/POSA/VORI 3. leu 98 + duplication 34.bp promoter cyp51A ITRA/POSA/VORI Rodriguez‐Tudela JL et al., Antimicrob. Agents Chemother., 52: 2468‐72, 2008 Verweij PE et al., Drug Resist. Updat., 12:141‐7, 2009 Pfaller MA et al., J. Clin. Microbiol.,ESCMID 47:3142‐6, 2009 Online Lecture Library Espinel‐Ingroff A et al., J. Clin. Microbiol., 48:3251‐7, 2010 Strategies for prevention and treatment of invasive fungal infection (IFI) Strategy Definition Prohylaxis Administration of the antifungal drug is initiated at a period of high risk of infection to prevent fungal infections Empirical treatment Initiation/modification of an existing antifungal regimen in persistently febrile patients with neutropenia unresponsive to appropriate antibacterial agents Preemptive therapy Similar to empirical antifungal therapy, preemptive therapy aims to treat a suspected early IFI but uses radiologic studies, laboratory markers, or both rather than fever alone Treatment of established IFI Corresponds© by to patients author who meet European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria for proven and probable Segal et al., CID, 2007, 44:402-409ESCMID Online Lecture Library Antifungal prophylaxis for IFI in HSCT recipients Ref.