Expanded Therapeutic Options in the Treatment of Invasive Candidiasis Mazen Kherallah, MD, FCCP Critical Care & Infectious Disease Consultant King Faisal Specialist Hospital & Research Center

Outline Major Challenges in the Management of Invasive Candidiasis Antifungal Prophylaxis in ICUPreemptive Antifungal Therapy in ICU Expanded Options in the Treatment of Documented Invasive Candidiasis

Outline Major Challenges in the Management of Invasive Candidiasis Antifungal Prophylaxis in ICUPreemptive Antifungal Therapy in ICU Expanded Options in the Treatment of Documented Invasive Candidiasis

Crit Care Med May;27(5): Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System

Distribution of Candida bloodstream Isolates: Number of Isolates3,863 All non-albicans45.6% c. glabrata18.3 c. krusei2.1% Number of Isolates376 All non-albicans52.4% c. glabrata26.3% c. krusei3.7% Pfaller et al. Clin Microbiol Infect. 2004;10(suppl 1):11–23

KFSHRC-R Slide 6

Nonspecific Presentation and Risk Factors Colonization of Skin and Mucus Membranes with Candida Prolonged ICU stay Use of antibiotics Critically ill status: APACHE II score Alteration of Natural Host Barriers Wounds and burns Surgery Intravascular devices Urinary catheters Slide 7 Pittet D et al. Ann Surg Dec;220(6): Total parenteral nutrition 2.Acute renal failure 3.Hemodialysis 4.Immunosuppressive agents 5.Debilitating underlying diseases 6.Antacids 7.Mechanical ventilation

Disseminated Candidiasis Slide 8

Late diagnosis with culture-based methods Slide 9 Blood cultures lack sensitivity (<50%) Positive cultures are usually late Invasive tissue sampling is often problematic Radiological signs appear often late in the course of infection

Non-culture-based Methods Slide 10 CLINICAL MICROBIOLOGY REVIEWS, July 2002, p. 465–484

Diagnostic Tools Colonization Index Candida Score Prediction Rule Slide 11

The Colonization Index (CI) & CCI Slide 12 Pittet D et al. Ann Surg Dec;220(6):751-8 Number of colonized sites Number of tested sites CI= Number of site with heavy colonization Number of tested sites CCI= CI X

The Colonization Index (CI) & CCI Slide 13 Pittet D et al. Ann Surg Dec;220(6):751-8

The Colonization Index Slide 14 Pittet D et al. Ann Surg Dec;220(6):751-8

The Candida Score Slide 15 Leon C et al. Crit Care Med Mar;34(3):730-7 Coefficient (β)Rounded Multifocal Candida species colonization Surgery on ICU admission Severe sepsis Total parenteral nutrition Calculation of the Candida score:

The Candida Score Slide 16 Leon C et al. Crit Care Med Mar;34(3):730-7 With a cut-off value of 2.5: sensitivity of 81% and a specificity of 74%, we shall only need the presence of sepsis and any one of the three other remaining risk factors or the presence of all of them together except sepsis in order to consider starting antifungal treatment for one particular patient.

One of the following factors: Systemic AntibioticPresence of CVC + at least two other risk factors Total parenteral nutrition Major surgery Pancreatitis Any use of steroids Use of immunosuppressive agents Clinical Prediction Rule Slide 17 Ostrosky-Zeichner L et al. Eur J Clin Michrobiol Infect Dis 2007, 26: Sensitivity of 34% and specificity of 90%, a positive predictive value of 10% an a negative predictive value of 97%. Manily helps in ruling out invasive candidiasis

Outline Major Challenges in the Management of Invasive Candidiasis Antifungal Prophylaxis in ICUPreemptive Antifungal Therapy in ICU Expanded Options in the Treatment of Documented Invasive Candidiasis

Fluconazole Prophylaxis Prevents Intra-abdominal Candidiasis in High-risk Surgical Patients Slide 19 Crit Care Med 1999, 27:

Fluconazole Prophylaxis Prevents Intra-abdominal Candidiasis in High-risk Surgical Patients Slide 20 Crit Care Med 1999, 27:

Antifungal agents for preventing fungal infections in non- neutropenic critically ill and surgical patients: Mortality Slide 21 E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638

Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: Invasive Infections Slide 22 E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638

Antifungal agents for preventing fungal infections in non- neutropenic critically ill and surgical patients: Fungal colonization with C. glabrata or C. krusei Slide 23 E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638

Antifungal agents for preventing fungal infections in non- neutropenic critically ill and surgical patients: Conclusion Slide 24 E. G Playford et al Journal of Antimicrobial Chemotherapy (2006) 57, 628–638 Prophylaxis with fluconazole or ketoconazole in critically ill patients reduces invasive fungal infections by one half and total mortality by one quarter. Although no significant increase in azole-resistant Candida species associated with prophylaxis was demonstrated, trials were not powered to exclude such an effect. In patients at increased risk of invasive fungal infections, antifungal prophylaxis with fluconazole should be considered.

Outline Major Challenges in the Management of Invasive Candidiasis Antifungal Prophylaxis in ICUPreemptive Antifungal Therapy in ICU Expanded Options in the Treatment of Documented Invasive Candidiasis

Preemptive Treatment to Prevent Severe Candidiasis in Critically Ill Surgical Patients Slide 26 Piarroux R et Crit Care Med (2004) 57, 628–638 Rate of Proven Candidiasis%

Outline Major Challenges in the Management of Invasive Candidiasis Antifungal Prophylaxis in ICUPreemptive Antifungal Therapy in ICU Expanded Options in the Treatment of Documented Invasive Candidiasis

Antifungal Agents GroupAgentMajor Concerns PolyenesAmphotericin B deoxycholate Poorly tolerated, infusion-related reaction, and nephrotoxicity Lipid formulation Amphotericin Cost AzolesFluconazoleResistant C.Krusei and glabrata VoriconazoleTransient visual adverse event, LFT abnormalities Posaconazole EchinocandinsCaspofungin Micafungin Inidulafungin Slide 28

Slide 29 Phospholipid bilayer of fungal cell membrane Mechanism of Action: Targets of Different Antifungal Classes Ergosterol  -(1,6)-glucan  -(1,3)-glucan Echinocandins inhibit  -(1,3)-glucan synthesis Polyenes bind to ergosterol Azoles inhibit CYP-450 enzyme responsible for ergosterol synthesis Adapted from Maertens J et al. Curr Med Chem Anti-Infect Agents. 2002;1:65–81. Mannoproteins Glucan synthase

Slide 30 Voriconazole in Invasive Candidemia

Voriconazole in Candidemia: RCT: DAMB 3-7 Days then Fluconazole vs Voriconazole IV>3 Days then PO Slide 31 Kullberg BJ et al. Lancet 2005, 366: Success (%)

DRC Assessed Success by Baseline Pathogen: (MITT Population) Slide 32 Kullberg BJ et al. Lancet 2005, 366: Success (%)

Slide 33 Echinocandins in Invasive Candidiasis

Slide 34 AnidulafunginCaspofungin Micafungin Glarea lozoyensisAspergillus nidulansColeophoma empetri Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Debono M, Gordee RS. Annu Rev Microbiol. 1994;48:471–497; Debono M et al. J Med Chem. 1995;38:3271–3281. Chemical Structures N O O O NH O H H H H O H CH 3 O O H2NH2N OH NH HO H2NH2N NH HNHN OH HN OH NHNH HO H3CH3C CH 3 O O O N O O HN N O O O O O N O H3CH3C S O O HO OH HO OH HNHN NH H3CH3C H2NH2N HO OH NH OH CH 3 O O N H3CH3C O N O O O O O HO OH HNHN NH OH HO OH NH HN CH 3 OH NH H3CH3C H3CH3C Side chains are key determinants of lipophilicity, solubility, antifungal activity, and toxicity

Slide 35 In Vitro & In Vivo Susceptibility

Slide 36 In Vitro Activity* *Standardized susceptibility testing methods for the echinocandins have not been established, and the results of susceptibility studies do not necessarily correlate with clinical outcome. CaspofunginMicafunginAnidulafungin Candida spp C albicans C glabrata C parapsilosis C tropicalis C krusei C dubliniensis C guilliermondii C kefyr C lipolytica C lusitaniae C rugosa C albicans C glabrata C parapsilosis C tropicalis C krusei C albicans C glabrata C parapsilosis C tropicalis Aspergillus spp A fumigatus A flavus A niger A nidulans A terreus A candidus Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information.

Slide 37 "Patients with isolates for which the MICs were highest (>2 µg/mL) had better outcomes than patients with isolates for which the MICs were lower (<1 µg/mL). Additionally, no correlation between MIC and outcome was identified for specific Candida species." Caspofungin: Analysis of MICs and Treatment Outcomes From Kartsonis N et al. Antimicrob Agents Chemother. 2005;49:3616–3623.

Slide 38 Lack of Correlation of Caspofungin MICs to Clinical Outcome: MITT Population* *Patients with invasive candidiasis. MITT = modified intention-to-treat. Caspofungin MIC, μg/mL Number of Isolates Favorable outcome Unfavorable outcome From Kartsonis N et al. Antimicrob Agents Chemother. 2005;49:3616–3623.

Slide 39 Echinocandin MIC Values for Candida spp: Effect of Serum a n=number of isolates. b Values are averages for triplicate experiments with <15% variance. Numbers in parentheses represent N-fold changes relative to values for the zero-serum control. c C glabrata strains grew poorly in serum so mouse serum was used. Candida spp a MIC 50, µg/mL b CaspofunginAnidulafunginMicafungin No serum 50% serum Fold Change No serum 50% serum Fold Change No serum 50% serum Fold Change C albicans (n=47) C glabrata c C krusei (n=10) C parapsilosis (n=10) C tropicalis (n=10) ≤0.25 ( – 0.5) 0.5 (0.25–0.5) ≤1 (0.25 – 2) 1 (0.5–2) (0.015–0.25) 0.5 (0.03–2) 1 (1–2) 8 (0.5–16) 4 (2–16) 0.5 (0.125–0.5) 2 (1–16) 4 (2–4) 8 (2–16) 4 (2–8) 4 (1–33) (0.0156) (0.0156–0.125) 0.25 (0.0156–0.25) 2 (1–4) (0.0156–0.031) 0.25 (0.125–4) 1 (0.5–2) 8 (2–16) 16 (16) 2 (0.125–2) 16 (8–256) 64 (16–64) 32 (16–256) 8 (4–16) 128 (8–128) (0.0156) (0.015) 0.06 (0.0156–0.06) 1 (0.0125–2) (0.0156) 1 (0.5–2) 1 (1) 8 (2–16) 16 (16) 2 (0.5–4) 64 (32–128) 64 (64) 133 (8–267) (8–128) 128 (8–256) Adapted from Paderu P et al. Antimicrob Agents Chemother. 2007;51:2253–2256.

Slide 40 Does MIC Predict In Vivo Response? Caspofungin Versus Micafungin in a Murine Model of Candidiasis Caspofungin had higher MICs than micafungin in vitro, but was more potent in vivo, with much lower ED90/ED99 values for reduction of kidney burden (caspofungin: 1.07/1.15 mg/kg/day; micafungin: 1.97/3.71 mg/kg/day). CFU = colony-forming unit; ED90/ED99 = effective dose against 90%/99% of isolates. Control (no treatment) Control (amphotericin B) CaspofunginMicafungin 4.0 mg/kg1.0 mg/kg0.1 mg/kg0.05 mg/kg1.0 mg/kg0.1 mg/kg0.05 mg/kg –1.00 Kidney Burden, Log CFU/g Tissue Kidney average Adapted from Paderu P et al. Antimicrob Agents Chemother. 2007;51:2253–2256.

Slide 41 Does MIC Predict In Vivo Response? Caspofungin Versus Anidulafungin in a Mouse Model Although caspofungin had a higher MIC than anidulafungin in vitro, caspofungin was more potent than anidulafungin in vivo in an animal model of C glabrata infection at lower doses. *P<0.05 versus the results for the control. Anidulafungin-treated mice Caspofungin-treated mice Median fungal burden Caspofungin-Susceptible C glabrata Log CFU/g Tissue Control1 mg/kg * P< mg/kg * P=NS * 10 mg/kg P=NS 0.5 mg/kg P<0.001 * Adapted from Wiederhold NP et al. Antimicrob Agents Chemother. 2007;51:1616–1620.

Slide 42 In vitro susceptibilities of Candida spp. to caspofungin: 6 years of global surveillance Pfaller MA et al. J Clin Micro 2008; Jan; 46(1): MIC 50 MIC 90 % inhibited at ≤2 mcg/mL All > 99 C. Albicans C. Glabrata C. Parapsilosis C. Tropicalis C. Krusei C. Guilliermondii >5000 isolates: 91 mdical center worlwide No shift in caspofungin MIC distribution profile toward higher MICs

Slide 43 Activities of Micafungin against 315 invasive clinical isolates of fluconazole-resistant Candida spp Messer SA et al. J Clin Microbiol. 2006;44:324–326; MIC 90 C. Albicans0.03 C. Glabrata0.015 C. Krusei0.06 Micafungin has excellent in vitro activity Fluconazole-resistant candida isolates

Slide 44 Indications and Clinical Trial Experience

Slide 45 Echinocandins: Indications and Dosing a Dosage adjustment to 35 mg QD after 70-mg loading dose recommended for moderate hepatic insufficiency. b Not studied in endocarditis, osteomyelitis, and meningitis due to Candida. HSCT = hematopoietic stem cell transplant; QD = once daily. Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information. Caspofungin a MicafunginAnidulafungin Treatment of esophageal candidiasis*See footnote below*150 mg QD100 mg load; 50 mg QD (higher relapse rates after anidulafungin therapy: 53.3% anidulafungin vs 19.3% fluconazole) Treatment of candidemia and the following Candida infections b : intra-abdominal abscesses, peritonitis 70 mg load; 50 mg QD200 mg load; 100 mg QD Not studied in sufficient number of neutropenic patients to determine efficacy in that group Empirical therapy for presumed fungal infections in febrile neutropenic patients 70 mg load; 50 mg QD Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (ie, amphotericin B, lipid formulations of amphotericin B, and/or itraconazole) 70 mg load; 50 mg QD Not studied as initial therapy for invasive aspergillosis Prophylaxis of Candida infections in HSCT patients 50 mg QD * Approved Indication by the Food and Drug Administration (FDA) and not approved indication in Saudi Arabia.

Slide 46 Overall Survival to 7-day follow-up Resolution of fever Successful treatment of baseline infection No breakthrough infection No premature discontinuation Difference, % –10– Favors Caspofungin P=0.04 P=0.56 P=0.05 P=0.03 P=0.95 L-AmB = liposomal amphotericin B. Phase 3, randomized, double-blind, multicenter study in adults of caspofungin 50 mg/day (70 mg on day 1) versus L-AmB 3 mg/kg/day (N=1111) –Overall favorable response: Caspofungin 34% (n=556) versus L-AmB 34% (n=539) Caspofungin: The Only Echinocandin With Data in Empiric Therapy of Febrile Neutropenia Favors L-AmB Adapted from Walsh TJ et al. N Engl J Med. 2004;351:1391–1402.

Slide 47 Overall Rate of Survival to 7 Days Posttherapy in Empiric Therapy Study Number at risk CaspofunginN = L-AmBN = Percent Survival Caspofungin (N=556) L-AmB (N=539) Study day P= Phase 3, randomized, double-blind, multicenter study in adults of caspofungin 50 mg/day (70 mg on day 1) versus L-AmB 3 mg/kg/day (N=1111) 0 Adapted from Walsh TJ et al. N Engl J Med. 2004;351:1391–1402.

Slide 48 Invasive Candidiasis Studies: Efficacy Patients a Loading dose of 70 mg; b 0.7–1.0 mg/kg/d in patients with neutropenia; c Loading dose 200 mg; d Loading dose 800 mg; e 100 mg for patients >40 kg and 2 mg/kg for patients ≤40 kg. After 5 days, dose could be increased to 200 mg; f Starting dose of 3 mg/kg could be increased to 5 mg/kg after day 5. IV = intravenous. Caspofungin StudyAnidulafungin StudyMicafungin Study CaspofunginAmBAnidulafunginFluconazoleMicafunginL-AmB Daily Dose50 mg QD a 0.6– 0.7 mg/kg b 100 mg c 400 mg d 100–200 mg e 3–5 mg/kg f # of Patients Mean APACHE II Neutrophil Count < %8.7%2%3%13%10% C. Albicans35.6%54.1%64%59%42%44% Non-albicans64.4%45.9%43%50%62%59% C. glabrata12.8%9.2%16%25%11%7.4% C. Krusei4%0.9%NR 3%3.5% Mora-Duarte J et al. N Engl J Med. 2002;347:2020–2029; Reboli AC et al. N Engl J Med. 2007;356:2472– 2482; Kuse E-R et al. Lancet. 2007;369:1519–1527.

Slide 49 Invasive Candidiasis Studies: Efficacy Results a Loading dose of 70 mg; b 0.7–1.0 mg/kg/d in patients with neutropenia; c Loading dose 200 mg; d Loading dose 800 mg; e 100 mg for patients >40 kg and 2 mg/kg for patients ≤40 kg. After 5 days, dose could be increased to 200 mg; f Starting dose of 3 mg/kg could be increased to 5 mg/kg after day 5. IV = intravenous. Caspofungin StudyAnidulafungin StudyMicafungin Study CaspofunginAmBAnidulafunginFluconazoleMicafunginL-AmB Daily Dose50 mg QD a 0.6– 0.7 mg/kg b 100 mg c 400 mg d 100–200 mg e 3–5 mg/kg f MITT End of IV Therapy 73%62%76%60%74%70% PP Results Independent Review Board 81%72%N/A 81%80% PP Results Investigator Adjudicated N/A 90% Mortality Due to Fungal Infection 4%7%2%4%13%9% Mora-Duarte J et al. N Engl J Med. 2002;347:2020–2029; Reboli AC et al. N Engl J Med. 2007;356:2472– 2482; Kuse E-R et al. Lancet. 2007;369:1519–1527.

Invasive Candidiasis Studies: Efficacy Results (Primary Analysis) Slide 50 Mora-Duarte J et al. N Engl J Med. 2002;347:2020–2029 Caspofungin (n= 109) Amphotericin B (n= 115) % Response P= 0.09

Invasive Candidiasis Studies: Efficacy Results (Secondary Analysis) Slide 51 Mora-Duarte J et al. N Engl J Med. 2002;347:2020–2029 Caspofungin (n= 88) Amphotericin B (n= 97) % Response P= 0.03

Slide 52 Invasive Candidiasis Studies: Efficacy Results Mora-Duarte J et al. N Engl J Med. 2002;347:2020–2029

Invasive Candidiasis Studies: Success Rates per Pathogen Slide 53 Mora-Duarte J et al. N Engl J Med. 2002;347:2020–2029 Success (%)

Invasive Candidiasis Studies: Toxic Effects Requiring Change in Therapy Slide 54 Mora-Duarte J et al. N Engl J Med. 2002;347:2020–2029 (%)

Caspofungin for the Treatment of less Common Forms of Invasive Candidiasis Slide 55 Cornely OA et al. JAC 2007;60(2):

Slide 56 Safety Profiles

Slide 57 Safety Profile of the Echinocandins: Contraindications, Warnings, and Precautions Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information. CaspofunginMicafunginAnidulafungin Contraindications Hypersensitivity to any component of the product Yes Warnings Serious hypersensitivity NoYesNo Precautions Hepatic effects Renal effects Hematologic effects + (Evaluate risk/benefit when using with cyclosporine) – + (Isolated cases of significant hepatic dysfunction, hepatitis, or worsening hepatic failure reported) + (Elevation in blood urea nitrogen and creatinine; isolated cases of significant renal dysfunction or acute renal failure reported) + (Acute intravascular hemolysis, hemoglobinuria, isolated cases of significant hemolysis and hemolytic anemia reported) + (Isolated cases of significant hepatic dysfunction, hepatitis, or worsening hepatic failure reported) – Pregnancy Category C

Slide 58 Safety Profile of the Echinocandins: Most Common Drug-Related Adverse Events ALT = alanine aminotransferase; AST = aspartate aminotransferase; AP = alkaline phosphatase. Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information. Caspofungin (>1% of 1440 patients) Micafungin (≥1% of 260 patients) Anidulafungin (≥1% of 300 patients) GeneralFever, headache, pain, abdominal pain, chills Pyrexia GastrointestinalNausea, vomiting, diarrheaNausea, vomiting, abdominal pain Nausea, vomiting, aggravated dyspepsia Liver↑ ALT, AST, AP, direct/total bilirubin ↑ AST, AP, blood lactate dehydrogenase ↑ AST, gamma-glutamyl transferase Hepatobiliary–Hyperbilirubinemia– VascularPhlebitis/thrombophlebitis, infused-vein complication, flushing Phlebitis Blood/lymphaticAnemiaLeukopenia, neutropenia, thrombocytopenia, anemia, lymphopenia Neutropenia, leukopenia SkinRash, pruritus, sweatingRash, pruritusRash RespiratoryDyspnea–– Kidney↑ Serum creatinine– CardiacTachycardia–– Nervous system–Headache Psychiatric–Delirium–

Summary: Invasive Candidiasis Invasive candidiasis is the most frequent invasive mycosis in critically ill patients Changing epidemiology with increased non- albicans Candida spp. Nonspecific risk factors and clinical presentation along with late diagnosis with culture-based methods are major challenges in the management of invasive candidiasis Preventive strategies and development of new noninvasive diagnostic tools are encouraging Echinocandins provide at least the same efficacy of the traditional agents without toxic effects Slide 59

Slide 60 Summary: Caspofungin in Invasive Candidiasis  6 years of marketed experience  The only echinocandin proven to be at least as effective as L-AmB in the treatment of febrile neutropenia  Efficacy comparable or superior to conventional amphotericin B in invasive candidiasis/candidemia  In extensive use, demonstrated efficacy and excellent safety profile  In vitro activity against more species of Candida and Aspergillus  Rare incidence of reduced susceptibility of Candida spp

Slide 61 Thank You