LA NEUTROPENIA FEBBRILE

1. LA NEUTROPENIA FEBBRILE Anna Marina Liberati Istituto di Medicina Interna e Scienze Oncologiche Policlinico Monteluce Perugia

2. ORIGINE DELLE INFEZIONI NEL PAZIENTE ONCOEMATOLOGICO

3. LE INFEZIONI NEL PAZIENTE ONCOEMATOLOGICO

4. FATTORI PREDISPONENTI ALLE INFEZIONI NEL PAZIENTE NEOPLASTICO

5. PREDOMINANT PATHOGENS IN COMPROMISED PATIENTS: ASSOCIATION WITH SELECTED DEFECTS IN HOST DEFENCE(Rubin M et al. in Hematology: basic principles. Churchill Livingstone)

11. BATTERIEMIE STUDI GIMEMA I, II, IV, VI

12. Andamento nel tempo delle batteriemie monomicrobiche negli studi dell�IATCG-EORTC

18. TERAPIA ANTIBIOTICA EMPIRICA : RAGIONI ACCETTABILI

19. TERAPIA ANTIBIOTICA EMPIRICA: CARATTERISTICHE 1. Ampio spettro, diretto contro tutti i potenziali patogeni batterici (conoscere l�epidemiologia locale e dell�ospite) 2. Elevati livelli di batteriocidia 3. Efficacia nei neutropenici 4. Scarsa tossicit� 5. Basso potenziale di emergenza di resistenze 6. Livelli plasmatici monitorabili 7 Basso costo

20. TERAPIA Orale: Amoxicillina/Ac. Clavulanico+Ciprofloxacin MONOTERAPIA e.v. : Ceftazidime, Imipenem, Meropenem, Cefepime, Piperacillina-Tazobactam TERAPIA ANTIBIOTICA EMPIRICA:POSSIBILI OPZIONI

23. TERAPIA COMBINATA e.v.: Beta-lattamico antipseudomonas/ carbapenemico + Aminoglicoside MONOTERAPIA e.v. : Ceftazidime, Imipenem, Meropenem, Cefepime, Piperacillina-Tazobactam +/- GLICOPEPTIDE (Vancomicina, Teicoplanina) TERAPIA ANTIBIOTICA EMPIRICA:POSSIBILI OPZIONI PERIL PAZIENTE NEUTROPENICO�ALTO RISCHIO�

28. Studi clinici randomizzati (17) Metaanalisi Paul et al JAC 2005; 55:436-444 Vardakas Lancet Infect Dis 2005; 5:431-439 �linee guida� L�uso dei glicopeptidi nel paziente neutropenico

29. L�uso dei glicopeptidi nel paziente neutropenico: STUDI CLINICI RANDOMIZZATI

33. INCLUSION OF A GLYCOPEPTIDE IN THE INITIAL EMPIRICAL THERAPY REGIMEN(CDC, 1995) Clinically suspected serious catheter related infections (e.g. bacteremia, cellulitis) Known colonization with penicillin-resistant S. aureus Positive results of blood culture for gram-positive bacteria before final identification and susceptibility testing Hypotension or other evidence of cardiovascular impairment

34. INCLUSION OF A GLYCOPEPTIDE IN THE INITIAL EMPIRICAL THERAPY REGIMEN(IDSA, 2002) Development of hypotension or shock Known colonisation with MRSA or Penic. Resistant Pneumococcus Positive results for G+ before identification Clinically supected serious Catheter related infection (e.g cellulitis, bacteremia) (Institutions with high rate of infections due to MRSA or Penic. Resistant Strept.)

37. ADDITION OF A GLYCOPEPTIDE IN PERSISTENTLY FEBRILE NEUTROPENIC PATIENTS (IDSA, 2002) Development of hypotension or shock Documented infections due to Gram + resistant to broad-spectrum antibiotics Clinically documented infections potentially due to Gram + resistant bacteria (e.g Catheter related infection or cellulitis)

40. Quali sono i vantaggi ed il razionale dell�associazione beta-lattamico + aminoglicoside ?

44. Paul M, Soares-Weiser K, Grozinsky S, Leibovici L

45. Primary outcome measure: all cause mortality No significant difference between monotherapy and combination (also in six subgroups): RR 0.85 Secondary outcome measure: treatment failure no difference in 9 trials comparing the same betalactam RR 1.12 advantage to monotherapy in 37 trials comparing different betalactams (mainly for patients with documented infection or with hemat. malignancy) RR 0.86 advantage to combination treatment in patients with severe neutropenia RR 1.49 All cause mortality- death at follow-up for the infectious episode; up to 30 days. Treatment failure: composite end-point with one or more of following: death, modification, persistance, worsening or reccurence of clinicla signs/symptoms of infection. Average mortality rate was 6.2 % with decline correlating with the year of study. 6 planned subgroups are: underlying hem. Malignancies, episodes of severe neutropenia, episodes of documented infections, episodes of bacteremia, episides of documented gram-negative infections, episodes of Pseudomonas spp. infections. The trend observed for all subgroups was similar � RR not significantly favouring monotherapy Advantage for combo group in severe neutropenic patients � only 2 studies included in comparisonAll cause mortality- death at follow-up for the infectious episode; up to 30 days. Treatment failure: composite end-point with one or more of following: death, modification, persistance, worsening or reccurence of clinicla signs/symptoms of infection. Average mortality rate was 6.2 % with decline correlating with the year of study. 6 planned subgroups are: underlying hem. Malignancies, episodes of severe neutropenia, episodes of documented infections, episodes of bacteremia, episides of documented gram-negative infections, episodes of Pseudomonas spp. infections. The trend observed for all subgroups was similar � RR not significantly favouring monotherapy Advantage for combo group in severe neutropenic patients � only 2 studies included in comparison

47. E� obbligatoriamente necessario usare un aminoglicoside nel trattamento di prima linea del paziente neutropenico febbrile ?

48. Quale � la migliore modalit� di somministrazione degli aminoglicosidi nei pazienti neutropenici (monosomministrazione o dosi multiple) ?

49. Quando utilizzare un beta-lattamico anti-pseudomonas ?

53. Profilassi con chinoloni in pazienti ad �alto rischio�, non dati conclusivi sui pazienti a �basso rischio� (terapia precoce o profilassi ?) Terapia orale possibile nei pazienti a �basso rischio� Glicopeptidi da usare in seconda linea quando documentata o forte sospetto di infezione da gram+ MR. Aminoglicoside possibilmente utile in alcune circostanze (shock, infezione documentata da Pseudomonas); utilizzare la dose singola giornaliera. Monoterapia con betalattamici antipseudomonas possibile nei pazienti ad �alto rischio� CONCLUSIONI

54. CHEMIOPROFILASSI E INFEZIONI DA GRAM-POSITIVI

55. Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. Kern WV, Cometta A, De Bock R, Langenaeken J, Paesmans M, Gaya H International Antimicrobial Therapy Cooperative Group of the EORTC New England Journal of Medicine, 1999; 341 (5): 305-311. 312 episodi febbrili : Terapia orale (Ciprofloxacin + Amocicillina/Ac. Clavulanico) Terapia e.v. (Ceftriaxone + Amikacina) RISPOSTA : Terapia Orale , 86% di successi; Terapia e.v., 84% di successi. Nessun paziente deceduto in entrambe i gruppi di trattamento. Buona tollerabilit� di entrambe i regimi. �.....CONCLUSIONS: In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy.....�

56. A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. Freifeld A, Marchigiani D, Walsh T, Chanock S, Lewis L, Hiemenz J, Hiemenz S, Hicks JE, Gill V, Steinberg SM, Pizzo PA National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. New England Journal of Medicine, 1999; 341 (5): 305-311. 116 episodi febbrili : Terapia orale (Ciprofloxacin oral e+ Amoxicillina/Ac. Clavulanico); Terapia e.v. (Ceftazidime). RISPOSTA : Terapia Orale , 71% di successi; Terapia e.v., 67% di successi. Nessun paziente deceduto in entrambe i gruppi di trattamento. Tollerabilit� peggiore (16% vs. 8%) per lo schema orale. � .... CONCLUSIONS: In hospitalized low-risk patients who have fever and neutropenia during cancer chemotherapy, empirical therapy with oral ciprofloxacin and amoxicillin-clavulanate is safe and effective...�

58. SINGLE AGENT GRAM-POSITIVE BACTEREMIAS. GIMEMA TRIALS I, II, IV, VI

62. Neutropenia moderata (>500/cmm) Neutropenia di breve durata (< 7 days) No comorbidit� (ipotensione, alterazione dello stato di coscienza, insuff. respiratoria , insuff. renale-epatica, disidratazione etc.) Neoplasia controllata (tumori solidi, linfomi) CARATTERISTICHE DEI PAZIENTI NEUTROPENICI A BASSO RISCHIO Patients with mild neutropenia of short duration, generally represented by those with solid tumours and lymphomas, are considered to be at lower risk of infection. Febrile neutropenia may have a better prognosis in these patients if they lack adjunctive risk factors. Monotherapy can be used to treat this group of patients, depending on local epidemiology. The most commonly used therapeutic options are third-generation cephalosporins, and the carbapenems or fluoroquinolones. Several alternatives to hospital-based therapy have been evaluated in such patients. These include early discharge to home antibiotic therapy after initial stabilization in the hospital, or treatment of the entire febrile episode with intravenous and/or oral antibiotics in the ambulatory setting or at home.Patients with mild neutropenia of short duration, generally represented by those with solid tumours and lymphomas, are considered to be at lower risk of infection. Febrile neutropenia may have a better prognosis in these patients if they lack adjunctive risk factors. Monotherapy can be used to treat this group of patients, depending on local epidemiology. The most commonly used therapeutic options are third-generation cephalosporins, and the carbapenems or fluoroquinolones. Several alternatives to hospital-based therapy have been evaluated in such patients. These include early discharge to home antibiotic therapy after initial stabilization in the hospital, or treatment of the entire febrile episode with intravenous and/or oral antibiotics in the ambulatory setting or at home.

63. CARATTERISTICHE DEI PAZIENTI NEUTROPENICI AD ALTO RISCHIO Neutropenia profonda (< 500/cmm) Neutropenia prolugata (> 7 days) Precedenti ospedalizzazioni Neoplasia non controllata (LA, TMO) Comorbidit� (ipotensione, alterazione dello stato di coscienza, insuff. respiratoria , insuff. renale-epatica, disidratazione etc.) Mucosite Profound and persistent neutropenia is the hallmark for patients in the high-risk group. Other factors have also been identified as predictive of poor outcome including history of hospitalization, active underliyng disease, and presence of other comorbidity conditions. Patients with acute leukemia or those undergoing allogeneic bone marrow transplantation represent high-risk neutropenic patients. For these patients combination antibiotic therapy is usually recommended. Profound and persistent neutropenia is the hallmark for patients in the high-risk group. Other factors have also been identified as predictive of poor outcome including history of hospitalization, active underliyng disease, and presence of other comorbidity conditions. Patients with acute leukemia or those undergoing allogeneic bone marrow transplantation represent high-risk neutropenic patients. For these patients combination antibiotic therapy is usually recommended.

71. PREVENZIONE

72. PREVENZIONE DELLE INFEZIONI NEL PAZIENTE ONCOEMATOLOGICO (Strategie) RAFFORZARE LE DIFESE DELL�OSPITE - mandare in remissione la malattia di base - granulociti - nutrizione EVITARE LA ROTTURA DELLE BARRIERE - procedure invasive - �care� dei cateteri RIDURRE ACQUISIZIONE DI NUOVI PATOGENI - lavaggio accurato delle mani - carica microbica cibo - ambiente protetto SOPPRIMERE I MICROORGANISMI COLONIZZANTI - decontaminazione Totale - decontaminazione Selettiva

73. PROFILASSI ANTIBATTERICA:Presupposti 80% dei patogeni responsabili delle infezioni � di origine endogena Le infezioni sono causate in prevalenza da microorganismi colonizzanti il tratto intestinale l�invasione del torrente circolatorio avviene attraverso le mucose danneggiate dalla chemioterapia

74. CHEMIOPROFILASSI ANTIBIOTICA NEL PAZIENTE ONCOEMATOLOGICO DECONTAMINAZIONE TOTALE CON ANTIBIOTICI NON ASSORBIBILI - scarso o nullo assorbimento sistemico - azione locale - sterilizzazione totale DECONTAMINAZIONE SELETTIVA - assorbimento sistemico - azione locale e sistemica - risparmio della flora anaerobia intestinale

75. Selective decontamination of the digestive tract: general principles.  Van der Waaij D  Eur J Cancer Clin Oncol 1988;24 Suppl 1:S1-4  RESISTENZA ALLA COLONIZZAZIONE - Capacit� da parte della flora microbica intestinale di prevenire la sovracrescita e/o colonizzazione intestinale da parte di germi potenzialmente patogeni - Tale capacit� risiede nella componente anaerobica della flora intestinale

76. DECONTAMINAZIONE SELETTIVA COTRIMOXAZOLO FLUOROCHINOLONI Norfloxacin Ciprofloxacin Ofloxacin Enoxacin

77. FLUOROCHINOLONI ampio spettro antibatterico (in particolare gram -) buon assorbimento elevata concentrazione fecale elevata attivita� battericida sistemica risparmio della flora anaerobia intestinale non frequente comparsa di ceppi resistenti (?) buona tollerabilit� basso costo

90. Martino R et al Effect of discontinuing prophylaxis with norfloxacin in patients with hematologic malignancies and severe neutropenia. A matched case-control study of the effect on infectious morbidity.Acta Haematol 1998;99(4):206-11  PROPHYLAXIS NO PROPHYLAXIS p (NORFLOXACIN) Coag.Neg. Staph. Bacteremias 11 / 91 5 / 91 ns Enterobacterial Bacteremias 2 / 91 13 / 91 0.01 Escherichia coli Bacteremias 1 / 91 9 / 91 0.01 Enterobacterial susceptible to quinolones 0 / 2 12 / 13 0.07 �....The selection of resistent flora in an inpatient ward by prophylactic quinolones may be reversible following the discontinuation of the prophylactic agent.�

91. WHO to treat ? Adult patient receiving intensive chemotherapy for a Acute leukemia Adult recipients of stem cell transplant after myeloablative therapy Unit with a low background level resistant gram-negatives

92. DURATION OF PROPHYLAXIS Start at the start of chemotherapy (AII) * Stop at the start of empirical antibacterial therapy (AII) or until the resolution of neutropenia (AII) * Because it has been reported that prophylactic administration of Ciprofloxacin during Cyclophosphamide conditioning was a risk factor for relapse in patients undergoing allogeneic bone marrow transplant and, more recently, that ciprofloxacin administration prior to Cyclophosphamide has resulted in significantly lower exposure to the active metabolite 4- hydroxy-cyclophosphamide in patients with non-hodgkin lymphoma, antibacterial prophylaxis with fluoroquinolones must be started 24-48 hours after the end of administration of high dose Cyclophosphamide (AIII).

93. WHICH COMPOUNDS ? Ciprofloxacin (500 mg/twice daily) orally (AI) or Levofloxacin (500 mg/once daily) orally (AI)

94. �Caveat� (1) Periodic monitoring for any marked increase in (AIII): Use of empirical antibacterial therapy Fluoroquinolone resistance among gram-negative Mortality

95. �Caveat� (2) If antibacterial prophylaxis is adopted, the empiric antibacterial regimen for a febrile episode must cover (AIII) as possible causative pathogen : Pseudomonas spp. or quinolone-resistant strains. in case of a failure of the �first line� therapy also a MR gram-positive organism must be considered.