Reducing the antifungal drugs consumption in the ICU

Reducing the antifungal drugs consumption in the ICU Philippe Montravers Département d Anesthésie et Réanimation Chirurgicale CHU Bichat Claude Bernard Pole TCAUR, HUPNVS Assistance Publique-Hôpitaux de Paris Université Paris VII Denis Diderot Sorbonne Cité Paris, France

Disclosures Speaker: Astellas, Astra Zeneca, Basilea, Cubist, Gilead, MSD, The Medicines Company, Pfizer Advisory board: Astellas, Astra Zeneca, Cubist, MSD, Parexel, Tetraphase, The Medicines Company, Pfizer

Candida is the predominant fungal pathogen in the ICU setting Fungal infections in the ICU 7% 5% 88% Global surveillance study of 13,796 adults in 1265 ICUs in 75 countries Candida responsible for 88% of fungal infections (n=963) 89% in Europe (n=633) 85% elsewhere (n=330) Candida Aspergillus Vincent JL et al. JAMA. 2009;302:2323 9

Candida is the 3 rd most common cause of ICU infections globally Proportion of microorganismpositive isolates (%) 25 20 20,5 19,9 15 10 5 0 Pseudomonas species Global data* 17,0 17,0 16,0 12,7 10,8 10,2 Candida Other Gram- Escherichia coli Klebsiella species S epidermidis MRSA * 7087 patients; 69.8% with microorganism-positive isolates ** Other than E. coli, Enterobacter, Klebsiella, Pseudomonas, or Acinetobacter Vincent JL et al. JAMA. 2009;302:2323 9

...and the 2 nd most common cause of ICU infections in Western Europe Proportion of microorganismpositive isolates (%) 25 20 15 10 5 0 Western European data* 19,6 18,5 18,2 17,1 17,1 11,2 9,7 8,7 Candida Other Gram- Escherichia coli Pseudomonas species S epidermidis Klebsiella species MRSA * 3683 patients; 72.7% with microorganism-positive isolates ** Other than E. coli, Enterobacter, Klebsiella, Pseudomonas, or Acinetobacter Vincent JL et al. JAMA. 2009;302:2323 9

Trends in the incidence in candidemia episodes incidence of candidemia episodes/10 000 patient-days/year; DDD's of fluconazole ~ 100 pts/days. +131 % Bassetti M. BMC Infect Dis 2006;6:21 +20 % Lortholary O. Intensive Care Med 2014;40:1303-12

Many ways to prescribe antifungal agents Prophylaxis: to prevent development of invasive fungal infections during periods of risk Pre-emptive or presumptive therapy: early treatment of the infection with use of clinical, laboratory, or radiologic surrogate markers of disease in high-risk hosts before clinical signs and symptoms or full-blown disease develops Empiric therapy: for critically ill patients with risk factors for invasive candidiasis, no other known cause of fever, based on clinical assessment of risk factors, serologic markers for invasive candidiasis, and/or culture data from non sterile sites Directed therapy: for microbiologically or histologically documented infection Ostrosky-Zeichner L. Crit Care Med 2006, 34:857-63 Bow EJ et al. Can J Infect Dis Med Microbiol 2010;21: e122-150 Cornely O et al. Clin Microbiol Infec 2012; 18 Suppl 7: 19-37 Pappas PG, et al. Clin Infect Dis 2016;62: e1-50

Polyens : Complexes with Ergosterol Triazoles : Interruption of the sterol synthesis Echinocandins : Inhibition of glucane synthesis

Antifungal therapy: recent trends Echinocandins Azoles Amphotericin B Leroy 2005-06 N=271 18 71 4 Azoulay 2008 N=154 25 69 6 Bassetti 2011-13 N=481 64 32 4 Leroy 2012-13 N=291 63 34 2 Expressed as proportions of the total number of prescriptions Leroy O et al. Crit Care Med 2009;37:1612-18 Azoulay E et al. Crit Care Med 2012;40:813-22 Bassetti M et al. Intensive Care Med 2015;41:1601-10 Leroy O et al. Ann Intensive Care 2016;6:2

Recommended drugs for candidemia/invasive candidiasis Guidelines Recommendation ESCMID 2012 1 SITI/ISC 2013 2 ITALIC 2013 3 Middle East Expert panel 4 Echinocandins/Liposomal amphotericin B /Voriconazole Echinocandins/Lipid amphotericin B/Azoles Echinocandins Echinocandins/Liposomal amphotericin B /Azoles IDSA 2016 5 Echinocandins/Fluconazole ESCMID, European Society of Clinical Microbiology and Infectious Diseases; IDSA, Infectious Disease Society of America; ISC, International Society of Chemotherapy; ITALIC, Italian consensus for invasive candidiasis mangement; SITI, Italian Society of Intensive Care 1. Cornely OA, et al. Clin Microbiol Infect 2012;18(Suppl 7):19 37 2. Bassetti M, et al. Intensive Care Med 2013;39:2092 2106 3. Scudeller L, et al. Infection 2014;42:263 279 4. Alothman AF, et al. J Infect Public Health 2014; 7:6-19 5. Pappas PG et al. Clin Infect Dis 2016;62:e1-50

Why decreasing the prescription of antifungal agents? Poor justification/quality of the prescription Ecological issues Emergence of resistance Cost containment

Poor justification/quality of the prescription Madrid December 2010 to January 2011 One hospital 100 adult inpatients Systemic antifungals prescribed Empirical (42%) Pre-emptive (20%) Targeted treatment (20%) Cultures obtained in 78.8% of the prescriptions Positive fungal cultures in 56.7% Inappropriate therapy (agent, dose) in 57% of the cases Antifungals were unnecessary in 16% of cases Valerio M et al. J Antimicrob Chemother 2014; 69: 1993 1999

Poor justification of the prescription France 169 ICUs a single day (dec 8 th 2008) 2,047 patients recruited 1,893 patients without antifungal agents (AF) 154 (7.5%) patients received systemic AF Fluconazole (60%) caspofungin (24%) voriconazole (8%) liposomal Ampho B (5%) 100 (65%) pts without definite invasive fungal infection (IFI) 54 patients with documented IFI Mortality rate at Day 28 19% in patients without AF therapy 20% in patients receiving AF therapy without definite IFI Azoulay E et al. Crit Care Med 2012; 40: 813 22

Poor justification of the prescription France 87 ICUs (Oct 2012-Oct 2013) prospective registery 835 patients analyzed receiving antifungal agents (AF) 291 documented therapy for proven invasive candidiasis 544 empiric systemic AF for suspected invasive candidiasis 112 secondarily confirmed invasive candidiasis 432 (432/544=79%) finally non-documented infections Duration of antifungal therapy 12±10 days Leroy O et al. Ann. Intensive Care 2016;6:2

C. albicans rate Trends in the incidence in candida species 182 episodes of candidemia Single centre study 1999-2003 35 30 25 20 15 10 5 1999 2000 2001 2002 2003 Fluconazole usage (DDD/year) Candida albicans and Candida non-albicans isolates rates during the study period. Bassetti M. BMC Infect Dis 2006;6:21

Proportion of isolates (%) Trends in the incidence in candida species Single centre study 2007-2013 1,712 positive samples from 5,360 ICU patients 2,403 candida isolates (+29% of candidas over the study period) 70 60 50 40-11% +11% 30 20 10 0 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 C albicans C glabrata C parapsilosis C tropicalis C krusei C non-albicans Bailly S. J Infect 2016;71:103-111

13% Changes in epidemiology of candidemia: Importance of prior antifungal exposure 2,289 cases Without previous AF exposure 3% 10% 18% C. albicans C. glabrata 56% C. parapsilosis C. tropicalis C. krusei 14% 13% 31% 8% 13% 29% 36% 21% 35% Lortholary O et al. Antimicrob. Agents Chemother. 2011; 55 : 532 538

Proportion of resistance in candidemia 995 episodes of candidemias from 5 tertiary care teaching hospitals in Italy and Spain (CLSI breakpoints) % of resistance Caspofungin Fluconazole Voriconazole C albicans (n=558) 0% 1.4% 1.2% C parapsilosis (n=186) 2.7% 2.7% 1% C glabrata (n=79) 0% 45.6% NA C tropicalis (n=89) 0% 4.5% 3.4% Bassetti M.J Clin Microbiol 2013;51:4167-72 338 episodes of candidemias from 30 Belgium hospitals (EUCAST breakpoints) % of resistance Anidulafungin Fluconazole Voriconazole C albicans (n=169) 0% 3.9% 3.9% C parapsilosis (n=186) 0%* 5.6% 5.6% C glabrata (n=27) 1% 11.3% NA C tropicalis (n=19) 0% 20% 20% * All strains were classified as intermediate susceptible Trouve C. Eur J Clin Microbiol Infect Dis 2016;nov 17, Epub

Caspofungin consumption (DDD/1000HD) MIC of Caspofungin for C. glabrata Increased resistance toward echinocandins 160 140 120 100 80 60 40 20 0 Caspofungin Consumption (DDD/1000HD) Predicted MIC of Caspofungin for C. glabrata 0,18 0,16 0,14 0,12 0,1 0,08 0,06 0,04 0,02 0 Increased caspofungin use correlated significantly with increased MIC values of: C. parapsilosis isolates (P=0.01) 3 months later, C. glabrata isolates (P=0.001) 2 months later C. albicans (P=0.02) 7 months later Bailly S. J Infect 2016;71:103-111

Drug use (DDDs/1000 HD) Trends in the use of antifungal agents Single centre study in ICU patients 2007-2013 Antifungal use determined in Defined Daily Dose (DDD) per 1000 hospital Days 180 160 140 120 100 80 60 40 20 +42% +298% +11% -58% 0 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 Amphotericin B Fluconazole Echinocandins All Antifungal agents Bailly S. J Infect 2016;71:103-111

Increased resources use Catalonia Spain- 52 acute care hospitals 2008-201 assessed in daily doses (DDD)/100 patient-days Antifungal consumption : intensive care units: 14.79 DDD/1000-patient-days medical departments: 3.08 surgical departments: 1.19 + 20.5 % increased antifungal consumption + 12.4 % In ICUs with a trend towards substitution of old agents by the new ones Upward trend both for azoles and echinocandins. Fondevilla E et al. Expert Rev Anti Infect Ther. 2016;14:137-44 Montreal Canada 10 years survey (2000-2011) - University hospital 2.97-fold increase in the number of DDD/1000 patient-days 2.97-fold increase in the number of days of therapy /1000 patient-days Guillot J et al. J Pediatr Pharmacol Ther 2014; 19: 196 201 Madrid December 2010 to January 2011 One hospital Costs 2,194 per patients 50,536 possible savings in case of optimized therapy (-23%) Valerio M et al. J Antimicrob Chemother 2014; 69: 1993 1999

Key issues to address for optimizing antifungal therapy Does the patient need an antifungal therapy? Valerio M et al. J Antimicrob Chemother 2014; 69: 1993 1999

Non-Specific Acute renal failure Specific Risk factors for invasive candidiasis Central venous catheter placement Total parenteral nutrition ICU stay Severity of sepsis Diabetes and immunosuppression Prolonged broad-spectrum antibacterial therapy Recurrent abdominal surgery (laparoscopies included) Gastro-intestinal tract perforations (recurrent perforations and/or perforations untreated within 24 h - control of upper GI perforations is more problematic) Gastro-intestinal anastomosis leakage (more severe if the leakage is in the upper GI tract, in particular that involving the esophagus) Multifocal colonization by Candida spp. Bassetti M et al. Intensive Care Med 2013;39:2092-2106

Predictive scores of candida isolation Dupont H.Crit Care Med 2003;31:752 7 Leon C. Crit Care Med. 2006;34:730 7 Ongoing antimicrobial therapy 48 h Surgery on ICU admission Per-operative cardiovascular failure Severe sepsis Cardiovascular failure Total parenteral nutrition Upper gastrointestinal tract perforation Multifocal Candida species colonization Paphytou NI. Med Mycol. 2005;43:235 43 Diabetes mellitus New onset hemodialysis Total parenteral nutrition Broad spectrum antibiotics Dupont H. Crit Care 2015;19:60 Length of stay 48 h before surgery Per-operative cardiovascular failure Generalized peritonitis Upper gastrointestinal tract perforation Ostrosky-Zeichner L. Eur J Clin Microbiol Infect Dis 2007;26:271-6. Antibiotic use day 1-3 Central venous catheter Surgery Immunosuppressive use Pancreatitis Total parenteral nutrition Dialysis Steroid use

Additional tools for assessing candidiasis Rapid diagnostic tests Conventional mycologic tests Biomarkers Previous candida colonization Cornely OA, et al. Clin Microbiol Infect 2012;18(Suppl 7):19 37 Bassetti M, et al. Intensive Care Med 2013;39:2092 2106 Scudeller L, et al. Infection 2014;42:263 279 Alothman AF, et al. J Infect Public Health 2014; 7:6-19 Ruhnke M. Clin Microbiol Infect 2014; 20 (Suppl. 6): 11 18 Pappas PG et al. Clin Infect Dis 2016;62:e1-50

Key issues to address for optimizing antifungal therapy Does the patient need an antifungal therapy? Does the antifungal cover the suspected fungi Valerio M et al. J Antimicrob Chemother 2014; 69: 1993 1999

C albicans C glabrata C krusei C parapsilosis C tropicalis Spectrum of activity against yeasts Polyenes Fluconazole Voriconazole EChinocandins

DALI Fluconazole results Fluconazole Number of patients 15 Age (yrs) 56 (44-82) Weight (kg) 82 (80-90) Male sex 11 (73) Dose received (mg) 400 (200-400) Dose (mg/kg) 4.9 (2.3-5.0) APACHE II score 22 (10-30) DALI Buijk (surgical pts) Sobue (volunteers 800 mg/d) AUC 0-24 359 (259) 409 (336-482) 608 (118) C max 20 (14) 25 (22-28) 34 (6) C min 14 (11) 15 (10-20) 20 (NR) Buijk SLCE. Intensive Care Med.27:115-121. Sobue S. Br J Clin Pharmacol.58:20-25. Target fauc 0-24 /MIC 100 was reached in 86% patients when the assumed MIC was 1 mg/l If MIC 2 mg/l (clinical breakpoint) and 4 mg/l (clinical breakpoint for resistance using EUCAST methods and susceptible dose-dependent using CLSI methods) fauc 0-24 /MIC 100 was reached in only 67% and 13% of patients Sinnollareddy MG et al. Crit Care. 2015;19(1):33

DALI Echinocandins results Anidulafungin Caspofungin Number of patients 9 6 Age (yrs) 51 (41-66) 62 (58-72) Weight (kg) 81 (76-92) 80 (75-85) Male sex 7 (78) 5 (71) Dose received (mg) 100 70 (L dose) AUC; mg.h/l Plasma Peak; µg/ml Anidulafungin Caspofungin 44.4-53 87.9-114.8 7.5 12 Chen SC et al. Drugs 2011;71:11-41 Dose (mg/kg) NA NA APACHE II score 18 (15-32) 22 (20-26) Parameters DALI Caspofungin Wurthwein (general pts) Stone (volunteers) DALI Anidulafungin Liu et al (volunteers) Liu et al (volunteers) AUC 0-24 52.0 (53) 170.0 (34) 97.0 (87-109) 55 (28) 93.0 (41) 105.0 (22) C max 3.9 (55) 13.8 (31) 12.1 (11-13) 3.9 (29) 7.7 (56) 7.0 (22) C min 1.5 (57) 4.2 (2.56) 1.4 (1.1-1.8) 1.8 (30) 3.0 (44) 3.1 (25) Wurthwein G. Antimicrob Agents Chemother.57:1664-1671. Stone JA. Antimicrob Agents Chemother.46:739-745. Liu P et al. Antimicrob Agents Chemother 2013;57:1672-1676 Sinnollareddy MG et al. Crit Care. 2015;19(1):33

Key issues to address for optimizing antifungal therapy Does the patient need an antifungal therapy? Does the antifungal cover the suspected fungi Is it the first option recommended by guidelines? Is the dosage correct according to the bodyweight, the liver and renal function and potential interaction with other drugs? Is the antifungal adjusted after microbiological results (microorganism identification, antifungal susceptibility tests and indirect tests) were available? Valerio M et al. J Antimicrob Chemother 2014; 69: 1993 1999

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Key issues to address for optimizing antifungal therapy Does the patient need an antifungal therapy? Does the antifungal cover the suspected fungi Is it the first option recommended by guidelines? Is the dosage correct according to the bodyweight, the liver and renal function and potential interaction with other drugs? Is the antifungal adjusted after microbiological results (microorganism identification, antifungal susceptibility tests and indirect tests) were available? Is de-escalatation performed when possible? Is intravenous switched to oral performed when possible? Valerio M et al. J Antimicrob Chemother 2014; 69: 1993 1999

Key issues to address for optimizing antifungal therapy Does the patient need an antifungal therapy? Does the antifungal cover the suspected fungi Is it the first option recommended by guidelines? Is the dosage correct according to the bodyweight, the liver and renal function and potential interaction with other drugs? Is the antifungal adjusted after microbiological results (microorganism identification, antifungal susceptibility tests and indirect tests) were available? Is intravenous switched to oral or de-escalatation performed when possible? Is the duration of therapy correct according to the guidelines? Valerio M et al. J Antimicrob Chemother 2014; 69: 1993 1999

Implementation of stewardship programs France Nivoix Y et al. J Antimicrob Chemother 2012;67:2506-13 Mondain V et al. Infection 2013;41:621-8 UK Micallef C et al. J Antimicrob Chemother 2015;70:1908-11 USA Aitken Sl et al. Ann Pharmacother 2014;48:683-90 Huang AM et al. Clin Infect Dis 2013;57:1237-45 Spain Valerio M et al. Clin Microbiol Infect 2015; 21: 492.e1 492.e9

Conclusions Need for cautious use of antifungal agents 65 up to 79% of ICU patients who receive AF agents do not need them Short course or no initiation of AF therapy could be decided in some cases without endangering these patients Major ecological and economic consequences of overuse of AF agents Few data in the ICU setting Best approach through stewardship programs