Third Interactive Session Invasive Aspergillosis. by author. Speakers: Claudio Viscoli Francesco Barchiesi Nikolai Klimko Roman Kozlov

Transcription

1 Third Interactive Session Invasive Aspergillosis Speakers: Claudio Viscoli Francesco Barchiesi Nikolai Klimko Roman Kozlov

2 Nikolai Klimko On the incidence of Invasive Aspergillosis you think that

3 Incidence of Invasive Aspergillosis 1.- Incidence of IA in SCT is 20% 2.- Incidence of IA in SOT is 15% 3.- Liver transplant recipients suffer more disseminated aspergillosis than other SOT recipients 4.- Incidence of IA after multiple myeloma is 10% 5.- All are true

4 Incidence of Invasive Aspergillosis 1.- Incidence of IA in SCT is 20% 2.- Incidence of IA in SOT is 15% 3.- Liver transplant recipients suffer more disseminated aspergillosis than other SOT recipients 4.- Incidence of IA after multiple myeloma is 10% 5.- All are true

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8 Estimates of IFD Patient group Invasive candidiasis risk estimates Invasive aspergillosis risk estimates AlloHSCT 4% 10% Leukaemia 3% 6% Solid tumour (neutropenic) 3% 2% Advanced cancer 1% 1.5% Solid organ Tx 5% 1.9% HIV/AIDS 0.2% 4% Burns 5.6% 1.9% ICU 1% 0.2% Renal dialysis 0.2% 0.02% Advisory Committee on Fungal Infections' report on Fungal Diseases in the UK

9 Invasive fungal infections after stem cell transplant, (Transnet) Cumulative incidence (%) Kontoyiannis et al., Clin Infect Dis, Days from transplantation 360 Allo MMR: 8.1% Allo URD: 7.7% Allo MRD: 5.8% Overall: 3.4% (range by site: %) Auto: 1.2%

10 IA in transplant patients Singh N. and Paterson DL, Clin Microb Reviews; 2005, 18, N 1:

11 Попова М.О IFD after SCT in Saint Petersburg, Russia (n=356) 23,2% 19% (68/356) 10,9% allo SCT auto SCT 55/237 * 13/119* * p<0,001

12 Попова М.О IFD after SCT in Saint Petersburg, Russia (n=356) allo SCT auto SCT

13 IFD after SCT in Saint Petersburg, Russia (n=356) Allo SCT Auto CST Aspergillosis 19% 9% Candidosis 3% 2% Mucormycosis 1,5% 0 Crypococcosis 0,5% 0

14 Roman Kozlov The most common underlying condition of culture proven IA is?

15 IA: Underlying conditions 1.- Allogeneic hematopoietic stem-cell transplants. 2.- Lung transplantation. 3.- C.O.P.D. receiving corticosteroids. 4.- Chronic renal failure. 5.- Solid neoplasia.

16 IA: Underlying conditions 1.- Allogeneic hematopoietic stem-cell transplants. 2.- Lung transplantation. 3.- C.O.P.D. receiving corticosteroids. 4.- Chronic renal failure. 5.- Solid neoplasia.

17 Roman Kozlov Which of the following is the best recognized risk factor for IA?

18 IA: Best recognized risk factors? 1.- Chronic renal failure 2.- Broad spectrum antimicrobials 3.- Use of infliximab 4.- Prolonged ICU admission 5.- Use of corticosteroids

19 IA: Best recognized risk factors? 1.- Chronic renal failure 2.- Broad spectrum antimicrobials 3.- Use of infliximab 4.- Prolonged ICU admission 5.- Use of corticosteroids

20 Nikolai Klimko Which of the following species cause infection in humans?

21 Which of the following species cause infections in humans? 1.- A. fumigatiaffinis 2.- A. lentulus 3.- Neosartoria fisheri 4.- Neosartoria udagawae 5.- All of them

22 Which of the following species cause infections in humans? 1.- A. fumigatiaffinis 2.- A. lentulus 3.- Neosartoria fisheri 4.- Neosartoria udagawae 5.- All of them

23 Classification of Aspergillus. ~260 species, 38 have caused diseases Balajee & Marr,2006. Future Microbiology, 1:

24 Neosartorya Anamorphs closely related to to A. A. fumigatus. Teleomorphs only differentiated by by subtle differences in in ascospores ornamentation. Thermophilic.

25 Neosartorya N. fischeri N. pseudofischeri N. udagawae N. hiratsukae

26 Neosartorya Pulmonary infection Disseminated infection Cerebral infection Osteomyelitis Endocarditis Peritonitis Keratitis

27 Neosartorya Underdiagnosed (regarded as as contaminants in in the lab) Difficult to to identify at at species level. Antifungal susceptibility similar to to A. A. fumigatus? Little experience in in the treatment.

28 Claudio Viscoli In the definitions of IA of the EORTC-MSG which of the following host or clinical criteria are included?

29 EORTC Definitions 1.- Autologous stem cell transplant. 2.- Bolus of corticosteroids. 3.- Nodular lesion in a chest x ray. 4.- Nasal ulcer in a patient with sinusitis. 5.- All of them

30 EORTC Definitions 1.- Autologous stem cell transplant. 2.- Bolus of corticosteroids. 3.- Nodular lesion in a chest x ray. 4.- Nasal ulcer in a patient with sinusitis. 5.- All of them

31 EORTC/MSG definitions of IFD Developed to facilitate conduct of clinical studies abot IFD (treatment, epidemiology, prophylaxis??) Standardized definitions developed by consensus panels, based on published literature Not validated clinically Not to be used in in the daily clinical practice 31

32 EORTC/MSG Criteria Possible Probable Proven Host criteria Host criteria Not needed Clinical criteria Clinical criteria Not needed Cytol/HP not done or negative Culture not done or negative Hyphae in Cytol/HP of respiratory/sinu s secretions Culture positive or Galactomannan De Pauw B, Clin or Infect β glucan Dis 2008; 46: 1813 Hyphae in Cytol/HP of tissue specimens with tissue damage Culture from sterile site positive 32

33 Host criteria Recent neutropenia for >10 days Allogeneic SCT Prolonged use of corticosteroids at a mean minimum dose of 0.3 mg/kg/d of prednisone equivalent for >3 weeks Treatment with other recognized T cell immunosuppressants during the past 90 days Inherited De Pauw B, severe Clin Infect Dis immunodeficiency 2008; 46:

34 Clinical criteria Lower respiratory tract fungal disease Presence of 1 of the following 3 signs on CT Dense, well-circumscribed lesion(s) with or or without a halo sign Air-crescent sign Cavity Text: can also manifest as wedge-shaped infiltrates and De Pauw B, Clin Infect Dis 2008; 46: 1813 segmental or lobar consolidation 34

35 Clinical criteria Tracheobronchitis Ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis Sinonasal infection Imaging showing sinusitis + at least 1 of the following 3 signs Acute localized pain Nasal ulcer with black eschar Extension from the paranasal sinus across bony barriers, including into the orbit De Pauw B, Clin Infect Dis 2008; 46:

36 Clinical criteria CNS infection 1 of the following 2 signs Focal lesions on on imaging Meningeal enhancement on on MRI MRI or or CT CT Disseminated candidiasis At least 1 of the following 2 entities after an episode of candidemia within the previous 2 weeks Small target-like abscesses in in liver or or spleen Progressive retinal exudates on on ophthalmologic examination De Pauw B, Clin Infect Dis 2008; 46:

37 Mycological criteria Direct tests (cytology, direct microscopy, or culture Mold in in sputum, BAL, bronchial brush, or or sinus asperirate, indicated by by 1 of of the following: Presence of of fungal elements Recovery by by culture of of a mold Indirect tests Aspergillus Galactomannan in in plasma, serum, BAL, CSF CSF IFD other than cropto & zygo Beta glucan in in serum De Pauw B, Clin Infect Dis 2008; 46:

38 Proven IFD Microscopic analysis of sterile material Histopathologic, cytopathologic, or or direct microscopic examination of of a specimen obtained by by needle aspiration or or biopsy in in which hyphae or or melanized yeast-like forms are seen accompanied by by evidence of of associated tissue damage Culture: Recovery of of a mold or or black yeast by by culture of of a specimen obtained by by a sterile procedure from a normally sterile and clinically or or radiologically abnormal site consistent with an an infectious disease process, excluding BAL, cranial sinus cavity De specimen, Pauw B, Clin and Infect urinedis 2008; 46:

39 Claudio Viscoli In what of the following clinical situations in a non Immunosupressed patient would you consider IA?

40 When would you consider IA? 1.- Prosthetic valve endocarditis. 2.- Wound infection. 3.- Ocular lesions in patients with chronic liver disease. 4.- Brain abscess. 5.- All of them

41 When would you consider IA? 1.- Prosthetic valve endocarditis. 2.- Wound infection. 3.- Ocular lesions in patients with chronic liver disease. 4.- Brain abscess. 5.- All of them

42 Risk of Invasive aspergillosis HIGH (> (> 10%) Chronic granulomatous disease Lung Lung transplant recipients Acute Acute myeloid leukemia Allogenic BMT BMT recipients with with GVHD GVHD > > grade grade II II MODERATE (1-10%) AIDS AIDS patients Liver, Liver, heart, heart, or or pancreas transplant recipients Acute Acute myeloid leukemia (in (in protected environment) Allogenic BMT BMT recipients without GVHD GVHD or or grade grade I Autologous BMT BMT recipients Intensive care care patients on on steroids Severe Severe combined immunodeficiency syndrome Lymphoma Major Major burn burn (> (> 30%) 30%) Verweij PE,Denning DW. IJID 1997; 2: 61-3

43 Risk of Invasive Aspergillosis LOW (< 1%) Systemic lupus erythematosus on prednisolone Diabetes mellitus Alcoholism Corticosteroid treatment Patients treated for solid tumors Intensive care patients Agammaglobulinemia Verweij PE,Denning DW. IJID 1997; 2: 61-3

44 CLASSIFICATION OF ASPERGILLOSIS Airways/nasal exposure to airborne Aspergillus Invasive aspergillosis Acute (<1 month course) Subacute/chronic necrotising (1-3 months) Chronic aspergillosis (>3 months) Chronic cavitary pulmonary Aspergilloma of lung Chronic fibrosing pulmonary Chronic invasive sinusitis Maxillary (sinus) aspergilloma Allergic Allergic bronchopulmonary (ABPA) Extrinsic allergic (broncho)alveolitis (EAA) Asthma with fungal sensitisation (SAFS) Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)

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47 Clin Infect Dis 2011;

48 Med Mycol 2011

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50 Franchesco Barchiesi What is true, in your opinion, regarding diagnostic methods of IA?

51 Regarding diagnostic methods for IA 1.- Direct examination of elements compatible with fungi in clinical samples can only be performed by the pathologist. 2.- Galactomannan detection is very useful in SOT recipients. 3.- Aspergillus PCR in blood is very useful. 4.- Septifast can detect IA. 5.- Glucatell is not useful for detecting IA.

52 Regarding diagnostic methods for IA 1.- Direct examination of elements compatible with fungi in clinical samples can only be performed by the pathologist. 2.- Galactomannan detection is very useful in SOT recipients. 3.- Aspergillus PCR in blood is very useful. 4.- Septifast can detect IA. 5.- Glucatell is not useful for detecting IA.

53 SeptiFast Test (multiplex real-time PCR assay) is capable of detecting genetic material belonging to several bacterial and fungal pathogens, representing approximately 90% of the species responsible for nosocomial bacteremia The assay uses dual fluorescent resonance energy transfer (FRET) probes targeting the species-specific internal transcribed spacer (ITS) regions. The detection limit ranges from 3 to 30 CFU/ml, depending on single pathogens, whereas the turnaround time is approximately 6 h The main technical advantage of this assay is its real-time format that markedly reduces the risk of contamination. Current limitations of the assay include its very high cost (150 to 200 [$215 to $290] per test) and the lack of any information on antimicrobial susceptibility Mancini et al., Clin Microbiol Rev, 2010, 23:

54 Pathogens detected by SeptiFast Gram negative bacteria: E. coli, K. pneumoniae, K. oxytoca, S. marcescens, E. cloacae, E. aerogenes, P. mirabilis, P. aeruginosa, A. baumannii, S. maltophilia Gram positive bacteria: S. aureus, C-N Staphilococci, S. penumoniae, Streptococcus spp., E. faecium, E. faecalis Fungal pathogens: C. albicans, C. tropicalis, C. parapsilosis, C. krusei, C. glabrata, A. fumigauts Clin Microbiol Infect, 2009; BMC Infect Dis 2009; J Clin Microbiol 2009; Clin Microbiol Infect 2009; J Infect 2009; Transpl Infect Dis 2009; J Med Microbiol 2008; J. Chemother 2007

55 Major findings at least as sensitive as coltures faster identification of pathogens faster identification of negative samples not influenced by ongoing therapy rapid detection and identification from blood of fastidious organisms such as A. fumigatus

56 Pool sensitivity and specificity of the GM assay for diagnosis of IA Pfeiffer et al., CID, 2006

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58 Sens. Spec. PPV NPV Rt-PCR GM Sens. Spec. PPV NPV Rt-PCR JCM 2008, 46: JCM 2009, 46:

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60 Fungal Fungal cell wall Fungal cell wall -(1,6)- glucan cell wall -(1,3)-glucan Phospholipid bilayer of the fungal cell membrane -(1,3)-glucan synthase Ergosterol Candida, Aspergillus, Penicillium, Cephalosporium, Trichosporon, Fusarium, Saccharomyces, Acremonium, Histoplasma e Pneumocystis jiroveci NO Cryptococcus e Zygomycetes

61 Franchesco Barchiesi Regarding antifungal resistance of Aspergillus?

62 What is false regarding Aspergillus resistance? 1.- Aspergillus fumigatus isolates are fully susceptible to voriconazole and posaconazole. 2.- Aspergillus terreus isolates are resistant to amphotericin B. 3.- There is a growing number of azole-resistant A. fumigatus isolates found in some European countries. 4.- Statements 1 and 2 are correct. 5.- Statements 2 and 3 are correct.

63 What is correct regarding Aspergillus sensitivity? 1.- Aspergillus fumigatus isolates are fully susceptible to voriconazole and posaconazole. 2.- Aspergillus terreus isolates are resistant to amphotericin B. 3.- There is a growing number of azole-resistant A. fumigatus isolates found in some European countries. 4.- Statements 1 and 2 are correct. 5.- Statements 2 and 3 are correct.

64 N isolates In Vitro Amphotericin B Resistance in Clinical Isolates of Aspergillus terreus, with a Head-to-Head Comparison to Voriconazole MIC distribution (mcg/ml) Sutton et al., J. Clin. Microbiol., Jul 1999; 37: VORI AMB Experimental Pulmonary Aspergillosis Due to Aspergillus Experimental Pulmonary Aspergillosis Due to Aspergillus terreus: Pathogenesis and Treatment of an Emerging terreus: Pathogenesis and Treatment of an Emerging Fungal Pathogen Resistant to Amphotericin B Fungal Pathogen Resistant to Amphotericin B Walsh et al., JID, 2003, 188:305-19

65 % mortality at 12 wks Infections Due Due to to Aspergillus terreus: terreus: A Multicenter Retrospective Analysis of of Cases Cases ,8 55,8 00 Steinbach et al., Clin Infect Dis. (2004) 39(2): ,4 73,4 Vori Vori Am Am

66 Emergence of of Azole Azole Resistance in in Aspergillus fumigatus and and Spread of of a Single Single Resistance Mechanism Snelders et al., PLoS MEDICINE, 2008, 11:

67 Snelders et al., PLoS MEDICINE, 2008, 11:

68 Roman Kozlov When Aspergillus spp. is recovered from a respiratory sample, you consider that

69 Aspergillus in respiratory samples 1.- Antifungal treatment should always be started. 2.- Antifungal treatment should always be started in immunosuppressed patients. 3.- Treatment should be only provided to patients with compatible radiological findings in the thoracic CT scan. 4.- Treatment should be only provided when the fungal invasion is confirmed by biopsy. 5.- Treatment should be only provided to patients who fulfill criteria of proven or probable invasive aspergillosis.

70 Aspergillus in respiratory samples 1.- Antifungal treatment should always be started. 2.- Antifungal treatment should always be started in immunosuppressed patients. 3.- Treatment should be only provided to patients with compatible radiological findings in the thoracic CT scan. 4.- Treatment should be only provided when the fungal invasion is confirmed by biopsy. 5.- Treatment should be only provided to patients who fulfill criteria of proven or probable invasive aspergillosis.

71 Franchesco Barchiesi Which of the following statements regarding the Galactomannan test is false

72 The following is false, regarding galactomannan 1.- It is highly sensitive for neutropenic patients with invasive aspergillosis (cut-off > 0.5). 2.- The test has a low sensitivity in solid organ transplant recipients. 3.- Patients receiving some antibiotics could have false positive test results. 4.- It helps in the antifungal treatment s follow-up. 5.- It can only be performed in serum samples.

73 The following is false, regarding galactomannan 1.- It is highly sensitive for neutropenic patients with invasive aspergillosis (cut-off > 0.5). 2.- The test has a low sensitivity in solid organ transplant recipients. 3.- Patients receiving some antibiotics could have false positive test results. 4.- It helps in the antifungal treatment s follow-up. 5.- It can only be performed in serum samples.

74 Probable... Clin. Infect. Dis., 2008; 46:

75 Histoplasma antigen test test (EIA, (EIA, sensitivity: 85-95% disseminated infection; 75-83% pulmonary infection; false false positive results in in patients with with other other endemic mycoses) Wheat et et al., al., DMID, 2002, 43:29-37 Cryptococcal antigen test test (LA, (LA, EIA, EIA, sensitivity and and specificity >95%) >95%) Yeo Yeo and and Wong, Clin. Clin. Microbiol. Rev., 2002, 15: Galactomannan test test (EIA, (EIA, sensitivity: 80.7%; specificity 89.2% in in HSCT HSCT recipients and and patients with with leukemia) Platelia aspergillus EIA EIA [package insert]. Redmond, WA: WA: Bio-Rad Laboratories, 2003 (1 (1 3) -D-glucan test test ( panfungal antigen ) Odabasi Z. Z. et et al., al., Clin. Clin. Infect. Dis., Dis., 2004, 39:

76 Aspergillus galactomannan testing in patients with long-term neutropenia: implications for clinical management. In patients with infiltrates in chest X-ray or computed tomography scan, GM testing in BAL has a favorable diagnostic accuracy as compared with GM testing in serum (sensitivity100% versus 71%). Penack et al., Annals of Oncology, 2008

77 GAL in BAL Maertens et al., Clinical Infectious Diseases 2009;49: Cutoff 1 Sens 91.3% Spec 87.8% PPV 76.3% NPV 96%

78 Aspergillus Galactomannan Antigen in the Cerebrospinal Fluid of Bone Marrow Transplant Recipients with Probable Cerebral Aspergillosis Viscoli et al., J. Clin. Microbiol., Apr 2002; 40:

79 GM index Zalerion arboricola Aspergillus nidulans Coleophoma empetri 0.5

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81 Claudio Viscoli In a patient with invasive pulmonary aspergillosis, which antifungal treatment would you choose before having the antifungal susceptibility data?

82 IA: which antifungal treatment before susceptibility data? 1.- Voriconazole 2.- Voriconazole + Caspofungin 3.- Liposomal Amphotericin B 3 mg/kg/daily 4.- Amphotericin B + Voriconazole 5.- Liposomal Amphotericin B 10mg/kg/daily

83 IA: which antifungal treatment before susceptibility data? 1.- Voriconazole 2.- Voriconazole + Caspofungin 3.- Liposomal Amphotericin B 3 mg/kg/daily 4.- Amphotericin B + Voriconazole 5.- Liposomal Amphotericin B 10mg/kg/daily

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85 First line therapy for IA ECIL III 2009 IDSA 2008 BSH 2008 Voriconazole A I (oral CIII) A I (1 line) Recommended L-AMB B I A I (1 line for some pts) Recommended ABLC B II - - ABCD D I - - D-AMB D I - Not recommended - A I Caspofungin C II Alternative Recommended Micafungin Alternative - Posaconazole Alternative - Itraconazole C III Alternative - Combination D III Not recommended B II Discouraged A I Surgery (selected pts) C III B III B III

86 N Engl J Med, Vol. 347, No. 6 August 8, 2002

87 Week 12 successful response rate (%) Overall (MITT) Pulmonary only Extra pulmonary Allogeneic HSCT Other hemat. dis. Other Neutropenic Non-neutropenic Definite IA Probable IA Favors AmB Favors vori Vori Ampho B Overall (ITT) Difference in proportions (%) and 95% CI

88 Survival (%) Overall survival Voriconazole arm Amphotericin B arm Weeks Improved survival 13% Herbrecht et al. NEJM 2002

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90 Cornely et al, CID 2007

91 A couple of additional aspects one should keep in mind Azole metabolism and the possible role of Therapeutic Drug Monitoring The role of the underlying disease

92 Voriconazole: variability of blood concentrations Pascual A et al. CID 2008; 46:

93 Voriconazole trough blood levels and clinical response to antifungal therapy Pascual A et al. CID 2008; 46:

94 Voriconazole TDM Internal protocol for voriconazole testing, indications for TDM: day 4 after starting therapy; weekly during the first 42 days of therapy; anytime upon clinical indication, particularly inf treatment failures, toxicity or modified dosing. Therapeutic range: μg/ml (Pasqual et al, CID 2008).

95 Voriconazole TDM in our center From January 2010, 452 samples from 56 patients (both paediatric and adults) were tested for TDM Medium number of samples per patient was 8 (range: 1-33) Median voriconazole concentration was 1.7 μg/ml, ranging from 0.1 μg/ml to 11.2 μg/ml Distribution of voriconazole levels: 60% 60% 1-5 μg/ml 1-5 μg/ml > 5 μg/ml > 5 μg/ml 6% 6% < 0,5 μg/ml < 0,5 μg/ml 12% 12% 0,5-1 μg/ml 0,5-1 μg/ml 22% 22% 53 samples - < 0.5 μg/ml 99 samples μg/ml 272 Samples samples - > 5 μg/ml

96 A couple of additional aspects one should keep in mind Azole metabolism and the possible role of Therapeutic Drug Monitoring The role of the underlying disease

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98 Karnofsky score Underlying disease not in remission Neutropenia at EOT Factor associated with survival at at multivariate analysis (57/61 pts) OR <0.01 <0.01 Only hematological patients pvalue 32

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100 12 Week Survival: Adjusting Treatment Effect by Predictive Factors AmBi-3 (72%) vs. AmBi-10 (59%) P- value* Unadjusted.053 Adjusted for Allo-SCT.078 Uncontrolled malignancy.078 Allo-SCT + Uncontrolled malignancy.12 *P-value *P-value for for treatment treatment effect effect (3 (3 vs. vs. 10mg) 10mg) on on survival survival at at weeks weeks Survival driven by by underlying risk factors, not

101 BMT 2009 In our study, a relapsing underlying disease was strongly associated with the risk of developing invasive aspergillosis and was also associated with the risk of dying from aspergillosis (OR=3.8)

102 Infections in compromised patients are unique because we treat an infection in a patient with another disease. The backgroud noise of the other disease is crucial in evaluating the results of the antinfective therapy

103 Franchesco Barchiesi What is your opinion concerning the measurement of antifungal drug levels?

104 Regarding the measurement of antifungal drug levels? 1.- Up-to-date guidelines do not recommend its systematical determination. 2.- They can be useful to identify under-dosed patients receiving azoles. 3.- There is no indication to determine serum levels of Liposomal Amphotericin B. 4.- It can help to identify azole-related toxicity. 5.- All of the above are true.

105 Regarding the measurement of antifungal drug levels? 1.- Up-to-date guidelines do not recommend its routine determination. 2.- They can be useful to identify under-dosed patients receiving azoles. 3.- There is no indication to determine serum levels of Liposomal Amphotericin B. 4.- It can help to identify azole-related toxicity. 5.- All of the above are true.

106 Justification for therapuetic drug monitoring of antifungals? Lewis, 2010, Curr Fungal Infect Rep, 4: PK Variabilty Correlation of serum drug concentration & efficacy/toxici ty Assay available? AMB No No Yes 5FC Yes Yes Yes FLUCO Yes Yes Yes ITRA VORI POSA Yes Yes Yes ECHINOCANDINS No No Yes

107 Voriconazole Therapeutic Drug Monitoring in in Patients with Invasive Mycoses Improves Efficacy and Safety Outcomes Pascual et al., CID, 2008, 46:201-11

108 CYP 2C19 Genotype Strongly Affects Voriconazole Clearance Scholtz et al., Br J Clin Pharmacol, 2009, 68:906-15

109 5FC Antifungal therapeutic drug monitoring: established and emerging indications ITRA VORI POSA Indication Routine during first week therapy, renal insuff., poor response Routine during first week therapy, GI disfunction, comedication Lacking response, GI dysfunction, comedication, children, IV to oral switch, unexplained neurological symptoms/signs Lacking response, GI dysfunction, comedication, PPI therapy Andes et al., AAC, 2009, 53: Time of first measurement Efficacy (mcg/ml) Safety (mcg/ml) 3-5 days Peak > 20 Peak < days Prophylaxis > 0.5; therapy through > days Prophylaxis > 0.5; therapy through > days Prophylaxis > 0.5; therapy through > NA Through <6 NA

110 Drugs that significantly decrease the serum levels of antifungal agents Drugs Concomitant drug(s) Action ITRA H-2 antagonists and proton pump inhibitors, rifampin Monitor ITRA serum levels and considering increase the dose of ITRA or choosing alternate drug(s) FLUCO Rifampin Consider increasing the dose of FLU VORI POSA CASPO Rifampin, rifabutin, efavirenz, ritonavir, carbamazepine, longacting barbiturates, and phenytoin Cimetidine, rifabutin, and phenytoin Rifampin, efavirenz, nevirapine, dexamethasone, phenytoin, and carbamazepine Nucci and Perfect, Clin. Infect. Dis. 2008;46: Controindicated coadministration with carbamazepine, long-acting barbiturates, rifampin and rifabutin; with phenytoin and efavirenz, double VORI dosage and monitor for the increase of the concomitant drugs Avoid concomitant use Increase maintenance dose of CAS to 70 mg/day

111 Claudio Viscoli What is your opinion regarding the indication of combined antifungal therapy in invasive aspergillosis?

112 Indications of combined antifungal therapy 1.- Invasive pulmonary aspergillosis in patients with COPD. 2.- Invasive pulmonary aspergillosis in neutropenic patients or transplant recipients. 3.- It is not sufficiently supported by clinical evidence. 4.- In cases caused by non-fumigatus Aspergillus species. 5.- It is only recommended as rescue therapy, when previous antifungal treatment has failed.

113 Indications of combined antifungal therapy 1.- Invasive pulmonary aspergillosis in patients with COPD. 2.- Invasive pulmonary aspergillosis in neutropenic patients or transplant recipients. 3.- It is not sufficiently supported by clinical evidence. 4.- In cases caused by non-fumigatus Aspergillus species. 5.- It is only recommended as rescue therapy, when previous antifungal treatment has failed.

114 Combination therapy Combination therapy

115 Animal models Animal models

116 Combination Therapy in in Treatment of Experimental Pulmonary Aspergillosis: Synergistic Interaction between an Antifungal Triazole and an echinocandin Vidmantas Petraitis, Ruta Petraitiene, Alia A. A. Sarafandi, Amy M. Kelaher, Caron A. A. Lyman, Heather E. E. Casler, Tin Sein, Andreas H. H. Groll, John Bacher, Nilo A. A. Avila, and Thomas J. J. Walsh J. Infectious Disease 15 June 2003

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118 PROBLEMS IN EVALUATING DATA FROM ANIMAL MODELS Means for generating the invasive disease (should mimic the human infection) Doses often chosen arbitrarily Blood or tissue levels very different from those obtained in humans with different exposure

119 Clinical studies of combination therapy in aspergillosis and guidelines

120 Historical controlled study (retrospective review) comparing the outcomes (90 days survival) of patients with IA who failed initial therapy with AmB formulations and received either voriconazole Or voriconazole + caspofungin (CID 2004)

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122 First line therapy for IA ECIL III 09 IDSA 08 BSH 08 Voriconazole A I (oral CIII) A I (1 line) Recommended L-AMB B I A I (1 line for some pts) Recommended ABLC B II - - ABCD D I - - D-AMB D I - Not recommended - A I Caspofungin C II Alternative Recommended Micafungin Alternative - Posaconazole Alternative - Itraconazole C III Alternative - Combination D III Not recommended B II Surgery (selected pts) Discouraged A I C III B III B III

123 Salvage therapy ECIL III 2009 IDSA 2008 BSH 2008 L-AMB B III A II No recommendation ABLC B III Posaconazole B II B II Vorico B II Itraconazole C III B II Caspofungin B II B II Micafungin Combination therapy C II (Caspo + L-AMB or Caspo + Vori) B II B II The design of these trials is so heterogeneous that it is not possible to make a recommendation on the basis of their evidence.

124 Possible role of calcineurin inhibitors in invasive aspergillosis (IA) Calcineurin has a role in in the fungal cell wall homeostasis, fungal growth and virulence The use of of calcineurin-inhibitors (cyclosporin) was associated with a decrease in in the incidence of of IA in in solid organ transplant recipients compared with The conventional challenge immunosuppression is to develop a calcineurin-inhibitor (Hoflin, Ann Int Med not 1987, cross-reacting Singh, Clin Inf with Dis human 2003) calcineurin These data have been confirmed in in experimental models (Steinback, 2006) Calcineurin inhibition prevents the caspofunginassociated paradoxical effect (regrowth at at high concentrations)

125 Claudio Viscoli What should be, in your opinion, the proper length of treatment for solid organ transplant recipients with invasive aspergillosis?

126 Length of treatment of IA in SOT patients weeks weeks. 3.- A minimum of 6-12 weeks. 4.- Three to six months. 5.- More than six months

127 Length of treatment of IA in SOT patients weeks weeks. 3.- A minimum of 6-12 weeks. 4.- Three to six months. 5.- More than six months

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131 Claudio Viscoli Anti Aspergillus prophylaxis is indicated in?

132 Anti Aspergillus prophylaxis is indicated in? 1.- In all SOT recipients during the first month 2.- In Allogeneic SCT in the neutropenic period 3.- After induction therapy of Acute leukemia 4.- In liver transplant recipients with rejection 5.- All of them are true

133 Anti Aspergillus prophylaxis is indicated in? 1.- In all SOT recipients during the first month 2.- In Allogeneic SCT in the neutropenic period 3.- After induction therapy of Acute leukemia 4.- In liver transplant recipients with rejection 5.- All of them are true

134 Incidence of IFI, % Posaconazole : 200 mg tid Posaconazole Prophylaxis in Patients with Severe GvHD or Neutropenia P =.07 P = HSCT + GVHD (Fixed time point: 112 days) /301 27/299 7/301 21/299 All IFIs Invasive aspergillosis Ullmann AJ et al. N Engl J Med 2007;356: Fluconazole 400 mg/d Fluco 400 mg/d or itra 200 mg/d po AML/MDS (While on treatment + 7 days) P < /304 14/304 25/298 33/298 2/304 20/298 All IFIs P < Invasive aspergillosis Cornely OA et al. N Engl J Med 2007;356:348-59

135 Wingard J et al. Blood 2010 Voriconazole vs Fluconazole Prophylaxis in Allo BMT Patients: Fungal-free survival n=600 Allo-BMT patients Double-blind study Voriconazole 200 mg bid Fluconazole 400 mg/d 100 or 180 days 1 o endpoint: fungal free survival at 180 d IFI: 180 d: Vori 7.3% vs fluco 11.2%(p=0.12); 12 m: Vori 12.7% vs fluco 13.7% (p=0.56) IA: 180 d: Vori 9 cases vs fluco 17 cases (p=0.09) Toxicity: similar in the two arms Probability Fluconazole (N=295) Voriconazole (N=305) P= Months Post Transplant

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137 ECIL II: AF prophylaxis in cancer patients Allogeneic hematopoietic stem cell transplantation Fluconazole mg mg qd qd iv/oral: AI AI 2 2 Itraconazole mg mg IV IV followed by by oral oral solution mg mg bid: bid: BI BI 1,2,3 1,2,3 Posaconazole mg mg tid tid oral: oral: AI AI 2,3 2,3 Micafungin mg mg qd qd iv: iv: CI CI Voriconazole Polyene 4 4 iv: added iv: CI in the 2009 review of the guidelines CI Recommedation to be reviewed Fluconazole September mg mg qd qd iv/oral: CI CI 2 2 Itraconazole oral oral solution mg/kg mg/kg bid: bid: CI CI 1,2,3 1,2,3 Posaconazole mg mg tid tid oral: oral: AI AI 2,3 2,3 Candins iv: iv: no no data data Polyene 4 4 iv: iv: CI-CII CII Induction chemotherapy of of acute leukemia 1 may be limited by drug interactions and/or patient tolerability 2 azoles should not be used empirically in case of prior azole prophylaxis 3 it is recommended to monitor serum drug concentrations 4 includes low doses of conventional amphotericin B and lipid formulations. The ECIL recommendation for aerosolized amphotericin B is DI

138 Number needed to treat Number needed to treat

139 Cornely, CID 2008