1. University Health Network
Echinocandins for Treatment of Life Threatening Candida Infections: A Clinical and Pharmacoeconomic Advance?
Coleman Rotstein MD
University of Toronto
University Health Network
Toronto, Ontario

2. Epidemology of Candidemia/Invasive Candidiasis (C/IC)
Most common invasive fungal infection encountered in the hospital setting & its incidence is rising.
Produces considerable morbidity and mortality.

3. Fungal Sepsis: USA 1980–2000
Based on ICM-9-CM codes from discharge diagnosis *
* Based on codes for disseminated fungal-candida infections/endocarditis
Martin GS, et al. N Engl J Med 2003;348:

4. Olaechea PM et al. Eur J Clin Microbiol Infect Dis 2004;23:323-330
Economic Impact of Candida Colonization & Infection in ICU Patients (Europe)
Candida colonization associated with prolonged LOS in ICU of 6.22 d compared with non-colonized pt.
Candida infected patients had prolonged LOS in ICU of 12.7 d (p<.0001).
Candida colonization produced increased costs of 8,126€ & Candida infection 15,803€.
Olaechea PM et al. Eur J Clin Microbiol Infect Dis 2004;23:

5. Mortality Rates from Candidemia in RCTs
Reference
Antifungal Agents
Mortality Rates
Rex J et al. NEJM 1994;331:
Amphotericin B
vs.
Fluconazole
40%
33%
Phillips P et al. Eur J Clin Microbiol Infect Dis 1997;16:
Amphotericn B
43%
46%
Rex J et al. CID 2003;36:
Amphotericn B + Fluconazole vs.
39%
Mora-Duarte J et al. NEJM 2002;347:
Caspofungin
30.4%
34.2%
Kullberg BJ et al. Lancet 2005;366:
Voriconazole
42%
36%
Reboli A, Rotstein C, Pappas P et al. NEJM 2007;356:
Anidulafungin
22.8%
31.4%
Kuse E-R et al. Lancet 2007;369:
Micafungin
Vs.
Liposomal Amphotericin B
Pappas P, Rotstein C, Betts RF et al. CID 2007;45:
Micafungin 100 vs.
Micafungin 150 vs.
29%
33.2%
26.4%

6. Treatment of C/IC in the ICU

7. Two Key Principles of Treatment
Hit Early
Hit Right

8. Survival = 0.79/1.119x x = delay (hrs)
Risk of Death with Increasing Antimicrobial Delay in ICU Sepsis: Subgroup Analysis
Survival = 0.79/1.119x x = delay (hrs)
Kumar A et al. Crit Care Med 2006;34:

9. Antimicrobial Initiation Delay
Delay-Stratified Survival to Hospital Discharge in Septic Shock: Bacterial vs Fungal
Survival (% total)
Antimicrobial Initiation Delay
Kumar A et al. Personal Communication from CATSS database

10. Ibrahim EH et al. Chest 2000;118:146-155
Increased Hospital Mortality with Inadequate Antimicrobial Therapy for Candidemia
Bloodstream infection-related mortality rate higher for patients receiving inadequate antimicrobial therapy 29.9% vs. 11.9% with adequate antimicrobial therapy (p<.001)
Multiple logistic regression analysis showed that: Candida spp. associated with inadequate therapy (AOR 51.86, 95% CI to , p<.001)
Ibrahim EH et al. Chest 2000;118:

11. Mortality in Candidemia Patients with Septic Shock Receiving Adequate vs Inadequate Initial Therapy
Aadequate initial therapy
Inadequate initial therapy
p <
p =
Difference
22% 95
Difference
29% 94 73
Mortality (%) 65
C. albicans
C. non-albicans
Kumar A et al. ICAAC 2007;poster L-477

12. Issues with AmB ? Agent of choice for C/IC in ICU patients
Toxicity - nephrotoxicity
- infusion-related toxicity
- hypokalemia
- hypomagnesemia
- LFT abnormalities
Toxicity limits efficacy
At times lack of efficacy  mortality rates of 40%
Lipid formulations too costly

13. Azole Issues Well tolerated and good safety profile
Resistance: Candida glabrata, Candida krusei (fluconazole)
Cross resistance for Candida glabrata (voriconazole)

14. Resistance to Fluconazole and Voriconazole among Isolates of C
Resistance to Fluconazole and Voriconazole among Isolates of C. glabrata 2001 to 2003
Region
Antifungal Agent
No. of Isolates Tested
% Resistant
Asia-Pacific
Fluconazole
1,859
10.6
Voriconazole
1,727
4.1
Europe
4,962
16.5
4,801
5.6
Latin America
940
13.2
910
5.4
North America
1,276
18.0
1,278
9.8
Pfaller MA, Diekema DJ. Clin Microbiol Rev 2007;20:

15. New Agents for Treatment of C/IC in ICU: Echinocandins

16. Pfaller MA et al. J Clin Microbiol 2008;46:2620-2629
In Vitro Activity of Echinocandins Against Bloodstream Isolates of Candida Species
Species
No. of isolates tested
Results for:
ANID
CASP
MICA
MIC90 %
 2 g/ml
C. albicans
2,869
0.06
100
0.03
C. glabrata
747
0.12
99.9
0.015
C. tropicalis
625
99.8
C. krusei
136
0.25
C. parapsilosis
759 2
92.5 1
C. guilliermondii 61
90.2
95.1
All Candida spp.
5,346
98.8
Pfaller MA et al. J Clin Microbiol 2008;46:

17. Pfaller MA et al. J Clin Microbiol 2008;46:2620-2629
In Vitro Activity Against Fluconazole-Resistant Isolates of Candida Species
Species
No. of isolates tested
Results for:
ANID
CASP
MICA
MIC90 %
 2 g/ml
C. albicans 41
0.06
100
0.03
C. glabrata
110
0.12
0.015
C. krusei
146
0.25
All Candida spp.
315 1
0.5
Pfaller MA et al. J Clin Microbiol 2008;46:

18. Clinical Studies

19. Caspofungin

20. Caspofungin VS. AmB End of IV Therapy
Response Rate %
p = 0.03
MITT
Evaluable
Mora-Duarte J et al. NEJM 2002;347:

21. Caspofungin vs. AmB: Clearance of Candida from Follow-up Blood Cultures
100 90
Caspofungin Acetate (N=92)
Amphotericin B (N=94) 80 70
Caspofungin Amphotericin B
Day % %
Day % %
Day % % 60
PERCENT 50 40 30 20
No difference in time to first negative blood culture:
Reference not available electronically, data contained in Coleman Rotstein’s presentation at the meeting. 10 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
STUDY DAY
Mora-Duarte J et al. IDSA 2002 Abstract # 13, Chicago, IL

22. Caspofungin vs. AmB: Failure or Relapse Rates50
Caspofungin (n=109) 70/50 mg
Amphotericin B (n=115) 0.6–1.0 mg/kg
38.3% 40
26.6% 30
Percentage of patients 20
16.5%* 10
6.4%
7.0%
Slide 22
Caspofungin demonstrated higher success rates than amphotericin B (p=0.0861)30
Overall, 38.2% of amphotericin B patients were termed as having failed therapy (at end of IV study therapy) vs. 26.6% of caspofungin patients. Failure was defined as having persistent positive culture, persistent signs or symptoms, or new lesions at distant sites, toxicity requiring additional therapy, or indeterminate withdrawal 4 days30
The main difference occurred in the number of patients who required additional treatment because of toxicities: Only 2.7% of caspofungin patients vs. 16.5% of amphotericin B patients (p=0.0277)30
In terms of relapse (6 to 8 weeks after IV study therapy), the overall % rates were similar: 6.4% of caspofungin patients vs. 7.0 of amphotericin B patients required additional treatment due to toxicity. Relapse was defined as having recurrent candidemia, non-blood Candida infection, received systemic antifungal therapy, or abscess (no culture and no therapy)30
However, only 0.9% of caspofungin patients vs. 5.2 of amphotericin B patients were in the relapse subcategory of those who received systemic antifungal therapy following relapse30
2.8%
Failure
(End of IV study therapy)
Relapse
(6–8 weeks post-Rx)
Toxicity requiring additional treatment
*p=0.03
Mora-Duarte J et al. N Engl J Med 2002;347:

23. Caspofungin vs. AmB in ICU Patients (n=97)
67.5
56.1
45.0
40.4
Response Rates
10.5
5.0
No p value given in the DiNubile article, only a confidence interval and the difference is not significant.
DiNubile MJ et al. J Crit Care 2007;22:

24. Anidulafungin Clinical Data Review

25. Pharmacokinetics of Echinocandins

26. Pharmacokinetic Parameters of Anidulafungin in Healthy Adults
Variable
Value
Peak serum concentration, µg/mL
3.5
Trough serum concentration, µg/mL
2.0
Half-life, h
25.6
Volume of distribution, L
33.2
Protein binding, %
> 80
Excretion pathway
> 90% chemically degraded in the blood; bypasses hepatic metabolism; eliminated in feces
Renal excretion, %
< 1
Vazquez JA, Sobel JD. Clin Infect Dis 2006;43:

27. Pharmacokinetic Profile
Among echinocandins, anidulafungin has a unique elimination profile1-5
Anidulafungin
Chemical Degradation
Hepatic Metabolism
Micafungin*
Enzymatic Biotranformation
Renal Elimination
Caspofungin
* Micafungin has recently been approved in the EU.
1. ECALTA® SPC. 2. Cancidas for Injection [package insert]. Whitehouse Station, NJ: Merck & Co, Inc. February Mycamine for Injection [package insert]. Tokyo, Japan: Astellas Pharma, Inc. June Balani S.K., Xu X., Arison B.H. et al. Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine. Drug Metab Dispos. 2000;28: Raasch RH. Anidulafungin: review of a new echinocandin antifungal agent. Expert Rev Anti Infect Ther. 2004;2:

28. Metabolism and Interaction Profiles of Echinocandins
Caspofungin
Micafungin
Anidulafungin
Hepatic metabolism
Yes No
CYP3A4 inhibition
Weak
Dose adjustments
(with moderate hepatic dysfunction, with CYP inducers)
Drug interactions
(with cyclosporine, tacrolimus, rifampin, efavirenz, nevirapine, phenytoin, dexamethasone,
carbamazepine)
(with sirolimus,
nifedipine)
None known
Eraxis [package insert]; Cancidas for Injection [package insert]; Mycamine for Injection [package insert].
Dowell JA et al. J Clin Pharmacol 2007;47: Dowell JA et al. J Clin Pharmacol 2004;44:

29. Randomized Clinical Trial of Anidulafungin vs
Randomized Clinical Trial of Anidulafungin vs. Fluconazole for the Treatment of Candidemia/ Invasive Candidiasis

30. Anidulafungin vs. Fluconazole for Candidemia and Invasive Candidiasis
RCT
 Double blind multi-centre trial
Medications
 Anidulafungin 200 mg followed by 100 mg od IV vs. fluconazole 800 mg followed by 400mg od IV → po fluconazole 400 mg od
Patients
 261 patients enrolled; MITT 245 patients (1 dose of drug &  culture within 96 h for Candida); 16 yr. old
Analysis
 Primary Endpoint: Global response (clinical & microbiological response) at end of IV therapy in MITT population
 Secondary Endpoints: Global response at end of all therapy, 2 week & 6 week follow-up
Reboli AC, Rotstein C, Pappas P, et al. N Eng J Med 2007;356:

31. Patient Population Characteristics

32. Characteristics of the Modified Intention-to-Treat Population
Anidulafungin
(N=127)
Fluconazole
(N=118)
Gender – n (%)
Male
Female
65 (51.2)
62 (48.8)
60 (50.8)
58 (49.2)
Age – year
Mean (+/-SD)
Range
57 (+/-17.0)
16-89
59.2 (+/-16.5)
24-91
Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:

33. Characteristics of the Modified Intention-to-Treat Population
Anidulafungin
(N=127)
Fluconazole
(N=118)
Hepatic Impairment
Renal Failure/Insufficiency
Hemodialysis
Peritoneal Dialysis
Diabetes Mellitus
Mechanical Ventilation
Bacterial Sepsis
Neoplastic Disease
Transplantation
Prior azole therapy
43 %
37.0 %
15.7 %
2.4 %
34.6 %*
17 %
45.7 %
22.0 %
5.5 %
6%*
47 %
35.6 %
15.3 %
1.7 %
25.4 %
11 %
41.5 %
22.9 %
4.2 % 2%
Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:
Pfizer, data on file

34. Characteristics of the Modified Intention-to-Treat Population
Anidulafungin
(N=127)
Fluconazole
(N=118)
Apache II Score
 20 – n (%)
> 20 – n (%)
Mean (+/-SD)
101 (79.5)
26 (20.5)
15 (+/- 7.7)
98 (83.1)
20 (16.9)
14.4 (+/-6.8)
Absolute neutrophil count
> 500 – n (%)
 500 – n (%)
124 (97.6)
3 ( 2.4)
114 (96.6)
4 ( 3.4)
*APACHE=Acute Physiology and Chronic Health Evaluation
Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:

35. Anidulafungin vs. Fluconazole Study: Baseline Patient Characteristics (MITT Population)
Predisposing factors:
Central venous catheter
Broad-spectrum antibiotics
Recent surgery
Recent TPN
Malignancy
Immunosuppressive therapy
Transplant
99 (78)
88 (69)
53 (42)
31 (24)
28 (22)
18 (14)
6 (5)
92 (78)
82 (70)
51 (43)
31 (26)
25 (21)
27 (23)*
4 (3)
I.V. catheter removal: 96% anidulafungin*, 89% fluconazole
Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:

36. Anidulafungin vs. Fluconazole Study Baseline Infection Characteristics (MITT Population)
Candidemia only
116 (91)
103 (87)
Other systemic Candida infections+
11 (9)
15 (13)
Most common pathogens†:
C. albicans
81 (64)
70 (59)
C. glabrata
20 (16)
30 (25)* p=.08
C. parapsilosis
13 (10)
16 (14)
C. tropicalis
Other Candida spp.
15 (12)
6(5)
3(3)
+Includes patients with both candidemia and other systemic Candida infection 4 in each arm.
†Percentages are not additive because some patients had >1 species present at baseline.
Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:

37. Efficacy Results

38. Modified Intent to Treat
Anidulafungin vs. Fluconazole for Candidemia and Invasive Candidiasis - MITT Population
75.6
74.0
* statistically significant, p<.05
64.6 * *
60.2
56.8
55.9 *
49.2
44.1
Modified Intent to Treat
Global Response
Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:

39. Statistical Issues
*A multivariate logistic-regression analysis of global response was performed to adjust for differences in characteristics between the groups at baseline:
 Immunosuppressive therapy
 Diabetes mellitus
 Prior azole therapy
 C. glabrata at baseline
 Removal of central catheter
Multiple logistic-regression analysis of global response at end of IV therapy demonstrated that the differences between the groups remained significant after adjusting for these baseline characteristics (p=.04)

40. Efficacy in Critically Ill Patients

41. Efficacy of Anidulafungin in Key Sub-populations
Dialysis 73 53 20 40 60 80
100
Global response (%)
Hepatic impairment 79 57 20 40 60 80
100
Global response (%)
Mechanical ventilation
Anidulafungin
Fluconazole
(Pfizer, data on file)

42. Anidulafungin vs. Fluconazole for C/IC in 63 ICU Patients*
68.6
Response Rates (%)
21.9%
17.1%
42.9
All cause mortality (%)
*p=.03
29.3
Days
Anidulafungin associated with $15,037 lower cost
for hospitalization.
23.4
Kett D et al. ECCMID 2008, Barcelona, Spain
Reboli AC, Rotstein C, Kett DH et al. Manuscript in preparation

43. Microbiological & Global Responses at End of IV Therapy in MITT Population
Reboli AC, Rotstein C, Pappas P et al. NEJM 2007;356:

44. Microbiological Clearance of Blood Cultures over Time: Anidulafungin vs Fluconazole
Day
Anidulafungin
No. Negative
Total Number
Fluconazole
P Value 3
81/95
(85.2%)
63/84
(75.0%)
0.08 7
73/79
(92.4%)
56/67
(83.5%)
0.09
Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:

45. Fungal Persistence at End of Therapy
4: Efficacy of Anidulafungin in a Single Pivotal Candidemia Study 16
14.4%
Reboli/2477/A 14
p=0.06 12 10
Patients with persistent infection at end of IV therapy (%) 8
6.3%
In this single pivotal candidemia study, more than twice as many fluconazole patients had persistence of Candida in the bloodstream compared with anidulafungin1
More than half of these microbiological failures with fluconazole involved infection with C. albicans (53%; 9 of 17) compared with only 25% (2 of 8) for anidulafungin1
Reference
1. Reboli AC, Rotstein C, Pappas PG, et al, for the Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356:
Reboli/2477/A 6 4
Reboli/2477/A;2478/C 2
Supporting Information
Among patients with persistent infection at the end of intravenous therapy1:
Baseline catheter was removed in all but 1 patient in the fluconazole group
In the anidulafungin group: 3 had C. glabrata, 2 had C. parapsilosis, 2 had C. albicans, and 1 had C. tropicalis infection
In the fluconazole group: 9 had C. albicans, 6 had C. glabrata, and 2 had C. parapsilosis infection
Reboli/2477/D;2478/C
Anidulafungin
n=8/127
Fluconazole
n=17/118
Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:

46. Persistent Candida Species Anidulafungin Group Fluconazole Group
Persistence at End of IV Treatment in the Modified Intention-to-Treat Population (p=0.06)
4: Efficacy of Anidulafungin in a Single Pivotal Candidemia Study
Persistent Candida Species
Anidulafungin Group
Fluconazole Group
C. albicans 2 9
C. glabrata 3 6
C. parapsilosis
C. tropicalis 1
Among patients with persistent infection at the end of intravenous therapy1:
Baseline catheter was removed in all but 1 patient in the fluconazole group
In the anidulafungin group: 3 had C. glabrata, 2 had C. parapsilosis, 2 had C. albicans, and 1 had C. tropicalis infection
In the fluconazole group: 9 had C. albicans, 6 had C. glabrata, and 2 had C. parapsilosis infection
Reference
1. Reboli AC, Rotstein C, Pappas PG, et al, for the Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356:
Supporting Information
In this single pivotal candidemia study, persistent infection was documented in 8 patients (6.3%) in the andiulafungin group and 17 (14.4%) in the fluconazole group (p=0.06)1
Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:

47. Adverse Events

48. Survival Rates: Anidulafungin vs. Fluconazole
Mortality
Anidulafungin 22.8%
Fluconazole 31.4%
(p=.13)
Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:

49. 2 pts 1 pt had atrial fibrillation and 1 pt had seizures
Adverse Events
4: Efficacy of Anidulafungin in a Single Pivotal Candidemia Study
Anidulafungin Group
Fluconazole Group
Rate of treatment-related adverse events
59 events in 32 pts (24.4%)
64 events in 33 pts (26.4%)
Elevated levels of hepatic enzymes related to the study drug
2 pts (1.5%)
9 pts (7.2%)
p=0.03
Treatment-related serious adverse events
2 pts 1 pt had atrial fibrillation and 1 pt had seizures
2 pts 1 pt had deep-vein thrombosis and 1 pt had increased levels of hepatic enzymes
Adverse events leading to discontinuation of the study drug
15 pts
27 pts
p=0.02
The authors of the study publication concluded that anidulafungin had a safety profile similar to that of fluconazole1
Abnormalities in LFTs have been observed with anidulafungin. Clinically significant hepatic abnormalities have occurred in some patients with serious underlying medical conditions who were receiving multiple medications concomitantly with anidulafungin. Isolated cases of significant hepatic dysfunction, hepatitis, or worsening hepatic failure have been reported, but a causal relationship with anidulafungin has not been established. Patients who develop abnormal LFTs during anidulafungin therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing anidulafungin therapy
In the treatment of candidemia, the most common treatment-related AEs included diarrhea (3.1%), hypokalemia (3.1%), and elevated ALT (2.3%)
References
1. Reboli AC, Rotstein C, Pappas PG, et al., for the Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356:
2. Data on file. Pfizer Inc, New York, NY.
Reboli AC, Rotstein C, Pappas P et al. NEJM 2007;356:
Supporting Information
There were fewer total discontinuations (for any reason) of study medication in the anidulafungin arm (34; 26.0% based on the safety population) than in the fluconazole arm (48; 38.4%)2
A substantial majority of these discontinuations (67.6% [23/34] anidulafungin; 77.1% [37/48] fluconazole) were due either to adverse events or to worsening clinical status/lack of efficacy2

50. Recurrently positive blood cultures 2
Other Adverse Events in Anidulafungin vs. Fluconazole Candidemia/Invasive Candidiasis Study
4: Efficacy of Anidulafungin in a Single Pivotal Candidemia Study
Anidulafungin Group
Fluconazole Group
Endophthalmitis 1
Recurrently positive blood cultures 2
Hepatic candidiasis
1 (caused by C. albicans)
Late complications of invasive candidiasis were uncommon1
The two patients with endophthalmitis had negative funduscopic examinations at baseline1
Endophthalmitis was diagnosed at the 2-week follow-up in the patient in the andiulafungin group and on day 7 in the patient in the fluconazole group1
Reference
1. Reboli AC, Rotstein C, Pappas PG, et al, for the Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356:
Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:

51. Micafungin

52. Micafungin vs. L-AmB for Invasive Candidiasis: Response Rates at EOT
89.6
89.5
71.6
74.1
69.6
68.2
Response Rate %
Kuse E-R et al. Lancet 2007;369:

53. Pappas P, Rotstein C, Betts RF et al. CID 2007;45:883-893
Response Rates of Micafungin vs. Caspofungin for Candidemia/ Invasive Candidiasis
76.4
71.4
74.9
68.3
72.3
70.2
54.5
52.8
50.5
46.6
44.7
42.6
Response Rate %
Endpoints
Pappas P, Rotstein C, Betts RF et al. CID 2007;45:

54. Are all the Echinocandins Alike?

55. Persistence of Candida Infections with Echinocandins
11.6
14.4
(p=.06)
5.8
8.7
6.3
8.3
9.6
Percentage
Mora-Duarte J et al. N Engl J Med 2002;347:
Reboli AC, Rotstein C, Pappas P et al. NEJM 2007;356:
Pappas P, Rotstein C, Betts RF et al. CID 2007;45:

56. Treatment of C/IC in 2009

57. Comparison of 2004 to 2009 IDSA Guidelines for C/IC
Infectious Syndrome
2004 Guidelines
2009 Guidelines
Stable pt. (no prior azole therapy)
Fluconazole, Caspofungin or AmB (0.6 mg/kg/d)
Fluconazole or Echinocandin (Anidulafungin, Caspofungin or Micafungin)
2004 Clinically unstable pt. (species unknown)
2009 Moderately severe-severely ill +/- azole exposure
AmB (0.7 mg/kg/d), Fluconazole + AmB, Caspofungin or L-AmB 3mg/kg/d
Echinocandin (Anidulafungin, Caspofungin or Micafungin)
[AmB or L-AmB only if other agents not available or intolerance]
C. albicans, C. tropicalis, C. parapsilosis
Fluconazole, AmB or Caspofungin
C. parapsilosis: Fluconazole
Others as above: Echinocandin
C. glabrata
AmB (0.7 mg/kg/d), Fluconazole 800 mg or Caspofungin
Continue Fluconazole if used & improved
Pappas PG et al. Clin Infect Dis 2004;38:
Pappas PG et al. Clin Infect Dis 2009;48:

58. Comparison of 2004 to 2009 IDSA Guidelines for C/IC
Infectious Syndrome
2004 Guidelines
2009 Guidelines
C. krusei
AmB (1.0 mg/kg/d), Caspofungin or Voriconazole
Echinocandin (Anidulafungin, Caspofungin or Micafungin)
C. lusitaniae
Fluconazole, Caspofungin or Voriconazole
As above: Fluconazole or Echinocandin
Empiric therapy in non-neutropenic critically ill pt.
Fluconazole, AmB
Fluconazole or Echinocandin
Echinocandin preferred for pt. with prior azole exposure or moderately severe to severely ill
Pappas PG et al. Clin Infect Dis 2004;38:
Pappas PG et al. Clin Infect Dis 2009;48:

59. Summary of Key Points Optimum therapy for candidemia still not known.
Echinocandins preferred for initial therapy of candidemia in moderately severe to severely ill patients or prior azole exposure.
Anidulafungin has least complex metabolism and interaction profile of the echinocandins.
Anidulafungin has been shown to be superior to fluconazole in C/IC.