Japan Adult Leukemia Study Group 5 6 7 8 9 5 6 7 8 9 5 8 6 5 9 9 Japan Adult Leukemia Study GroupJALSG JALSG 96 5 6 polymixin B8 fluconazoleflcz amphotericin BAMPH B 6 Febrile neutropenia Empiric therapyet cephem carbapenem 5 5 Vancomycin ET 5 FLCZ66 AMPH B8 FLCZ 59 AMPH B57 AMPH B.5.7 mgkg mgkg life threatening infection 75 Key words: febrile neutropeniaempiric therapy Febrile neutropeniafn Japan Adult Leukemia Study Group JALSG 987 JALSG JALSG 76 JALSG FN I FN empiric therapyet Granulocyte colony stimulating factorg CSF 5 acute myelogenous leukemia AML JALSG 7.5. 8
II 96 5 6 high efficiency particulate air filter 6 Table Polymixin B8 fluconazoleflcz amphotericin BAMPH BAMPH B 66 6 Empiric therapy 7 57.5 88 6 FN ET Table ET 796 Table Antibacterial and antifungal prophylaxis Antibacterial Polymixin B ST 6 New quinolones 8 Combination Others 6 None 6 Antifungal AMPH B 6 mgday AMPH B mgday FLCZ mgday 9 FLCZ mgday ITCZ mgday Others None n5 ST: sulfamethoxazole trimethoprim, AMPH B: amphotericin B, FLCZ: fluconazole, ITCZ: itraconazole Table Empiric antibiotic therapy Antibiotic Cephem Carbapenem CephemAG 9 CarbapenemAG Antipseudomonal penicillin Antipseudomonal penicillinag CephemAntipseudomonal penicillin CephemAntipseudomonal penicillinag VCMCephem VCMCarbapenem VCMCephemAG VCMCarbapenemAG Others n5 AG: aminoglycoside, VCM: vancomycin Table ET cephem carbapenem monotherapy 5 cefepimecfpm 7panipenem betamipronpapm BP ceftazidimecaz7meropenemmepm9 Duotherapy 5 cephem carbapenem CAZ 6cefpirome cefozopran PAPMBP CFPM MEPM 9 VancomycinVCM st line nd line 6 MRSA 5MRSA high risk st line 9 ET ET Candida albicans Table ET FLCZ 66 FLCZ 59 AMPH B57 AMPH B.5.7 mgkg mgkg AMPH B 8 7
Table Second line therapy in cases refractory to initial empiric therapy after 7 96 h Modification of antibiotic andor antifungal Addition of or change to cephem, aminoglycoside, or carbapenem Continuation with first line ET, adding VCM Change from first line ET to second line antibiotics, adding VCM Continuation with first line ET, adding antifungals Change from first line ET to second line antibiotics, adding antifungals Continuation with first line ET, adding VCM and antifungals Change from first line ET to second line antibiotics, adding VCM and antifungals Others 7 5 5 n5 ET: empiric antibiotic therapy, VCM: vancomycin Table Antifungal therapy for deep fungal infection Antifungal agent Empiric therapy Candidemia Candidemia stable disease unstable disease Invasive pulmonary aspergillosis AMPH B 5 mgkg div AMPH B 7 mgkg div AMPH B mgkg div AMPH B 5 mgkg div FLCZ mg div FLCZ mg div ITCZ mg po MCZ, mg div AMPH B 7 mgkg divflcz mg div AMPH B 7 mgkg div5 FC mgkg po AMPH B 7 mgkg divitcz mg po AMPH B 7 mgkg divmcz, mg div AMPH B mgkg div5 FC mgkg po AMPH B mgkg divitcz mg po Others 8 8 7 5 6 8 6 n5 :Agentnot indicated in the question AMPH B: amphotericin B, FLCZ: fluconazole, ITCZ: itraconazole, MCZ: miconazole, 5 FC: flucytosine PCR 97 9 5 CSF G CSF AML acute lymphoblastic leukemiaall AML AML ALL ALL Table 5 AML life threatening infection 7ALL 5MacrophageM CSF 8 79 65 6 JALSG 7FN ET ET 7 G CSF 5 5 III 77 5
Table 5Use of G CSF Situation of patient AML remission induction AML consolidation ALL remission induction ALL consolidation Prophylactic if neutropenicafebrile FN FN if refractory to ET Clinically documented infection a Microbiologically documented infection b Life threatening infection Not used Variable Others 5 7 6 8 9 7 7 5 5 5 8 n5 a Pneumonia, perianal abscess, etc., b Sepsis, pneumonia, etc G CSF: granulocyte colony stimulating factor, AML: acute myelogenous leukemia, ALL: acute lymphoblastic leukemia, FN: febrile neutropenia, ET: empiric antibiotic therapy 6 8 polymixin B 6 7 AMPH B FLCZ itraconazole FLCZ 8 9 AMPH B AMPH B JALSG Empiric therapy ET 7.5 8 ET cephemag monotherapy duotherapy 55 VCM MRSA ET ET 5 FLCZVCM ET monotherapy duotherapy Monotherapy cephemag carbapenem 55 7 duotherapy 5 ET FLCZ66 AMPH B8 FLCZ AMPH B ET AMPH B ET FLCZ 7 FLCZ ET AMPH B FLCZ FLCZ 59 AMPH B 57 7 FLCZ AMPH B AMPH B mgkg 5
5. CSF AML G CSF life threatning infection 7AML G CSF 6 FN G CSF ET 79 JALSG AML ALL 5 6. JALSG ET cephem carbapenem G CSF Table 6 FN 76 5 : : : : : : : : : : : : : : : : : : : : : NTT : : : Table 6 Problems in infection management in leukemic patients Problems Antibacterial prophylaxis Antifungal prophylaxis Empric antibiotic therapy Empiric antifungal therapy Drug Timingfebrile days after empiric antibiotics Targeted therapy of proven fungal infection Candidiasis Aspergilosis Diagnostic tests for fungal infection Use of G CSF Comparative study required New quinolone vs polymixin B vs placebo FLCZ vs AMPH B vs ITCZ vs placebo Monotherapy vs duotherapy AMPH B vs FLCZ vs new drugmcfg, etc. After days vs after 7 days AMPH B vs FLCZ vs new drugmcfg, etc. AMPH B vs New drugmcfg, etc. β glucan, galactomannan, fungal DNA Afebrile neutropeniaprophylaxisfebrile neutropenia, refractory empiric antibiotics, clinicallymicrobiologically documented infection, life threatening infection G CSF: granulocyte colony stimulating factor, FLCZ: fluconazole, AMPH B: amphotericin B, ITCZ: itraconazole, MCFG: micafungin
: : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : NTT : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : NTT : : : : : : : : : : : : : De Pauw B EMeunier F: Infections in patients with acute leukemia and lymphoma. Mandell G L et aledsprinciples and practice of infectious diseases 5 th ednp.9churchill Livingstone Inc., New York Yoshida MTsubaki KKobayashi Tet al.: Infectious complications during remission induction therapy in 577 patients with acute myeloid leukemia in the Japan Adult Leukemia Study Group studies between 987 and 99. Int J Hematol 7: 667999 Hughes W TArmstrong DBodey G Pet al.: guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis : 775 Ozer HArmitage J OBennett C Let al.: update of recommendations for the use of hematopoietic colony stimulating factors: evidence basedclinical practice guidelines. J Clin Oncol 8: 558585 5 Murphy M ESepkowitz K AArmstrong D: Prevention of infection in patients with hematologic malignancy. Wiernik P Het aledsneoplastic Diseases of the Bloodp. 75Churchill Livingstone Inc., New York996 6 Pizzo P A: Empiric therapy and prevention of infection in the immunocompromised host. Mandell GLet aledsprinciples and practice of infectious diseases 5 th ednp. Churchill Livingstone Inc., New York 7 Cruciani MRampazzo RMalena Met al.: Prophylaxis with Fluoroquinolones for bacterial infections in neutropenic patients: a meta analysis. Clin Infect Dis : 79585996
8 Goodman J LWinston D JGreenfield Aet al.: A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantations. N Engl J Med 6: 8585 99 9 Kanda YYamamoto RChizuka Aet al.: Prophylactic action of oral fluconazole against fungal infection in neutropenic patients. A meta analysis of 6 randomizedcontrolled trials. Cancer 89: 665 Urabe ATakaku FMizoguchi Het al.: Prophylactic and therapeutic effects of oral administration of amphotericin B in mycosis associated with hematological diseases. Jpn J Antibiotics : 699 Pizzo P AHathorn J WHiemenz Jet al.: A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. N Engl J Med 5: 55 558986 Tamura KMatsuoka HTsukada Jet al.: Cefepime or carbapenem treatment for febrile neutrpopenia as asingleagent is as effective as a combination of th generation cephalosporin aminoglycoside : comparative study. Am J Hematol 7: 855 Viscoli CCastagnola EVanLint M Tet al.: Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic multicentreprospective and randomized clinical trial. Eur J Cancer A: 88996 Rex J HWalsh T JSobel J Det al.: Practice guidelines for the treatment of candidiasis. Infectious diseases society of America. Clin Infect Dis : 66678 5 Stevens D AKan V LJudson M Aet al.: Practice guidelines for diseases caused by Aspergillus. Infectious diseases society of America. Clin Infect Dis : 69679 6 Lowenberg BTouw I T: Hematopoietic growth factors and their receptors in acute leukemia. Blood 8: 8999 7 Maher D WLieschke G JGreen Met al.: Filgrastim in patients with chemotherapy induced febrile neutropenia: a double blindplacebo controlled trial. Ann Intern Med : 95 99 8 Mitchell P LMorland BStevens M Cet al.: Granulocyte colony stimulating factor in established febrile neutropenia: a randomized study of pediatric patients. J Clin Oncol 5: 67 997 9 Yoshida MKarasawa MNaruse Tet al.: Effect of granulocyte colony stimulating factor on empiric therapy with flomoxef sodium and tobramycin in febrile neutropenic patients with hematological malignancies. Int J Hematol 69: 888999 Masaoka T: Evidence based recommendations on antimicrobial use in febrile neutropenia in Japan. Int J Hematol 68suppl : 998
Management of infectious complications in patients with acute leukemia during chemotherapy Aquestionnaire analysis by the Japan Adult Leukemia Study Group Minoru Yoshida Nobu Akiyama Masatomo Takahashi Hirokuni Taguchi Jin Takeuchi 5 Kensuke Naito 6 Yoshiko Hodohara 7 Takafumi Matsushima 8 and Mitsuhiro Matsuda 9 Fourth Department of Internal MedicineTeikyo University School of Medicine 8 MizonokuchiTakatsu kukawasakikanagawajapan Department of HematologyMetropolitan Bokutoh Hospital Department of HematologyOncologySt. Marianna University School of Medicine Third Department of Internal MedicineKochi Medical School 5 First Department of Internal MedicineNihon University School of Medicine 6 Third Department of Internal MedicineHamamatsu University School of Medicine 7 Second Department of Internal MedicineShiga University School of Medicine 8 Third Department of Internal MedicineGunma University School of Medicine 9 Third Department of Internal MedicineKinki University School of Medicine A fact finding questionnaire on the management of infectious complications in patients with acute leukemiadeveloped by the Supportive Care Committee of the Japan Adult Leukemia Study Group JALSGwas distributed to 96 steering committees throughout Japan in autumn with responses by 56New quinolones were used by 8 of respondents and polymixin B by for antibacterial prophylaxisamphotericin BAMPH Bby and fluconazoleflczby for fungal prophylaxis. No prophylaxis was given by 6 for bacterial infection or by for fungal infection. Monotherapy with either cephem or carbapenem was used by 5 for empiric therapy of febrile neutropenia. Overall frequency of use of duotherapy with cephemcarbapenemor antipseudomonal penicillin plus aminoglycoside was 5Vancomycin was used by only as part of initial empiric therapy. Antifungal treatment was added by 5 after days of ineffective empiric therapy; FLCZ66was preferred over AMPH B8in such a scenario. FLCZ was selected by 59 in cases of stable diseaseand AMPH B by 57 in cases of unstable disease as therapy for Candidemia. AMPH B was selected as therapy for invasive Aspergillosisbut a dose of.5.7 mgkginadequate for this diseasewas used by Most of the respondents used G CSF in cases of life threatening infection among patients with acute myelogenous leukemia7but prophylactic use of G CSF was common5among patients with acute lymphocytic leukemia. This data should prove helpful in developing guidelines for the management of febrile neutropenia in Japan.