ESCMID Online Lecture Library. by author

Transcription

1 What is the best antifungal strategy for severe intra-abdominal infections? Philippe Montravers MD, PhD Anaesthesia and Surgical ICU Bichat Claude Bernard Hospital Assistance Publique Hopitaux de Paris Denis Diderot University Paris VII

2 Disclosures Speaker from Astellas, Astra Zeneca, Basilea, Cubist, Gilead, MSD, Pfizer, The Medicines Company Advisory board membership from Astra Zeneca, Cubist, MSD, The Medicines Company, and Pfizer

3 The classical colonisation/invasion process Adhesion Colonisation Invasion Blood stream dissemination Extravasation Chronic dissemination

4 Digestive perforation = Peritoneal diffusion of bowel flora Candida spp Gram positive Gram negative Colonisation or infection?

5 35 Incidence of candida peritonitis % Community-acquired peritonitis N=84 N=112 N=120 N=841 N=234 Dupont Riche Sotto Gauzit Montravers % Postoperative peritonitis N=137 N=100 N=35 N=68 Dupont Montravers Seguin Riche Dupont H. Crit Care Med 2003;31:752 Riche F. Crit Care ;R99 Sotto A. J Antimicrob Chemother 2002;50:569 Gauzit R et al. Surg Infect 2009; 10: Montravers P et al. J Antimicrob Chemother 2009;63: Dupont H. Crit Care Med 2003;31:752 Montravers P. Clin Infect Dis 1996;23:486 Seguin P. Clin Microbiol Infect 2006;12:980 Riche F. Crit Care ;R99

6 Recurrent GI perforation is associated with intraabdominal candidiasis 49 surgery patients with peritoneal fluid culture(s) positive for Candida p=0.005 p<0.001 Calandra T, Marchetti O. Clin Infect Dis 2004;39:S185 92

7 Species cultured from peritoneal and blood stream samples Expressed as proportions of the total number of isolates CAP: community-acquired peritonitis POP: post-operative peritonitis Dupont H. Crit Care Med 2003;31:752 Montravers P. Crit Care Med 2006;34:646 Sandven P. Crit Care Med 2002;30:541 Dupont Montravers Sandven Montravers Bassetti n=85 n=33 n=33 n=93 n=481 C albicans C glabrata C parapsilosis C tropicalis C krusei Other candidas Pure fungal Infection Positive blood culture Montravers P. Clin Microbiol Infect 2011;17: Bassetti M. Intensive Care Med 2015 in press

8 Fluconazole susceptibility in peritoneal samples % susceptible strains C albicans C glabrata C parapsilosis C tropicalis Other candidas Dupont 100% 100% 100% 100% 100% Sandven 100% 20% Montravers CCM 2006 Montravers CMI /5 SDD 100% 40% 91% (9/32) 6/15 SDD DDS: dose-dependent susceptible R: Resistant strains 100% - C norvegensis Dupont H, Arch Surg 2002;137:1341 2/2 R 100% 100% C krusei 2/2 R 36% 100% 100% C krusei 4/4 R C ciferi 1/2 R Sandven P. Crit Care Med 2002;30:541 Montravers P. Crit Care Med 2006;34:646 Montravers P. Clin Microbiol Infect 2011;17: % of Candida strains were susceptible to echinocandins, 89% to fluconazole, and 96% to voriconazole; all isolates were susceptible to amphotericin B Bassetti M. Intensive Care Med 2015 in press

9 Montravers CMI 2011 Echinocandins Fluconazole Voriconazole Amphotericin B N= Bassetti 2015 N= Montravers 2015 Antifungal therapy in recent studies N= Expressed as proportions of the total number of prescriptions Montravers P et al. Clin Microbiol Infect 2011, 17: Bassetti M. Intensive Care Med 2015 in press Montravers P et al. ECCMID 2015

10 Delay for appropriate management Retrospective analysis of BSI in 5 hospitals in Spain and Italy ( ) 216 episodes of septic shock attributable to candidemia (39% non albicans) 163 (75%) admitted to the ICU Death at D30 Risk factors for hospital survival Bassetti M et al. Intensive Care Med 2014;40:839-45

11 Choosing an antifungal agent for therapy Before identification After identification Broad spectrum of activity Renal function Renal function Parenteral route Empirical (or preemptive) therapy Targeted spectrum of activity IV/oral route Adverse effects Cost No clinical trial Targeted therapy in intra-abdominal infections

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

13 Ambisome LAmB 1995 Amphotericin B Polyens Abelcet ABLC 1997

14 Nephrotoxicity of Amphotericin B 239 neutropenic patients treated for aspergillosis 53% 29 % 15 % Wingard JR. Clin Inf Dis 1999; 29:

15 Nephrotoxicity (x2 blood creatinin) Nephrotoxicity and Amphotericin B * * Liposomal AMB AMB deoxycholate Walsh TJ. New Engl J Med. 1999; 340: Prentice HG. Brit J Hemat. 1997; 98: 711-8

16 Triazoles, a large family Ketoconazole Itraconazole Fluconazole Voriconazole Posaconazole Ravuconazole

17 FCZ ITZ VCZ PCZ Bio-availability >90% 50-75% >95% variable Plasma peak (µg/ml) >3 Unchanged urinary elimination (%) <80 <1 1.5 <1 Elimination half-life (hours) Protein binding (%) >90 Volume of distribution (L or L/kg) 0.7 L/Kg 11 L/kg 4.6 L/Kg 1,774 L CS fluid penetration (% of plasma) poor <10 90 poor Denning DW. Lancet 2003;362: Torres HA. Lancet ID 2005;5: Wagner C, et al. Pharmacology 2006;78: Greer ND. Proc Bayl Univ Med Cent 2007;20: Cunha BA. Antibiotic essentials. Jones & bartlett. New York 2009.

18 Many drug interactions Greer ND. Proc Bayl Univ Med Cent 2007;20:188-96

19 Echinocandins, first novel class of antifungals in two decades Caspofungin Anidulafungin Micafungin

20 Anidulafungin Caspofungin Micafungin Dose linearity Plasma Peak; µg/ml AUC; mg.h/l Serum Half life; hours Protein binding; % Volume of distribution; L (L/kg) (0.5) 9.5 (0.14) ( ) CNS diffusion; % of plasma <0.1% Low Low Unchanged urinary elimination; % < Route of elimination Degraded Faeces Degraded/Metabolised Urine>Faeces Metabolised Faeces>Urine Denning DW. Lancet 2003;362: Wagner C, et al. Pharmacology 2006;78: Kofla G et Ruhnke M. Eur J Med Res 2011;16: Chen SC et al. Drugs 2011;71:11-41

21 Limitations for using micafungin The European Medicines Agency has issued a black box warning on the basis of an elevated incidence of hepatic tumours in rats receiving prolonged dosing and drug exposures higher than typically seen in clinical contexts. These studies have not been performed for other echinocandins.

22 Drug interactions Chen SC et al. Drugs 2011;71:11-41

23 Adverse effects reported in clinical trials Chen SC et al. Drugs 2011;71:11-41

24 Spectrum of activity

25

26 Spectrum of activity against yeasts Polyenes FCZ VCZ Candins C albicans C glabrata C krusei C parapsilosis C tropicalis

27 Antibiotic exposure as a risk factor for fluconazole-resistant candidas? 440 episodes of candidemia 69 (15%) C glabrata 38 (8.5%) fluconazole R strains Does antibiotic exposure influence the emergence of fluconazole resistant candidas? Ben-Ami R et al. Antimicrob Agents Chem 2012;56:

28 Resistant Fluconazole Candida strains n=38 Clindamycin OR 3.7 [ ] p=0.03 Colistin OR 2.8 [ ] p=0.02 Carbapenems OR 2.3 [ ] p=0.01 TMP-SMX OR 4.5 [ ] p=0.001 Neutropenia (OR, 3.3; 95% CI, 1.5 to 7.3; p=0.002) Fluconazole (OR, 4.3; 95% CI, 1.5 to 12.2; p=0.005) AB exposure (OR, 2.8; 95% CI, 1.2 to 6.3; p=0.01) Ben-Ami R et al. Antimicrob Agents Chem 2012;56:

29 Abdominal candidiasis is a hidden reservoir of echinocandin resistance 25 pts exposed for a median of 42 days (range 4-438) to echinocandins for abdominal candidiasis FKS mutant Candida isolates recovered from 24% (6/25)pts Candida glabrata n=5 Candida albicans n=1 MDR bacteria were recovered from 83% of FKS mutant infections FKS Mutations were associated with prolonged echinocandin exposure (119 versus 27 days; P=0.01) 11 breakthrough infections (5/11 were FKS mutants; P=0.03) therapeutic failures despite source control interventions (100%) Shields RK et al. Antimicrob Agents Chemother 2014, 58:7601-5

30 Pharmacokinetic issues

31 BMC Infectious Diseases 2012, 12:152

32 Fluconazole Number of patients 15 Age (yrs) 56 (44-82) Weight (kg) 82 (80-90) Male sex 11 (73) Dose received (mg) 400 ( ) Dose (mg/kg) 4.9 ( ) APACHE II score 22 (10-30) DALI Fluconazole results Parameters DALI Buijk (surgical pts) Sobue (volunteers 800 mg/d) AUC (259) 409 ( ) 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: Sobue S. Br J Clin Pharmacol.58: 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

33 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) (L dose) 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 (53) (34) 97.0 (87-109) 55 (28) 93.0 (41) (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 ( ) 1.8 (30) 3.0 (44) 3.1 (25) Wurthwein G. Antimicrob Agents Chemother.57: Stone JA. Antimicrob Agents Chemother.46: Liu P et al. Antimicrob Agents Chemother 2013;57: DALI Echinocandins results AUC; mg.h/l Plasma Peak; µg/ml Anidulafungin Caspofungin Chen SC et al. Drugs 2011;71:11-41 Sinnollareddy MG et al. Crit Care. 2015;19(1):33

34 Choosing an antifungal agent AMB-d LF-AMB FCZ VRZ Candins Spectrum Broad Broad ± Broad Broad Renal toxicity Indication in ± + renal failure Indication in Anidula liver failure IV/Oral route IV IV IV/O IV/O IV Tolerance - ± Inter Inter + actions actions Cost Low +++ Low

35 Recent guidelines for antifungal therapy during intra-abdominal infections

36 IDSA guidelines Solomkin J et al. Clin Infect Dis 2010;50:

37 Bassetti M et al. Intensive Care Med 2013, 39:

38 First line therapy Fungicidal antifungal agents (echinocandins or lipid formulation of amphotericin B) should be prescribed for the empirical therapy of all critically ill patients or for patients with previous exposure to azoles (AII). For the subgroup of patients with C. parapsilosis colonization, lipid formulations of amphotericin B or fluconazole may be preferred (BII). Azoles (fluconazole and voriconazole) can be prescribed for the empirical therapy of non-critically ill patients without previous exposure to azoles unless they are known to be colonized with a Candida strain with reduced susceptibility to azoles (BII). Amphotericin B deoxycholate should not be used due to its welldocumented significant toxicity (DII). Bassetti M et al. Intensive Care Med 2013, 39:

39 Targeted therapy Fungicidal agents such as echinocandins or lipid formulations of amphotericin B should be used for targeted therapy of all critically ill patients or for patients with previous exposure to azoles (BII). For the subgroup of patients infected with C. parapsilosis, lipid formulations of amphotericin B or fluconazole should be preferred (BII). Azoles can be used for targeted therapy of non-critically ill patients with IAC due to susceptible strain(s) (BII). Amphotericin B deoxycholate should not be used due to its welldocumented significant toxicity (DII). Bassetti M et al. Intensive Care Med 2013, 39:

40 How long should antifungal therapy be continued? In patients with IAC and clinically ameliorating, antifungal treatment should be continued for at least days after the beginning of treatment for IAC (CIII). In patients without proven Candida infection but clinically improved, empirical antifungal therapy should be discontinued after 3 5 days (BIII). In patients without proven Candida infection and not clinically improved, empirical antifungal therapy should be stopped (BIII). Bassetti M et al. Intensive Care Med 2013, 39:

41 Which second-line therapy should be started? Second-line treatment for patients initially treated with fluconazole should include an echinocandin or lipid formulations of amphotericin B (BIII). Second-line treatment for patients initially treated with an echinocandin should include lipid formulations of amphotericin B (BIII). Bassetti M et al. Intensive Care Med 2013, 39:

42 French Guidelines for the management of intra-abdominal infections When it is decided to prescribe empirical antifungal therapy in a critically ill patient with community-acquired or healthcare-associated IAI, an echinocandin should probably be used. Antifungal therapy (echinocandins in the case of serious infection or fluconazole-resistant strains) should probably be initiated in all cases of healthcare-associated IAI in which peritoneal fluid culture (apart from closed succion drains and drainage systems, etc.) is positive for yeasts. Montravers P et al. Anesth Crit Care Pain Med 2015 in press

43 Conclusions Few advances in the understanding of intraabdominal infections «New» drugs more appropriate to the ICU patients Efficacy in ICU settings must be confirmed pk pd characteristics have to be assessed in patients with multiple organ dysfunction