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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.