Antifungal Treatment Strategies

Transkript

1 Kontroverse

2 Präemptive Therapie Prof. Dr. G. Maschmeyer Charité Universitätsmedizin Berlin Campus Virchow-Klinikum Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie (Dir.: Prof. Dr. B. Dörken) Berlin

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4 Antifungal Treatment Strategies Treatment Disease likelihood Temperature Granulocytes Empiric PCR + Galactomannan + Possible Pre-emptive Probable disease Culture + Tissue Days after transplant Specific Proven

5 Klinische Anwendungsfähigkeit der EORTC/MSG Klassifikation für invasive pulmonale Aspergillosen 22 Patienten mit hämatologischen Erkrankungen und autoptisch gesicherter IPA EORTC/MSG-Kriterien ante mortem: 2 gesicherte, 6 wahrscheinliche, 13 mögliche IPA, 1 nicht klassifizierbar Subira M et al, Ann Hematol 2003;82:80-2

6 Patienten mit Lungeninfiltraten sind eine Hochrisikogruppe, bei der eine frühzeitige, präemptive antimykotische Therapie zu empfehlen ist

7 Evidence Epidemiological studies (EORTC 1998) Autopsy results Bodey et al (Canada, Japan, Europe) 1992 Groll et al (Frankfurt) 1994 Boon et al (Birmingham) 1991 Nosari et al (Milan) 1991 Biopsy findings Pennington & Feldman 1977 Commers et al 1984 Haron et al 1993 Janzen et al 1993 BAL findings Response to systemic antifungal treatment

8 EORTC Survey of IA in Hematological Patients Sites of Disease Denning DW et al, J Infect 37: (1998)

9 Invasive Mycosis in Post-Mortem Findings n > 12,000 autopsies ( ) Presence of systemic mycosis: : 1.6 % : 2.5% : 4.1% 76% of cases only diagnosed post mortem Steady increase in Aspergillus infections 62% leukemia or lymphoma 82% pulmonary involvement Groll A et al. (Frankfurt/Main), J Infect 28 Suppl 1: 57 (1994)

10 Bodey G et al, Eur J Clin Microbiol Infect Dis 1992;11: Organ Involvement in Autopsy-Proven Fungal Infection Candidiasis n (%) Aspergillosis n (%) Lung 111 (42) 107 (78) Oesophagus 91 (34) 6 (4) Kidney 63 (24) 15 (11) Stomach 60 (23) 7 (5) Liver 49 (18) 5 (4) Spleen 47 (18) 9 (7) Intestines 47 (18) 6 (4) Heart 40 (15) 14 (10) Brain 15 (6) 20 (15) Meninges 2 (1) 8 (6) Bladder 10 (4) Š Total (n)

11 PEG Study Group Trial I: Response in Lung Infiltrates Related to Pathogens Pathogen n CR (%) NR (%) ED (%) Gram positive Gram negative Fungi P. jiroveci No pathogen isolated (Pts.) Total (Pts.) Maschmeyer G et al, Cancer 73: (1994)

12 PEG Study Group Trial I: Response in Fungal Pneumonias (n = 44) Related to Time of Documentation Time of n CR (%) NR (%) ED(%) Documentation Day Day Total Maschmeyer G et al, Cancer 73: (1994)

13 Von Eiff M et al, Respiration 1995;62:341-7 Invasive Pulmonary Aspergillosis: Early Diagnosis Improves Survival 33 patients with IPA, Since 1990, start of IV antifungal therapy after the onset of pneumonia shifted from day 12 to day 7 Reduction of mortality from 90% to 41% (p < 0.01)

14 PEG Studie II: Primäre antimykotische Behandlung bei allen febrilen neutropenischen Hochrisikopatienten mit Lungeninfiltraten

15 PEG Study I/II Patients with Fever and Lung Infiltrates Benefit from First-Line Amphotericin B n CR (%) NR (%) ED (%) Supplementation of AmB only in non-responders * Antibacterials plus empiric AmB from the start * *) p < 0.01 (Fisher's exact test, two-tailed)

16 Persistently Febrile Neutropenic Patients: Fluconazole vs AMB + 5-FC n = 98, high-grade hematologic malignancy Febrile neutropenia refractory to standard first-line therapy Addition of fluconazole 5.7 mg/kg/d vs. amphotericin B 0.75 mg/kg/d + 5-flucytosine 150 mg/kg/d CR rates: FUO AMB/5-FC 77 % FLU 59 % Lung infiltrates AMB/5-FC 74 % (20/27) FLU 25 % (5/20) Silling G et al, Mycoses 43 Suppl 2: (1999)

17 Haron E et al (MDACC), Medicine 72: (1993) Candida Pneumonia in Cancer Patients n = 31 primary Candida pneumonias in 20 yrs ( )...among 351 cases of autopsy-proven invasive Candida infections...among 7725 autopsies performed at MDACC Contribution to death: 21/31 pts 25/31 pts not treated with antifungals

18 Pre-Emptive AF Therapy in Patients with Lung Infiltrates Efficacy of New Antifungal Agents-1 L-AmB: not specified ABCD: SD/PR/CR in 28/59 pts (47%) with p/p pulmonary aspergillosis [Bowden 2002] Itraconazole: PR/CR in 15/31 pts. (48%) with p/p pulmonary aspergillosis (pos. CT scan in 93%) [Caillot 2001]

19 Pre-Emptive AF Therapy in Patients with Lung Infiltrates Efficacy of New Antifungal Agents-2 Voriconazole: PR/CR 54 and 60% in pulmonary IA and probable IA [Herbrecht 2002] Caspofungin (salvage): 32 of 64 (50%) with p/p pulmonary IA [Maertens 2002] Posa/Ravu/Mica/Anidula: no data available as yet

20 Diagnostische Optionen bei neutropenischen Patienten mit Fieber ± Lungenfiltraten Typische klinische Befunde Konventionelle Thoraxröntgenaufnahme HR-CT, Mehrzeilen-CT der Lungen Sputumkultur (-) Bronchoskopie + BAL ± Galactomannan und/oder PCR Offene Lungenbiopsie (TBB?) Galactomannan/PCR im Blut

21 Invasive pulmonaler Aspergillose (IPA): Klinische Zeichen n = 60 Patienten mit akuter Leukämie, davon 15 mit gesicherter IPA Klinische Symptomatik im Vergleich zu den 45 Patienten ohne IPA: Pleurale Schmerzen 100 vs 16% (p < 0.005) Husten 93 vs 49% (p = 0.002) Auskultat. RG 100 vs 53% (p < 0.005) 3 Befunde Sinus/Nase 60 vs 0% (p < 0.004) Gerson SL et al (Pennsylvania), J Clin Oncol 3: (1985)

22 HRCT of Lungs in Neutropenic Patients with Persisting Fever n = 146 neutropenic patients with fever persisting under empirical antibiotic therapy (>48 h) Chest radiograph abnormal: 14% HRCT abnormal: 48% CT-guided BAL: yield 43% HRCT normal: 38% subsequent HRCT (7 d) pathologic: 5% Heussel CP et al, Am J Roentgenol 1997;169:

23 Caillot D et al. J Clin Oncol 2001;19:253-9 IPA: Development of Pulmonary CT Scan d0 d3 d10

24 IPA: Halo Sign Kauffman CA, Infect Med 20: (2003)

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26 OLB in Patients with Hematologic Malignancies 67 open lung biopsies for diagnosis of an unknown pulmonary process Fungi and bacteria = most frequent pathogens Specific diagnosis in focal vs diffuse radiographic abnormality: 79 vs 36% (p = 0.003) Neutropenic or ventilated pts: lower yield White DA et al (MSKCC), Am J Respir Crit Care Med 161: (2000)

27 Maertens J et al, Blood 2001;97: Serial Aspergillus Galactomannan Screening n = 362 high-risk neutropenic patients Sandwich ELISA 2 times weekly, 11.7% positive n = 30 proven IA n = 9 probable IA n = 264 with no IA Sensitivity 89.7% Specificity 98.1% PPV 87.5% NPV 98.4%

28 Early Detection of Aspergillus Infection after AlloSCT by PCR Screening 84 allosct recipients, 1193 blood samples, 14.2% positive PCR+ (median) 2 days before first clinical signs, 9 days before clinical diagnosis PCR sensitivity 100%, specificity 65% None of the PCR-negative patients developed IA Hebart H et al, J Infect Dis 2000;181:

29 BAL Galactomannan Data Becker MJ et al, Br J Haematol 2003;121:448-57

30 Raad II et al, Chest 2002;121: Diagnosis of IPA in Cancer Patients Aspergillus-PCR from BAL Samples n = 249 cancer patients with lung infiltrates Proven aspergillosis (10), probable (22), possible (18)

31 D. Buchheidt, 5/03 BAL PCR Data Author Patients/ controls Number of samples Sensitivity [%] Specificity [%] Tang et al. (1993) 23/ Bretagne et al. (1998) 28/9 37 n.d. n.d. Jones et al. (1998) 12/ Einsele et al. (1998) 134/ Hayette et al. (2001) 74/ Buchheidt et al. (2001) 67/ Buchheidt et al. (2002) 141/ Raad et al. (2002) 249/ Meletiadis et al. (2003) n.d. n.d. Kawazu et al. (2003) 1 1 n.d. n.d. Spiess et al. (2003) 11/20 32 n.d. n.d.

32 Kami M et al. Clin Infect Dis 2001;33: Comparison of Methods for Detection of Pulmonary Aspergillosis 122 patients 323 samples 33 proven cases CT positive PCR antigen chest X-ray ß-glucan culture histology

33 Febrile neutropenische Patienten mit Lungeninfiltraten: Welche Patienten benötigen keine antimykotische Therapie? Keine invasive Pilzinfektion in der Vorgeschichte Keine verdächtigen klinischen Befunde (Haut, Oro-/ Nasopharynx, Lunge) Thorax-Röntgenaufnahme und HR-CT negativ oder typisch für andere Infektion Wegweisender mikrobiologischer Befund in BAL z. B. P. jiroveci, Legionella spp., Bakterien mit Resistenz gegen laufende Antibiotika, Mycobakterien, CMV (Evtl: PCR/Galactomannan negativ)

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