La terapia delle infezioni da Candida. Matteo Bassetti Clinica Malattie infettive A.O.U. San Martino Genova

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1 La terapia delle infezioni da Candida Matteo Bassetti Clinica Malattie infettive A.O.U. San Martino Genova

2 Road map Candidosi invasiva Epidemiologia Distribuzione delle specie Fattori di rischio Timing inizio terapia Profilassi? Terapia ragionata- terapia precoce? Quale farmaco? Il catetere La colonizzazione? Il biofilm

3 Increasing rate of candidiasis in the US +300% Martin et al, NEJM 2003;348:1546

4 17%

5 Edmond MB, et al. Clin Infect Dis 1999; 29: Candida is the fourth most common Rank cause of nosocomial septicaemia Data from 49 hospitals (USA): Pathogen 1 Coagulase-negative staphylococci Number of isolates % Crude mortality rate (%) 3, Staphylococcus aureus 1, Enterococci 1, Candida species Escherichia coli Klebsiella species Enterobacter species Pseudomonas species Serratia species Viridans streptococci

6 Nosocomial ICU Bloodstream Infections in US ( ) Pathogen CoNS S. aureus Candida species Enterococcus sp. Ps. aeruginosa Enterobacter species Klebsiella species E. coli Incidence (%) Mortality % (non-icu) 25.7 (13.8) 34.4 (18.9) 47.1 (29) 43 (24) 47.9 (27.6) 32.5 (18) 37.4 (27.3) 33.9 (16.9) Wisplinghoff et al CID 2004;39:309

7 Organisms isolated from patients with HAI in the 4- years observation period in ICU Organism No. (total 1,476) % of total Pseudomonas aeruginosa Staphylococcus aureus Klebsiella spp Acinetobacter spp Candida spp Enterococcus spp Coagulase-negative Staphylococcus Proteus spp Stenotrophomonas maltophilia Serratia spp Bassetti M et al. J Chemother 2006; 18:261-7

8 Tortorano AM, et al. Eur J Clin Microbiol Infect Dis 2004; 23: Underlying conditions in patients with candidaemia A total of 2,089 cases of candidaemia were documented by 106 institutions in the seven participating countries during the 28- month study period Underlying condition No. of patients (%) Surgery 933 (44.7) Intensive care 839 (40.2) Solid tumour 471 (22.5) Steroid treatment 364 (17.4) Haematological malignancy 257 (12.3) Premature birth 125 (6.0) Solid organ transplantation 74 (3.5) HIV infection 63 (3.0) Burns 29 (1.4)

9 Percentage (%) Distribution of Candida species* according to underlying pathology/medical care C. albicans C. parapsilosis C. glabrata C. tropicalis Other Surgery (933) Intensive care (839) Solid tumour (471) Haematological malignancy (257) Foetal immaturity (124) HIV infection (63) Tortorano AM, et al. Int J Antimicrob Agents 2006; 27: *Only the four most common Candida species are reported, with less common species being described as Other.

10 Pfaller MA, et al. J Clin Microbiol 2008; 46:150 6 Species distribution of Candida isolates by geographic region % of isolates Candida species EU a Global b (n = 1,787) (n = 5,346) C. albicans C. parapsilosis C. glabrata C. tropicalis C. krusei C. guilliermondii C. lusitaniae C. kefyr C. famata Candida spp. c

11 Isolates (%) Species distribution of Candida by European country C. albicans C. parapsilosis C. glabrata C. tropicalis Other 0 EU (2,089) France (645) Germany (231) Italy (569) Spain (290) Sweden (191) UK (163) Only the four most common Candida species are reported, with less common species being described as Other Tortorano AM, et al. Int J Antimicrob Agents 2006; 27:359 66

12 Percentage of total Candida isolates (%) Differences in Candida species distribution between northern and southern European countries ,8 64,4 C. albicans C. glabrata 58,5 C. parapsilosis C. tropicalis ,8 29, ,2 12,4 9,6 5,8 6,7 5,6 8,6 10,3 12,8 14,6 6, Norway Iceland Spain Italy 1. Sandven P, et al. J Clin Microbiol 2006; 44: ; 2. Asmundsdottir LR, et al. J Clin Microbiol 2002; 40: ; 3. Pemán J, et al. Eur J Clin Microbiol Infect Dis 2005; 24:23 30; 4. Tortorano AM, et al. J Hosp Infect 2002; 51:

13 Epidemiology of candidemia: US 60 45,6 North America; 2019 cases of candidemia 50 54, ,6 8,1 2,5 0 Total glabrata parapsilosis tropicalis krusei albicans Non albicans glabrata parapsilosis tropicalis krusei Horn DL et al. Clin Infect Dis 2009; 48:

14 Epidemiology of candidemia: Spain Spain; 984 cases of candidemia: albicans glabrata parapsilosis tropicalis krusei Cisterna R et al. J Clin Microbiol 2010; doi: /jcm

15 Epidemiology of candidemia: Italy C.albicans C.parapsilosis C. glabrata C. tropicalis Others Total Bassetti M et al. BMC Infect Dis 2006; 10;6:21

16 LET S HAVE A PARTY

17 Wey SB, et al. Arch Intern Med 1989; 149: ; Pappas PG, et al. Clin Infect Dis 2004; 38: Risk factors for invasive candidiasis Antibacterial treatment Invasive medical procedures (catheters and mechanical ventilation) Major surgery (particularly solid organ transplant) Prolonged treatment in an ICU Colonisation Immunodeficiencies

18 Risk factors for invasive Candida infection (n=271) 26% ** 21% 17% 11% *** * 8% 7% 1% Solid tumor Immunosuppression Renal failure Type 1 diabetes mellitus Hematological malignancy Neutropenia Current IVDU 91% 87% 76% * ** 59% 56% 6% CVC Urinary catheter Mechanical ventilation Antibiotherapy within 1 mo Surgery <3 mo Implantable drug delivery system *More frequent in fungemic patients (p<0.05) **Less frequent in patients with isolated candemia (p<0.05) ***More frequent in patients with isolated candidemia (p<0.05) Leroy et al. Crit Care Med 2009; 37:

19 Logistic regression analysis of risk factors of candidemia Z P value OR (95% CI) Length of hospitalization 3.70 < ( ) Central venous catheter ( ) Previous candidemia ( ) Previous bacteremia ( ) Parenteral nutrition 4.16 < ( ) Chronic renal failure 3.60 < ( ) Bassetti M et al. Diagn Microb Infect Dis 2007; 58:325-31

20 Risk factors for non-albicans Candida candidaemia Risk factors associated with infection with non-albicans Candida species include: - Cancer chemotherapy 1 - Age < 65 years 1 - Neutropenia and severe thrombocytopenia 1 - Prior gastrointestinal surgery 2 Risk factors associated with C. glabrata or C. krusei candidaemia include: - Prior gastrointestinal surgery 2 - Prior fluconazole exposure 2 1. Cheng M-F, et al. BMC Infect Dis 2005; 5:22; 2. Playford EG, et al. 47 th ICAAC. Chicago, IL, USA, Sep 2007; Poster M-1199a

21 Mortality for candidemia 60 North America; 2019 cases of candidemia 52, ,2 35,6 38,1 41, , All albicans glabrata parapsilosis tropicalis krusei Horn DL et al. Clin Infect Dis 2009; 48:

22 Tortorano AM, et al. 3 rd TIMM. Turin, Italy,28 31 Oct 2007; Oral communication O.07 Mortality associated with Candida infections in ICU Variable Mortality rate (%)* Department Medical Surgical Candida species C. albicans C. parapsilosis C. glabrata *Crude mortality. Overall 41

23 Hospital mortality (%) Morrell M, et al. Antimicrob Agents Chemother 2005; 49: Relationship between hospital mortality and the timing of antifungal treatment < > 48 Delay in start of antifungal treatment (hours)

24 Mean detection time (hours) Time to identification of Candida in Blood cultures P < , ,9 24,4 18,5 26,7 C. albicans C. glabrata C. parapsilosis C. tropicalis C. kruzei 10 0 Meyer et al. J Clin Microbiol 2004; 42:773

25 Proportion infected Fluco in High-risk SICU patients 260 surgical ICU patients (stay > 3days) randomized to double-blind oral antifungal prophylaxis Placebo Fluconazole 0.1 p < 0.01 by log-rank test Days Pelz Ann Surg 233: , 2001

26 Prophylaxis in the (S)ICU Pelz et al., Ann Surg 233: , Fluco vs. placebo in extremely high risk ICU - Placebo: 16% rate of invasive candidiasis This rates equals that in BMT - Fluco 400/d: 8% rate - P < 0.01 A very unusual population - Median APACHE III = 60, lots of liver transplant - Applicability in most ICUs is unclear

27 Sandven et al.: Low-risk surgical patients Double-blind single-dose antifungal prophylaxis in 109 patients with intra-abdominal perforation 60 % NS NS 43% 34% NS % 10% 10% 7,5% 0 Emergence of colonization Complications Death Sandven CCM 2002

28 100 % RESULTS OF CANDIDA PROPHYLAXIS IN ICU PATIENTS P< % Success of prophylaxis P< Garbino et al. Intensive Care Med 2002;28: % NS 39 41% Emergence Death colonization from by Candida any cause Fluconazole 100 mg/d Placebo NS 3% 7% P= % Invasive Candidemia candidosis

29 Antifungals in critically ill and surgical patients: meta-analysis Impact on Candidal infections NNT= 94 NNT in high-risk= 9 NNT in low risk= 188 Impact on mortality Playford et al. JAC 2006; 57:

30 PROPHYLACTIC FLUCONAZOLE.. HAS ELIMINATED CANDIDA COLONISATION! More patient comfort

31 ..BUT HAS ELIMINATED CANDIDA COLONISATION! More patient comfort DID NOT REDUCE MORTALITY HAS SELECTED RESISTANT CANDIDA SPECIES

32 Episodes/1,000 admissions Salavert Lletí M, et al. Enferm Infecc Microbiol Clin 2006; 24:36 45 Increase in the proportion of Candida infections caused by non-albicans Candida species Overall incidence of Candida infections and those caused by C. krusei and C. glabrata in haematology/oncology patients treated in a Spanish hospital C. glabrata + C. krusei All Candida infections Fluconazole prophylaxis programme initiated

33 Incidence of candidemia Fluconazole DDD's x 100 pts/days incidence of candidemia episodes/ patient-days/year; DDD s of fluconazole x 100 pts/days 3,50 Figure 1. Shift from CA to CNA ,00 2, ,00 1, ,00 0, ,00 Y 1999 Y 2000 Y 2001 Y 2002 Y 2003 Years observed 0 Bassetti M et al. BMC Infect Dis 2006; 10: 621

34 Restriction of prophylactic fluconazole use Bassetti et al JAC 2009; 64: Med-surg ICU ( 500 adm./an) 108 months (Jan 99-Dec 2007) Overall prevention of NI unchanged 213 candidemia (1.42/ patient-days) albicans (46%), parapsillosis (22%), glabrata 13% Intervention: Janv 1999-Janv 2003: Extensive Prophylaxis Janv 2003-Dec 2007:Incitation not to do Statistical analysis: Segmented linear regression

35 Incidence of Candidemia and fluconazole in ICU Stop fluco Stop fluco X Non-albicans candidaemia C. albicans candidaemia Bassetti M et al. J Antimicrob Chemother 2009: 64:625-9.

36 So what about preemptive therapy with predicitive rules?

37 Candida Score Leon C et al. Crit Care Med 2006; 34:

38 Candida score validation León C et al Crit Care Med. 2009;37:

39 Other Predictive rules The best performing predictive rule was: Patients in the ICU >4 days AND Any systemic antibiotic (days 1 3) OR Central venous catheter (days 1 3) AND at least two: Total parenteral nutrition (days 1 3) Any dialysis (days 1 3) Major surgery (days -7 0) Pancreatitis (days -7 0) Any use of steroids (days -7 3) Immunosuppressive agents (days -7 0) Ostrosky-Zeichner et al. Eur J Clin Microbiol Infect Dis 2007

40 (1 3)-β-D-GLUCAN CONCENTRATIONS 600 BG values Pg/ml CBSI PCBSI NCBSI CONTROLS CBSI: proven Candida BSI PCBSI: possible Candida BSI NCBSI: no Candida BSI CONTROLS: healthy volunteers Horizontal bars indicate median values Del Bono V et al. 49th ICAAC, 2009

41 Criteria to start pre-emptive antifungal therapy Pz. In ICU 4 days. Abx in the last 7 days O CVC from 7 days 2 of the following: Total parenteral nutrition (days 1 3) Any dialysis (days 1 3) Major surgery (days -7 0) Pancreatitis (days -7 0) Any use of steroids (days -7 3) Immunosuppressive agents (days -7 0) Start antifungal Candida colonization or (1-3)-ß-D-glucan

42 Different antifungal strategies Bassetti M et al. Crit Care 2010 in press

43 Bassetti M et al. Crit Care 2010 in press

44 Empiric use of antifungals in the ICU setting Still no good data clinical for empiric antifungal therapy in the non-neutropenic population Follow fundamental principles for treating candidemia Utilize serologic markers, surveillance cultures, and/or a scoring system to determine most appropriate use Duration of therapy not specifically addressed, although the implication is to curtail therapy in stable patients absent positive culture/serologic data Pappas PG, et al. Clin Infect Dis 2009; 48:

45 15 July 2008

46 Double-blind, placebo-controlled trial with fluconazol 800 mg (x 14d) in 270 adult IC-patients: 4 days of fever (>38.3 C) ICU stay > 96h APACHE II 16 Broad spectrum antibiotics Central line 24h n (ITT) Fluconazol Placebo 95% CI / P-value Success 44 (36%) 48 (38%) ; P = 0.78 Invasive mycosis 6 (5%) 11 (9%) RR 0.57; Day mortality 29 (24%) 22 (17%) RR 1.36; Schuster et al, Ann Intern Med 2008

47 Susceptibility profile of Candida species Dodds Ashely ES et al. Clin Infect Dis 2008 ; 43: S28 39

48 Distribution of the Candida spp. In vitro susceptibility to fluconazole 305 isolates identified, 210 isolates tested 17% fluconazole-r or S-DD (using validated susceptibility testing methods) Species Distribution In vitro susceptibility to fluconazole n tested S S-DD or R Candida albicans 174 (57%) % 4% Candida glabrata 51 (17%) 38 50% 50% Candida parapsilosis 23 (7.5%) 19 90% 10% Candida krusei 16 (5.2%) 6 17% 83% Candida tropicalis 15 (4.9%) 14 86% 14% Candida kefyr 11 (3.6%) 9 100% 0 Candida guilliermondii 5 (1.6%) 5 80% 20% Candida lusitaniae 2 (0.7%) 2 100% 0 Other Candida species 8 (2.6%) 4 50% 50% Total % 17% Leroy et al. Crit Care Med 2009; 37:

49 In vitro susceptibility to fluconazole in patients naïve and previously exposed to azoles in ICU Leroy et al. Crit Care Med 2009; 37:

50 Initial empiric antifungal treatment (n=271) Fluconazole 65,7% Caspofungin 18,1% Voriconazole 5,5% Caspofungin + Fluconazole 3,0% Liposomal amphotericin B 2,2% Amphotericin B deoxycholate 1,1% Itraconazole 1,1% Caspofungin + Voriconazole 1,1% Amphotericin B lipid complex 0,4% Amphotericin B deoxycholate + Fluconazole 0,4% Amphotericin B deoxycholate + Flucytosine 0,4% Amphotericin B deoxycholate + Voriconazole 0,4% Liposomal amphotericin B + Caspofungin 0,4% Liposomal amphotericin B + Flucytosine 0,4% Leroy et al. Crit Care Med 2009; 37:

51 Risk factors for fluconazole resistance Odds ratio 95 percent confidence Limits P - value Neoplasia Prior fluconazole use Cisterna R et al. J Clin Microbiol 2010; doi: /jcm

52 IDSA- Candidemia in nonneutropenic If species is unknown, either fluconazole (800mg loading dose, 400 mg daily) or an echinocandin is appropriate initial therapy for most adult patients (AI) An echinocandin is favored if - Moderately severe to severe illness, - Recent azole use for treatment or prophylaxis (AIII), or - Isolate is known to be C. glabrata or C. krusei (BIII) Fluconazole for patients who are - less critically ill and - who have no recent azole exposure (AIII). Move from candin to fluconazole when isolates likely susceptible to fluconazole (e.g., C. albicans) and patient is clinically stable (AIII) Remove or exchange intravenous catheters Treat for two weeks after clearance of bloodstream

53 Treatment Empirical treatment(ia) Azole exposure No (A-III) High risk of C. glabrata or krusei? Or severe (A- III) yes (A-III) No yes fluconazole echinocandin Clinical Infectious Diseases 2009; 48:503 35

54 Secondary adapted to results. Invasive candidiasis - IDSA 2008 Clinical Infectious Diseases 2009; 48: Clinicaly stable Yes Known fungi No Sensitive to fluconazole C. parapsilosis C. Glabrata (B-III) C krusei (A-I) Yes (B-III) No fluconazole AmB-L echinocandin

55 Criteria to start pre-emptive antifungal therapy Pz. In ICU 4 days. Abx in the last 7 days O CVC from 7 days 2 of the following: Total parenteral nutrition (days 1 3) Any dialysis (days 1 3) Major surgery (days -7 0) Pancreatitis (days -7 0) Any use of steroids (days -7 3) Immunosuppressive agents (days -7 0) Start Echinocandin or AmF- Lip Candida colonization

56 Major changes from the previous IDSA Guidelines (2004) Emphasis on fluconazole and echinocandins as the preferred choices for proven/suspected IC De-emphasis on AmB and LFAmB under most circumstances Concept of step down therapy is strongly encouraged There is little distinction made between the echinocandins

57

58 Fluconazol Amfotericine B Fluconazol (800) Amfotericine B + Flu Amfotericine B Caspofungin Caspofungin Micafungin Micafungin L-Amfotericine B Anidulafungin Fluconazole Voriconazole Amfotericine B Fluconazol Antifungal drug studies candidaemia P=.39 50% 53% P=.04 56% 69% P=.09 P=.82 P=.27 P=.009 P=.64 76% 73% 71% 72% 74% 72% 72% 70% 62% 60% Fluconazole AMB Phillips, 1995 Flu AMB Caspofungin Micafungin Anidulafungin AMB + Flu Caspofungin Micafungin Liposomal AMB Fluconazole Rex, 2003 Mora-Duarte, 2002 Pappas, 2007 Kuse, 2007 Reboli, 2007 MITT - Investigator-Assessed Response at End of Treatment (%) Voriconazole AMB->Flu Kullberg, 2005

59 Chemical Structures Caspofungin Glarea lozoyensis Micafungin Coleophoma empetri Anidulafungin Aspergillus nidulans H 2 N H 2 N HO HO O OH N O H NH NH O O HN H H NH O H H H N OH O OH N H O OH CH 3 H 3 C CH 3 CH 3 O O S O H 2 N OH H 3 C O HO O HO HO N O OH NH O H N HO NH O O HN OH N NH O O OH CH 3 OH O N O H 3 C H 3 C HO O HO HO N O NH OH O H N HO NH O O HN OH N NH O O OH CH 3 OH H 3 C O HO HO H 3 C HO Side chains are key determinants of lipophilicity, solubility, antifungal activity, and toxicity Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Debono M, Gordee RS. Annu Rev Microbiol. 1994;48: ; Debono M et al. J Med Chem. 1995;38:

60 Attività in vitro delle echinocandine nei confronti di Candida spp. Organismo Numero di isolati MIC 90 (µg/ml) Micafungina Caspofungina Anidulafungina C. albicans C. parapsilosis C. glabrata C. tropicalis C. krusei C. guilliermondii C. lusitaniae C. kefyr C. famata Candida spp Pfaller MA, et al. J Clin Microbiol 2008; 46:150 6

61 Pharmacology: Metabolism, Elimination, Bioavailability, and Protein Binding Metabolism Elimination/excreti on Caspofungin Micafungin Anidulafungin Hepatic metabolism by hydrolysis and N-acetylation Spontaneous nonhepatic chemical degeneration Urine 41% Feces 34% Hepatic metabolism by arylsulfatase and Biotrasformazione catechol-omethyltransferase enzimatica Urine + feces 82.5% Feces 71% Nonhepatic chemical degradation Urine <1% Feces 30% Protein Binding 97% >99% >99% Oral Bioavailability Degradazione chimica Metabolismo epatico Escrezione renale Metabolismo epatico Degradazione chimica <5% <5% <5% Dialyzable No No No Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Dodds Ashley ES et al. Clin Infect Dis. 2006;43:S28 S39.

62 Confronto dell Attività In vitro delle Echinocandine nei Confronti di Biofilm Prodotti da Candida spp. Specie GM MIC (mg/l) ANF CSF MCF C. albicans C. parapsilopsis C. tropicalis >16 C. dubliniensis 0.5 nd nd Total Schinabeck MK, et al. 44th ICAAC 2004: abst. M-1141 / Valentín A, et al. Rev Iberam Micol 2007;24:272 Katragkou A, et al. AAC 2008; 52:357 / Villar M, et al. J Chemother 2007:19:43. Review by Pemán J, et al. Rev Iberoam Micol 2008; 25:

63 Echinocandin studies Mora-Duarte Kuse Reboli Caspo AMB Mica L-AMB Anidu Fluco Apache <20 80, Apache > 20 19, Prior antifungal therapy NA NA NA NA C. albicans ,6 44, C. parapsilosis 19,8 18,3 18,3 15, C. glabrata 12,8 9,2 11,4 7, C. krusei 4 0,9 3 3,7 Excl.. Excl. Neutropenia (< 500) 12,8 8,7 12 7,9 2 3 Fav. response (EOT) 80,7 64,9 89,6 89,5 75, Mortality 34,2 30,4 NA NA 22,8 31,4

64 Candida colonization Is frequent in ICU patients The gut is the main portal of entry in neutropenic patients The skin is an important source of candidemia in non-neutropenic patients Tracheal colonization reflect oropharyngeal colonization and is not associated with candidal pneumonia in non- neutropenic ICU patients

65 1587 admissions 301 (19%) died 232 autopsies 135 (58%) with pneumonia 97 (42%) without pneumonia 77 patients with Candida in LRT 0 Candida pneumonia 58 patients with Candida in LRT 0 Candida pneumonia

66 Is Candida colonization of CVC in noncandidemic an indication for antifungals? 58 pts ( 91% in ICU) Independent predictors for outcome: - ultimately fatal underlying disease (P = 0.02) - severe sepsis, septic shock or multiorgan failure (P = 0.05). Antifungal therapy does not seem to have a significant influence on clinical outcome Perez-Parra A et al. Intensive Care Med 2009; 35:

67 OUTCOME OF CANDIDEMIA IN THE UK IMPACT OF CATHETER MANAGEMENT 58% No treatment (n=31) No line removal + antifungal (n=29) Day 30 mortality overall (n = 163) 31% 26% Line removal + antifungal (n=91) 14% Kibbler et al. J Hosp Infect 2003; 54:18-24

68 Early removal of central venous catheter in patients with candidemia does not improve outcome Nucci M et al. Clin Infect Dis 2010; 51:

69 Early removal of central venous catheter in patients with candidemia does not improve outcome Nucci M et al. Clin Infect Dis 2010; 51:

70 Candidemia in cancer patients: Impact of early removal of catheter Liu CY et al. J Infect 2009; 58:

71

72 OR (95% CI) P Inadequate antifungal therapy Infection biofilm-forming Candida species 2.35 ( ) ( ) APACHE score 1.03 ( ) Tumbarello et al JCM 2007

73 Biofilm Production by Candida spp 100 P = 0, C.albicans C.tropicalis C.glabrata.parapsilosis

74 Mortality (%) Mortality by Biofilm-Producing Isolates C.albicans P<0,001 C.parapsilosis P=0,003 C.tropicalis C.glabrata Other Biofilm-positive Biofilm-negative

75 Activity against Candida biofilms L-AMB L-AMB Kuhn et al AAC :1773