Echinocandins:Echinocandins:Were They All Were They All Created Equal? Created Equal?

Coleman Rotstein MDColeman Rotstein MD

Division of Infectious DiseasesDivision of Infectious Diseases

University of TorontoUniversity of Toronto

University Health NetworkUniversity Health Network

Toronto, OntarioToronto, Ontario

Similarities & Differences of the Similarities & Differences of the Echinocandins:Echinocandins:

Framework for DiscussionFramework for Discussion

�� Efficacy Efficacy -- in vitro activityin vitro activity

-- in vivo clinical trialsin vivo clinical trials

�� SafetySafety

�� Pharmacokinetics/Pharmacodynamics & Drug Pharmacokinetics/Pharmacodynamics & Drug InteractionsInteractions

�� Resistance IssuesResistance Issues

�� Cost Issues Cost Issues

EfficacyEfficacy

Classification of Antifungal Classification of Antifungal Agents & Sites of Action Agents & Sites of Action

Fungal Fungal cell wallcell wallFungal Fungal cell wallcell wall

ββββββββ--(1,6)(1,6)--glucanglucanββββββββ--(1,6)(1,6)--glucanglucan

Mechanism of Action: Pathogen TargetsMechanism of Action: Pathogen TargetsMechanism of Action: Pathogen TargetsMechanism of Action: Pathogen Targets

Nucleoside Analogs –5-FC

Nucleoside Analogs –5-FC

β-(1,3)-D-glucanβ-(1,3)-D-glucan

ErgosterolPolyenes: AmB,

Lipid AmB (fungicidal)Azoles: Flu, Itra, Vori, Posa

(fungistatic)

ErgosterolPolyenes: AmB,

Lipid AmB (fungicidal)Azoles: Flu, Itra, Vori, Posa

(fungistatic)

Phospholipid bilayerPhospholipid bilayerof the fungal cellof the fungal cellmembranemembrane

Phospholipid bilayerPhospholipid bilayerof the fungal cellof the fungal cellmembranemembrane

cell wallcell wallcell wallcell wall

ββββββββ-(1,3)-D-glucan synthase(FKS1 Gene codes for this)

Glucan SynthesisInhibitor

Echinocandins: Anidulafungin, Caspofungin, Micafungin (fungicidal)

ββββββββ-(1,3)-D-glucan synthase(FKS1 Gene codes for this)

Glucan SynthesisInhibitor

Echinocandins: Anidulafungin, Caspofungin, Micafungin (fungicidal)

nucleus

In Vitro Activity In Vitro Activity

Range of Activity of Range of Activity of EchinochandinsEchinochandins

Highly ActiveHighly Active Very ActiveVery Active Some Some ActivityActivity

InactiveInactive

Candida spp.Candida spp. C. parapsilosisC. parapsilosis BlastomycesBlastomyces ZygomycetesZygomycetesCandida spp.Candida spp. C. parapsilosisC. parapsilosis BlastomycesBlastomyces ZygomycetesZygomycetes

C. lusitaniaeC. lusitaniae CoccidioidesCoccidioides CryptococcusCryptococcus

Aspergillus spp.Aspergillus spp. HistoplasmaHistoplasma FusariumFusarium

TrichosporonTrichosporon

In Vitro Activity of Echinocandins Against In Vitro Activity of Echinocandins Against Bloodstream Isolates of Bloodstream Isolates of Candida Candida SpeciesSpecies

SpeciesSpeciesNo. of No. of isolates isolates testedtested

Results for: Results for:

ANIDANID CASPCASP MICAMICA

MICMIC9090 % %

≤≤≤≤≤≤≤≤ 2 2 µµµµµµµµg/mlg/ml

MICMIC9090 % %

≤≤≤≤≤≤≤≤ 2 2 µµµµµµµµg/mlg/ml

MICMIC9090 % %

≤≤≤≤≤≤≤≤ 2 2 µµµµµµµµg/mlg/ml

C. albicansC. albicans 2,8692,869 0.060.06 100100 0.060.06 100100 0.030.03 100100C. albicansC. albicans 2,8692,869 0.060.06 100100 0.060.06 100100 0.030.03 100100

C. glabrataC. glabrata 747747 0.120.12 99.999.9 0.060.06 99.999.9 0.0150.015 100100

C. tropicalisC. tropicalis 625625 0.060.06 100100 0.060.06 99.899.8 0.060.06 100100

C. kruseiC. krusei 136136 0.060.06 100100 0.250.25 100100 0.120.12 100100

C. parapsilosisC. parapsilosis 759759 22 92.592.5 11 99.999.9 22 100100

C. guilliermondiiC. guilliermondii 6161 22 90.290.2 11 95.195.1 11 100100

All All CandidaCandida spp.spp. 5,3465,346 22 98.898.8 0.250.25 99.999.9 11 100100

Pfaller MA et al. J Clin Microbiol 2008;46:2620Pfaller MA et al. J Clin Microbiol 2008;46:2620--26292629

In Vitro Activity of Echinocandins Against In Vitro Activity of Echinocandins Against FluconazoleFluconazole--Resistant Isolates of Resistant Isolates of CandidaCandida Spp.Spp.

SpeciesSpeciesNo. of No. of isolates isolates testedtested

Results for:Results for:

ANIDANID CASPCASP MICAMICA

MICMIC9090 % %

≤≤≤≤≤≤≤≤ 2 2 µµµµµµµµg/mlg/ml

MICMIC9090 % %

≤≤≤≤≤≤≤≤ 2 2 µµµµµµµµg/mlg/ml

MICMIC9090 % %

≤≤≤≤≤≤≤≤ 2 2 µµµµµµµµg/mlg/ml

C. albicansC. albicans 4141 0.060.06 100100 0.060.06 100100 0.030.03 100100

C. glabrataC. glabrata 110110 0.120.12 100100 0.060.06 100100 0.0150.015 100100

C. kruseiC. krusei 146146 0.120.12 100100 0.250.25 100100 0.060.06 100100

All All CandidaCandida spp.spp. 315315 11 100100 0.250.25 100100 0.50.5 100100

Pfaller MA et al. J Clin Microbiol 2008;46:2620Pfaller MA et al. J Clin Microbiol 2008;46:2620--26292629

In Vivo Clinical TrialsIn Vivo Clinical Trials

Indications for EchinocandinsIndications for Echinocandins

�� Caspofungin:Caspofungin:

�������� Invasive candidiasis/candidemiaInvasive candidiasis/candidemia

�������� Esophageal candidiasisEsophageal candidiasis

�������� Invasive aspergillosis in patients refractory to or Invasive aspergillosis in patients refractory to or

intolerant of other therapiesintolerant of other therapies

�������� Empiric antifungal therapy for febrile neutropenic Empiric antifungal therapy for febrile neutropenic

episodesepisodesepisodesepisodes

�� Micafungin:Micafungin:

�������� Esophageal candidiasisEsophageal candidiasis

�������� Prophylaxis of Prophylaxis of CandidaCandida infections in HSCTinfections in HSCT

�������� Invasive candidiasis/candidemiaInvasive candidiasis/candidemia

�� Anidulafungin:Anidulafungin:

�������� IInvasive candidiasis/candidemianvasive candidiasis/candidemia

�������� Esophageal candidiasisEsophageal candidiasis

Candidemia/Candidemia/Invasive Candidiasis Invasive Candidiasis

(C/IC)(C/IC)(C/IC)(C/IC)

Caspofungin VS. AmBCaspofungin VS. AmBEnd of IV TherapyEnd of IV Therapy

73.4

61.7

80.7

64.9

60

70

80

90

100

0

10

20

30

40

50

60CaspofunginAmB

MITTMITT EvaluableEvaluable

MoraMora--Duarte J et al. NEJM 2002;347:2020Duarte J et al. NEJM 2002;347:2020--2029 2029

p = 0.03p = 0.03

Caspofungin vs. AmB: Clearance of Caspofungin vs. AmB: Clearance of Candida Candida from Followfrom Follow--up Blood Culturesup Blood Cultures

60

70

80

90

100

PERCENT

PERCENT

Caspofungin Acetate (N=92)Amphotericin B (N=94)

Caspofungin Amphotericin BDay 4 19.6% 19.1%Day 7 12.0% 9.0%

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

STUDY DAY

0

10

20

30

40

50

PERCENT

PERCENT

Day 7 12.0% 9.0%Day 9 6.5% 6.4%

STUDY DAYSTUDY DAY

MoraMora--Duarte J et al. IDSA 2002 Abstract # 13, Chicago, IL Duarte J et al. IDSA 2002 Abstract # 13, Chicago, IL

CaspofunginCaspofungin vs. vs. AmBAmB: : Failure or Relapse Rates Failure or Relapse Rates

30303030

40404040

26.6%26.6%

50505050

38.3%38.3%

Percentage of patients

Percentage of patients

0000

10101010

20202020

6.4%6.4%

FailureFailure

(End of IV (End of IV

study study

therapy)therapy)

7.0%7.0%

2.8%2.8%

16.5%*16.5%*

Relapse

(6–8 weeks post-Rx)

Relapse

(6–8 weeks post-Rx)

Toxicity requiring

additional treatment

*p=0.03

Toxicity requiring

additional treatment

*p=0.03

Percentage of patients

Percentage of patients

MoraMora--Duarte J et al. N Duarte J et al. N EnglEngl J Med 2002;347:2020J Med 2002;347:2020--20292029

50

60

70

80

Anidulafungin vs. Fluconazole for Candidemia Anidulafungin vs. Fluconazole for Candidemia and Invasive Candidiasis and Invasive Candidiasis -- MITT PopulationMITT Population

Global Response

Global Response

Modified Intent to Treat

Modified Intent to Treat

75.675.6

56.856.8

64.664.6

49.249.2

55.955.9

44.144.1

**

**

74.074.0

**60.260.2

* statistically * statistically significantsignificant

0

10

20

30

40

Primary

Endpoint-

End of IV

Therapy

Secondary

Endpoint End

of All

Therapy

Secondary

Endpoint-2

Week F/U

Secondary

Endpoint-6

Week F/U

Anidulafungin

Fluconazole

Global Response

Global Response

Modified Intent to Treat

Modified Intent to Treat

44.144.1

Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:2472Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:2472--24822482

Microbiological & Global Microbiological & Global Responses at End of IV Therapy in Responses at End of IV Therapy in

MITT PopulationMITT Population

ReboliReboli AC, AC, RotsteinRotstein C, Pappas P et al. NEJM 2007;356:2472C, Pappas P et al. NEJM 2007;356:2472--24822482

Microbiological Clearance of Blood Microbiological Clearance of Blood Cultures over Time: Cultures over Time:

Anidulafungin vs FluconazoleAnidulafungin vs Fluconazole

DayDay

AnidulafunginAnidulafungin

No. NegativeNo. Negative

Total Number Total Number

FluconazoleFluconazole

No. NegativeNo. Negative

Total NumberTotal Number

P ValueP Value

33 81/9581/95 63/8463/84 0.080.0833 81/9581/95

(85.2%)(85.2%)

63/8463/84

(75.0%)(75.0%)

0.080.08

77 73/7973/79

(92.4%)(92.4%)

56/6756/67

(83.5%)(83.5%)

0.090.09

Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:2472Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:2472--24822482

Response Rates of Response Rates of MicafunginMicafungin vs. vs. CaspofunginCaspofungin for for CandidemiaCandidemia//

Invasive Invasive CandidiasisCandidiasis

50

60

70

80

Response Rate %

Response Rate %

76.476.471.471.4

72.372.3

74.974.968.368.3 70.270.2

54.554.5

52.852.8 50.550.5 46.646.6

44.744.742.642.6

0

10

20

30

40

50

Primary

Endpoint End of

Blinded IV

therapy

End of All

Therapy

2 Weeks Post-

Therapy

4 Weeks Post-

Therapy

Micafungin 100

Micafungin 150

Caspofungin

Response Rate %

Response Rate %

44.744.742.642.6

Pappas P, Rotstein C, Betts RF et al. Pappas P, Rotstein C, Betts RF et al. CID 2007;45:883CID 2007;45:883--893893

EndpointsEndpoints

MicafunginMicafungin CaspofunginCaspofungin

Candida species Candida species recovered at recovered at baselinebaseline

100 mg 100 mg (n = 191)(n = 191)

150 mg 150 mg (n = 199)(n = 199) (n = 188)(n = 188) P P

ValueValue

C. albicansC. albicans 71/92 (77.2)71/92 (77.2) 71/102 (69.6)71/102 (69.6) 61/83 (73.5)61/83 (73.5) .5.5

C. glabrataC. glabrata 24/28 (85.7)24/28 (85.7) 30/34 (88.2)30/34 (88.2) 22/33 (66.7)22/33 (66.7) .07.07

Response Rates for Response Rates for Candida SpeciesCandida Species

C. tropicalisC. tropicalis 21/31 (67.7)21/31 (67.7) 20/33 (60.6)20/33 (60.6) 24/32 (75.0)24/32 (75.0) .5.5

C. parapsilosisC. parapsilosis 22/29 (75.9)22/29 (75.9) 15/21 (71.4)15/21 (71.4) 24/42 (64.3)24/42 (64.3) <.99<.99

C. kruseiC. krusei 6/8 (75.0)6/8 (75.0) 5/8 (62.5)5/8 (62.5) 3 / 4 (75.0)3 / 4 (75.0) .59.59

Other Other 10/14 (71.4) 10/14 (71.4) 6/12 (50.0)6/12 (50.0) 10/12 (83.3)10/12 (83.3)

Overall Overall 154/202 (76.2)154/202 (76.2) 147/210 (70.0)147/210 (70.0) 144/206 (69.9)144/206 (69.9)

Pappas P, Rotstein C, Betts RF et al. Pappas P, Rotstein C, Betts RF et al. CID 2007;45:883CID 2007;45:883--893893

Treatment Success Rates for Treatment Success Rates for CandidaCandida Isolates Isolates with MICwith MIC9090 Values of 1 Values of 1 µµg/mL and 2 g/mL and 2 µµg/mLg/mL

Treatment Treatment GroupGroup

In vitroIn vitrosusceptibilitysusceptibility

OrganismOrganism No. of No. of isolatesisolates

Treatment Treatment success success n/Nn/N(%)(%)

MicafunginMicafungin MICMIC9090 value = value =

1 1 µgµg/mL/mL

AllAll

C. parapsilosisC. parapsilosis

C. tropicalisC. tropicalis

55

44

11

4/5 (80.0)4/5 (80.0)

3/4 (75.0)3/4 (75.0)

1/1 (100.0)1/1 (100.0)

CaspofunginCaspofungin MICMIC9090 value = value =

1 1 µgµg/mL/mL

AllAll

C. glabrataC. glabrata

C. guilliermondiC. guilliermondi

5151

66

11

34/51 (66.6)34/51 (66.6)

5/6 (83.3)5/6 (83.3)

1/1 (100.0)1/1 (100.0)

C. kruseiC. krusei

C. lipolyticaC. lipolytica

C. lusitaniaeC. lusitaniae

C. parapsilosisC. parapsilosis

C. tropicalisC. tropicalis

33

11

11

2929

1010

2/3 (66.6)2/3 (66.6)

1/1 (100.0)1/1 (100.0)

1/1 (100.0)1/1 (100.0)

19/29 (65.5)19/29 (65.5)

5/10 (50.0)5/10 (50.0)

MICMIC9090 value = value =

2 2 µgµg/mL/mL

AllAll

C. albicansC. albicans

C. glabrataC. glabrata

C. parapsilosisC. parapsilosis

1212

11

22

99

8/12 (66.6)8/12 (66.6)

0/1 (0.0)0/1 (0.0)

2/2 (100.0)2/2 (100.0)

6/9 (66.6)6/9 (66.6)

Caspofungin Caspofungin

TotalTotal

42/63 (66.6)42/63 (66.6)

(Cornely OA et al. Submitted for publication)(Cornely OA et al. Submitted for publication)

15Caspofungin

AmB

Anidulafungin

Persistence of Candida Infections Persistence of Candida Infections with with EchinocandinsEchinocandins

Percentage

Percentage

8.78.7

6.36.3

14.414.4 (p=.06)(p=.06)

5.8 5.8

11.611.6

0

5

10

Caspo

vs.

AmB

Anid

vs.

Fluco

Mica

vs.

Caspo

Anidulafungin

Fluconazole

Micafungin 100

Micafungin 150

1.1. MoraMora--Duarte J et al. N Duarte J et al. N EnglEngl J Med 2002;347:2020J Med 2002;347:2020--202920292.2. ReboliReboli AC, AC, RotsteinRotstein C, Pappas P et al. NEJM 2007;356:2472C, Pappas P et al. NEJM 2007;356:2472--248224823.3. Pappas P, Pappas P, RotsteinRotstein C, Betts RF et al. CID 2007;45:883C, Betts RF et al. CID 2007;45:883--893893

Percentage

Percentage

8.38.3

6.36.3

9.69.6

Safety Safety Safety Safety

Comparison of Safety of all 3 Comparison of Safety of all 3 EchinocandinsEchinocandins

�� Hematologic abnormalities: Neutropenia Hematologic abnormalities: Neutropenia (Micafungin 1.2%, Anidulafungin 1%); (Micafungin 1.2%, Anidulafungin 1%); eosinophilia (Caspofungin 3%); eosinophilia (Caspofungin 3%); thrombocytopenia (Caspofungin <4%); anemia thrombocytopenia (Caspofungin <4%); anemia (Caspofungin 3(Caspofungin 3--12%).12%).(Caspofungin 3(Caspofungin 3--12%).12%).

�� Gastrointestinal: (all 3 n+v <3%).Gastrointestinal: (all 3 n+v <3%).

�� Elevated AST/ALT: (Caspofungin 11Elevated AST/ALT: (Caspofungin 11--24%).24%).

�� Hypokalemia: (Caspofungin <4%).Hypokalemia: (Caspofungin <4%).

�� Phlebitis: (Caspofungin, Anidulafungin)Phlebitis: (Caspofungin, Anidulafungin)

�� No difference between Micafungin & Caspofungin No difference between Micafungin & Caspofungin in RCT (withdrawls 2in RCT (withdrawls 200 to drug: M100 2.5% vs. to drug: M100 2.5% vs. M150 3% vs. C 3.6%).M150 3% vs. C 3.6%).

Eschenauer G et al. Ther Clin Risk Man 2007;3:71Eschenauer G et al. Ther Clin Risk Man 2007;3:71--9797Pappas P, Rotstein C, Betts RF et al. CID 2007;45:883Pappas P, Rotstein C, Betts RF et al. CID 2007;45:883--893893

Micafungin EMEA WarningMicafungin EMEA Warning

�� European Medicines Agency (EMEA) designated European Medicines Agency (EMEA) designated Special Warning when it approved micafungin.Special Warning when it approved micafungin.

�� Stated: Stated: �������� Formation of hepatic tumors in rats Formation of hepatic tumors in rats

after treatment for 3 months.after treatment for 3 months.

��������Warned of liver tumors in patients in Warned of liver tumors in patients in ��������Warned of liver tumors in patients in Warned of liver tumors in patients in

presence of persistent ALT/AST presence of persistent ALT/AST elevation.elevation.

�������� Micafungin treatment should be Micafungin treatment should be

conducted on a careful risk/benefit conducted on a careful risk/benefit basis particularly in patients having basis particularly in patients having severe liver function impairment.severe liver function impairment.

EMEA website for Mycamine Product MonographEMEA website for Mycamine Product Monograph

Pharmacokinetics/Pharmacokinetics/PharmacodynamicsPharmacodynamics& Drug Interactions& Drug Interactions& Drug Interactions& Drug Interactions

Pharmacokinetics of Echinocandins

CaspofunginCaspofungin MicafunginMicafungin AnidulafunginAnidulafungin

DoseDose 50 mg50 mg 50 mg50 mg 50 mg50 mg

CCmax max (mg/L)(mg/L) 10.510.5 4.44.4 22--3.5 3.5

AUCAUC 104.8104.8 6464--76.676.6 5151--7070

½ Life (hr)½ Life (hr) 99--1111 1313 25.625.6--3434

EliminationElimination HepaticHepatic HepaticHepatic HepaticHepatic

Stone ACC 2002;46:739Stone ACC 2002;46:739--745, Mukai ICAAC 2001745, Mukai ICAAC 2001Thye ICAAC 2002, Abstracts AThye ICAAC 2002, Abstracts A--34, 1391, 139234, 1391, 1392Dowell et al. J Clin Pharmacol 2004;44:590Dowell et al. J Clin Pharmacol 2004;44:590--598598Hiemenz et al. AAC 2005;49:1331Hiemenz et al. AAC 2005;49:1331--13361336

Eschenauer G et al. Ther Clin Risk Man 2007;3:71Eschenauer G et al. Ther Clin Risk Man 2007;3:71--9797

AnidulafunginAnidulafungin

ChemicalDegradation

MicafunginMicafungin

EnzymaticBiotranformation

CaspofunginCaspofungin

ChemicalDegradation

�� Among echinocandins, anidulafungin has a unique elimination Among echinocandins, anidulafungin has a unique elimination profileprofile11--55

Pharmacokinetic Profile Pharmacokinetic Profile

Hepatic Metabolism

Renal Elimination

Hepatic Metabolism

((11.. Eraxis,EcaltaEraxis,Ecalta SPCSPC.. 22.. CancidasCancidas forfor InjectionInjection [package[package insert]insert].. WhitehouseWhitehouse Station,Station, NJNJ:: MerckMerck && Co,Co, IncInc.. FebruaryFebruary 20052005.. 33.. MycamineMycamine forforInjectionInjection [package[package insert]insert].. Tokyo,Tokyo, JapanJapan:: AstellasAstellas Pharma,Pharma, IncInc.. JuneJune 20062006.. 44.. BalaniBalani SS..KK..,, XuXu XX..,, ArisonArison BB..HH.. etet alal.. MetabolitesMetabolites ofofcaspofungincaspofungin acetate,acetate, aa potentpotent antifungalantifungal agent,agent, inin humanhuman plasmaplasma andand urineurine.. DrugDrug MetabMetab DisposDispos.. 20002000;;2828::12741274--12781278.. 55.. RaaschRaasch RHRH..AnidulafunginAnidulafungin:: reviewreview ofof aa newnew echinocandinechinocandin antifungalantifungal agentagent.. ExpertExpert RevRev AntiAnti InfectInfect TherTher.. 20042004;;22::499499--508508))

Metabolism and Interaction Metabolism and Interaction Profiles of Profiles of EchinocandinsEchinocandins

CaspofunginCaspofungin MicafunginMicafungin AnidulafunginAnidulafungin

Hepatic Hepatic metabolismmetabolism

YesYes YesYes NoNo

CYP3A4 CYP3A4 NoNo WeakWeak NoNo

CYP3A4 CYP3A4 inhibitioninhibition

NoNo WeakWeak NoNo

Dose Dose adjustments adjustments

YesYes(with moderate hepatic (with moderate hepatic

dysfunction, with CYP inducers)dysfunction, with CYP inducers)

NoNo NoNo

Drug Drug interactionsinteractions

YesYes(with cyclosporine, tacrolimus, (with cyclosporine, tacrolimus, rifampin, efavirenz, nevirapine, rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, phenytoin, dexamethasone,

carbamazepine)carbamazepine)

YesYes(with sirolimus,(with sirolimus,

nifedipine, nifedipine, itraconazole)itraconazole)

None knownNone known

Anidulafungin [package insert]; Caspofungin for Injection [package insert]; Micafungin for Injection [package Anidulafungin [package insert]; Caspofungin for Injection [package insert]; Micafungin for Injection [package insert]. Dowell JA et al. insert]. Dowell JA et al. J Clin PharmacolJ Clin Pharmacol 2007;47:4612007;47:461--470. Dowell JA et al. 470. Dowell JA et al. J Clin PharmacolJ Clin Pharmacol 2004;44:5902004;44:590--598.598.

ResistanceResistance

Resistance in EchinicandinsResistance in Echinicandins

�� Point mutations in “hot spot” regions of Point mutations in “hot spot” regions of Fks1pFks1pgene subunit for 1,3gene subunit for 1,3--ββββββββ--DD--glucan synthase produce glucan synthase produce reduced susceptibility to echinocandins.reduced susceptibility to echinocandins.

Perlin D Drug Resist Updates 2007;10:121Perlin D Drug Resist Updates 2007;10:121--130130DesnosDesnos--Ollivier M et al. Antimicrob Agents Chemother 2008;52:3092Ollivier M et al. Antimicrob Agents Chemother 2008;52:3092--30983098

In Vitro In Vitro Paradoxical Effect of Paradoxical Effect of Echinocandins Against Different Echinocandins Against Different

Candida spp.Candida spp.Candida Candida speciesspecies

(no. of isolates)(no. of isolates) CASCAS MICAMICA ANIDANID CASCAS MICAMICA ANIDANID

C. albicansC. albicans(20)(20)

6060 00 4040 8/328/32 NANA 0.5/2.00.5/2.0

Paradoxical (%)Paradoxical (%) Median Paradoxical Growth Median Paradoxical Growth Start Point/Endpoint (Start Point/Endpoint (µµµµµµµµg/ml)g/ml)

(20)(20)

C. parapsilosisC. parapsilosis(10)(10)

9090 00 00 8/648/64 NANA NANA

C. tropicalisC. tropicalis(10)(10)

4040 7070 2020 16/4816/48 12/4812/48 0.125/1.00.125/1.0

C. kruseiC. krusei

(10)(10)

1010 6060 00 8/328/32--6464 0.125/0.50.125/0.5 NANA

C. glabrataC. glabrata(10)(10)

00 00 00 NANA NANA NANA

Chamilos G et al. Antimicrob Agents Chemother 2007;51:2257Chamilos G et al. Antimicrob Agents Chemother 2007;51:2257--22592259

CostCost

Summary – Were All The Echinocandins Created Equal?

� No

� ?Anidulafungin (& micafungin) clinical efficacy > Caspofungin for C. parapsilosis.

� Less persistence with anidulafungin (& � Less persistence with anidulafungin (& micafungin) compared with caspofungin.

� Anidulafungin no drug interactions.

� No dosage adjustment with renal or hepatic dysfunction for anidulafungin and micafungin.

� Unsure what paradoxical effect means clinically.