Combination Therapy in Cryptococcal Meningitis

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 Antifungal spectrum of activity against common fungi

Ashley et al., Clin. Infect. Dis. 2006;43:S28–S39 ESCMID Online Lecture Library 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

ESCMID Online Lecture Library 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

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© by 15 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. / Year publ. Drugs n° pts Comments

Goodman et al., 1992 FLU vs Placebo 356 Significant reduction of superficial and N Engl J Med systemic fungal infections

Slavin et al., 1995 FLU vs Placebo 300 Reduction of superficial and systemic J Infect Dis fungal infections – improved survival

Marr et al., 2000 FLU vs Placebo 300 Reduction of systemic candidiasis Blood and related mortality

Winston et al., 2003 ITRA vs FLU 140 ITRA > FLU at reducing IFIs but less Ann Intern Med tolerated - No differences in mortality rates

Marr et al., 2004 ITRA vs FLU 304 ITRA  FLU at reducing IFIs but less Blood tolarated - No differences in mortality rates

Ullmann et al., 2007 POSA vs FLU 600 POSA  FLU at reducing overall IFIs N Engl J Med POSA > FLU at reducing IA POSA > FLU at reducing the rate of ESCMID Online Lecturedeaths Library due to IFIs

ESCMID Online Lecture Library Measures Overall response • Fever resolved during neutropenic period • Breakthrough fungal infection • Base-line fungal infection cured • Survival (7 days) • Discontinuation due to toxicity or lack of efficacy © by author

ESCMID Online Lecture Library YES

ESCMID Online Lecture Library A Randomized Trial Comparing Fluconazole with Amphotericin B for the Treatment of Candidemia in Patients without Neutropenia

n° of persistent candidemia

% overall success

Rex et al., N Engl J Med.ESCMID 1994, 17;331:1325-30 Online Lecture Library Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial

% overall success •Tot pts. 422

•Similar clearance of blood cultures

•Discontinuation higher in vori group © by author Voriconazole was as effective as the regimen of amphotericin B followed by fluconazole in the treatment of candidaemia in non-neutropenic patients, Kullberg et al., Lancet,ESCMID 2005, 366:1435-42. Onlineand Lecture with fewer Library toxic effects Condition or treatment Therapy group Primary Alternative Recommendation Rank* Recommendation Rank*

Non-neutropenic patients

Candidaemia Fluconazole or an A-I Lipid formulation of A-I (targeted therapy) echinocandin† AmB (LFAmB) or AmB- d or voriconazole

Suspected candidiasis As for candidaemia; B-III LFAmB or AmB-d B-III (empirical therapy‡) echinocandin or fluconazole preferred†

Neutropenic patients Candidaemia Echinocandin or LFAmB© byA-II authorFluconazole § or B-III (targeted therapy) voriconazole

Suspected candidiasis LFAmB or caspofungin A-I Fluconazole¶ or B-I (empirical therapy‡) or voriconazole (B-I for itraconazole¶

voriconazole) ESCMID Online Lecture Library Pappas PG, et al. Clin Infect Dis 2009; 48:503–35

ESCMID Online Lecture Library VORICONAZOLE vs AMB-D

76/144

42/133

Voriconazole arm success = 52.8%; Amphotericin arm = 31.6% Difference (raw) = 21.2%, 95 % CI (9.9, 32.6) Difference (adjusted)ESCMID = 21.8%, 95% CIOnline (10.5, 33.0) LectureHerbrecht Library R, et al. N Engl J Med 2002; 347:408-415 Global Comparative Aspergillosis Study (307/602) DRC-Assessed Success at Week 12 (MITT)

Overall Pulmonary Extra Pulmonary Allogeneic BMT Autologous BMT / other hematological (e.g. leukemia) Other immunosuppressed state (e.g. SOT, HIV/AIDS) Neutropenic (ANC < 500) Non-Neutropenic (ANC  500) © by author Proven IA Probable IA ESCMID Online Lecture Library Herbrecht R, et al. N Engl J Med 2002; 347:408-415 % Difference in Success Rates (95% CI) Voriconazole

ESCMID Online Lecture Library Cryptococcus neoformans

5FC FLU ITRA

In vitro AMB + 0 0 5FC + +

Bava et al., 1992, Eur. J. Epidemiol. 8:422-6. Diamond et al., 1998, Antimicrob. Agents Chemother. 42:528-33. Schwarz et al., 2006, Antimicrob. Agents Chemother. 50:113-20. + Combination generally more effective than each single drug Allendoerfer et al., 1991, Antimicrob. Agents Chemother. 35:707-13. Larsen et al., 1996, Antimicrob. AgentsESCMID Chemother. 40:2178-82. Online Lecture Library Nguyen et al., 1997, Antimicrob. Agents Chemother. 41:1120-3. 0 Combination  to the most effective drug Larsen et al., 2004, Antimicrob. Agents Chemother. 48:985-91

Clinical studies of combination therapy in cryptococcal meningitis

Combination regimen Study Design / Population Comments

Prospective, randomized / no AIDS pts  Faster clearance of yeasts from the CSF AMB + 5FC Prospective, randomized / AIDS pts Prospective, randomized, open label /  Similar overall mortality AIDS pts

Noncomparative, prospective, open label FLU + 5FC / AIDS pts As FLU alone

A trend towards better Prospective,© random byized, openauthor label / AMB + FLU AIDS pts outcomes in the combination therapy arms Bennett et al., N Engl J Med 1979;301:126-131 Van der Horst et al., N Engl J Med 1997; 337:15-21 Brouwer et al., Lancet 2004; 363:1764-1767 Larsen et al., Clin Infect Dis 1994; 19:741-745 Bicanic et al., Clin Infect DisESCMID 2008;47:123–130 Online Lecture Library Pappas et al., Clin Infect Dis 2009;48:1775–1783 HIV + patients

Transplant recipients

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