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

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.

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;348:1546-1554

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;23:323-330

Mortality Rates from Candidemia in RCTs Reference Antifungal Agents Mortality Rates Rex J et al. NEJM 1994;331:1325-1330 Amphotericin B vs. Fluconazole 40% 33% Phillips P et al. Eur J Clin Microbiol Infect Dis 1997;16:337-345 Amphotericn B 43% 46% Rex J et al. CID 2003;36:1221-1228 Amphotericn B + Fluconazole vs. 39% Mora-Duarte J et al. NEJM 2002;347:2020-2029 Caspofungin 30.4% 34.2% Kullberg BJ et al. Lancet 2005;366:1435-1442 Voriconazole 42% 36% Reboli A, Rotstein C, Pappas P et al. NEJM 2007;356:2472-2482 Anidulafungin 22.8% 31.4% Kuse E-R et al. Lancet 2007;369:1519-1527 Micafungin Vs. Liposomal Amphotericin B Pappas P, Rotstein C, Betts RF et al. CID 2007;45:883-893 Micafungin 100 vs. Micafungin 150 vs. 29% 33.2% 26.4%

Treatment of C/IC in the ICU

Two Key Principles of Treatment Hit Early Hit Right

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;34:1589-96

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

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 24.57 to 109.49, p<.001) Ibrahim EH et al. Chest 2000;118:146-155

Mortality in Candidemia Patients with Septic Shock Receiving Adequate vs Inadequate Initial Therapy Aadequate initial therapy Inadequate initial therapy p < 0.0001 p = 0.0002 Difference 22% 95 Difference 29% 94 73 Mortality (%) 65 C. albicans C. non-albicans Kumar A et al. ICAAC 2007;poster L-477

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

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

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;20:133-163

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

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;46:2620-2629

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;46:2620-2629

Clinical Studies

Caspofungin

Caspofungin VS. AmB End of IV Therapy Response Rate % p = 0.03 MITT Evaluable Mora-Duarte J et al. NEJM 2002;347:2020-2029

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 4 19.6% 19.1% Day 7 12.0% 9.0% Day 9 6.5% 6.4% 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

Caspofungin vs. AmB: Failure or Relapse Rates 50 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;347:2020-2029

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;22:237-244

Anidulafungin Clinical Data Review

Pharmacokinetics of Echinocandins

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;43:215-222

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 2005. 3. Mycamine for Injection [package insert]. Tokyo, Japan: Astellas Pharma, Inc. June 2006. 4. 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;28:1274-1278. 5. Raasch RH. Anidulafungin: review of a new echinocandin antifungal agent. Expert Rev Anti Infect Ther. 2004;2:499-508.

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;47:461-470. Dowell JA et al. J Clin Pharmacol 2004;44:590-598.

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

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;356:2472-2482

Patient Population Characteristics

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;356:2472-2482.

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;356:2472-2482. Pfizer, data on file

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;356:2472-2482

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;356:2472-2482

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;356:2472-2482

Efficacy Results

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;356:2472-2482

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)

Efficacy in Critically Ill Patients

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)

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

Microbiological & Global Responses at End of IV Therapy in MITT Population Reboli AC, Rotstein C, Pappas P et al. NEJM 2007;356:2472-2482

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;356:2472-2482

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;356:2472-2482. 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;356:2472-2482

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;356:2472-2482. 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;356:2472-2482

Adverse Events

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;356:2472-2482

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;356:2472-2482. 2. Data on file. Pfizer Inc, New York, NY. Reboli AC, Rotstein C, Pappas P et al. NEJM 2007;356:2472-2482 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

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;356:2472-2482. Reboli AC, Rotstein C, Pappas P, et al. N Engl J Med 2007;356:2472-2482

Micafungin

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;369:1519-1527

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;45:883-893

Are all the Echinocandins Alike?

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;347:2020-2029 Reboli AC, Rotstein C, Pappas P et al. NEJM 2007;356:2472-2482 Pappas P, Rotstein C, Betts RF et al. CID 2007;45:883-893

Treatment of C/IC in 2009

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;38:161-189 Pappas PG et al. Clin Infect Dis 2009;48:503-535

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;38:161-189 Pappas PG et al. Clin Infect Dis 2009;48:503-535

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.