Advertisement

Annals of Hematology

, Volume 98, Issue 5, pp 1209–1216 | Cite as

Doripenem versus meropenem as first-line empiric therapy of febrile neutropenia in patients with acute leukemia: a prospective, randomized study

  • Tatsuo OyakeEmail author
  • Yuka Takemasa-Fujisawa
  • Norifumi Sugawara
  • Takahiro Mine
  • Yasuhiko Tsukushi
  • Ichiro Hanamura
  • Yukiteru Fujishima
  • Yusei Aoki
  • Shugo Kowata
  • Shigeki Ito
  • Yoji Ishida
Original Article
  • 109 Downloads

Abstract

Febrile neutropenia is often observed in patients with hematologic malignancies, especially in those with acute leukemia. Meropenem has potent and broad antibacterial activity against gram-positive and gram-negative bacteria, and is recommended as first-line empiric therapy for febrile neutropenia. In contrast, the safety and efficacy of doripenem in patients with febrile neutropenia and hematologic malignancies is limited. In this randomized, prospective, cooperative, open-label trial, we compared doripenem (1.0 g every 8 h) to meropenem (1.0 g every 8 h) as first-line empiric antibacterial treatment of febrile neutropenia. To evaluate efficacy and safety, 133 hospitalized patients with acute leukemia or high-risk myelodysplastic syndrome, who developed febrile neutropenia during or after chemotherapy, were randomized to each drug. Resolution of fever within 3 to 5 days without treatment modification (i.e., the primary endpoint) did not significantly differ between the doripenem and meropenem groups (60.0% vs. 45.6%, respectively; P = 0.136). However, resolution of fever within 7 days of treatment was significantly higher in the doripenem group than in the meropenem group (78.4% vs. 60.2%, respectively; P = 0.037). Similar rates of adverse events (grades 1–2) were observed in both groups. Thus, we conclude that both drugs are safe and well-tolerated for the treatment of febrile neutropenia in patients with acute leukemia or high-risk myelodysplastic syndrome, and that the clinical efficacy of doripenem is noninferior to that of meropenem. UMIN Clinical Trial Registry number: 000006124

Keywords

Doripenem Meropenem Febrile neutropenia Acute leukemia High-risk myelodysplastic syndrome 

Notes

Acknowledgments

The authors would like to thank all institutions and staff members that contributed to this study.

Author contributions

YI was the principal investigator and takes primary responsibility for the paper. TO and YI designed the study. YF, NS, TM, YT, IH, and YA recruited the patients. TO, YTF, and SK reviewed and analyzed the data collected from each institute. YA and SI participated in statistical analysis. TO and YI wrote the paper.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all participants included in the study.

References

  1. 1.
    Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JAH, Wingard JR (2011) Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 52(4):e56–e93CrossRefGoogle Scholar
  2. 2.
    Oguz A, Karadeniz C, Citak EC, Cil V, Eldes N (2006) Experience with cefepime versus meropenem as empiric monotherapy for neutropenia and fever in pediatric patients with solid tumors. Pediatr Hematol Oncol 23(3):245–253CrossRefGoogle Scholar
  3. 3.
    Kutluk T, Kurne O, Akyüz C, Ceyhan M, Kanra G, Büyukpamukçu M, Seçmeer G (2004) Cefepime vs. meropenem as empirical therapy for neutropenic fever in children with lymphoma and solid tumours. Pediatr Blood Cancer 42(3):284–286CrossRefGoogle Scholar
  4. 4.
    Shah PM, Stille W, Schaumann R, Heller A, Fuhr HG, Jung A, Köhler A, Walther F, Lips-Schulte C (1996) Empirical monotherapy with meropenem versus imipenem/cilastatin for febrile episodes in neutropenic patients. Infection 24(6):480–484CrossRefGoogle Scholar
  5. 5.
    Cometta A, Calandra T, Gaya H, Zinner SH, de Bock R, Del Favero A, Bucaneve G, Crokaert F, Kern WV, Klastersky J, Langenaeken I, Micozzi A, Padmos A, Paesmans M, Viscoli C, Glauser MP (1996) Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Infection Program. Antimicrob Agents Chemother 40(5):1108–1115CrossRefGoogle Scholar
  6. 6.
    The Meropenem Study Group of Leuven, London and Nijmegan (1995) Equivalent efficacies of meropenem and ceftazidime as empirical monotherapy of febrile neutropenic patients. J Antimicrob Chemother 36(1):185–200CrossRefGoogle Scholar
  7. 7.
    Reich G, Cornely OA, Sandherr M, Kubin T, Krause S, Einsele H, Thiel E, Bellaire T, Dörken B, Maschmeyer G (2005) Empirical antimicrobial monotherapy in patients after high-dose chemotherapy and autologous stem cell transplantation: a randomised, multicentre trial. Br J Haematol 130(2):265–270CrossRefGoogle Scholar
  8. 8.
    Paul M, Yahav D, Fraser A, Leibovici L (2006) Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 57(2):176–189CrossRefGoogle Scholar
  9. 9.
    Lucasti C, Jasovich A, Umeh O, Jiang J, Kaniga K, Friedland I (2008) Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicenter, randomized, double-blind, noninferiority study. Clin Ther 30(5):868–883CrossRefGoogle Scholar
  10. 10.
    Akiyama N, Kanamaru A, Tamura K, Tanimoto M, Ohyashiki K, Nakagawa Y, Urabe A, Masaoka T (2012) Efficacy and safety of doripenem for sepsis with neutropenia in Japanese patients with hematologic diseases. Jpn J Antibiot 65(4):251–262Google Scholar
  11. 11.
    Toya T, Nannya Y, Narukawa K, Ichikawa M, Kurokawa M (2012) A comparative analysis of meropenem and doripenem in febrile patients with hematologic malignancies: a single-center retrospective study. Jpn J Infect Dis 65(3):228–232CrossRefGoogle Scholar
  12. 12.
    Masaoka T (1998) Management of fever of unknown origin in the neutropenic patient: the Japanese experience. Int J Hematol 68(Suppl 1):S9–S11Google Scholar
  13. 13.
    Feld R, Paesmans M, Freifeld AG, Klastersky J, Pizzo PA, Rolston KVI, Rubenstein E, Talcott JA, Walsh TJ (2002) Methodology for clinical trials involving patients with cancer who have febrile neutropenia: updated guidelines of the Immunocompromised Host Society/Multinational Association for Supportive Care in Cancer, with emphasis on outpatient studies. Clin Infect Dis 35(12):1463–1468CrossRefGoogle Scholar
  14. 14.
    Imajo K, Ueda Y, Kawano F, Sao H, Kamimura T, Ito Y, Mugitani A, Suzuki K, Uike N, Miyamura K, Uski K, Morimatsu Y, Akiyama N, Nagai H, Ohara A, Tanimoto M, Takaki K, Chayama K, Urabe M, Nagatoshi Y, Tamura K (2012) A phase III study of the efficacy and safety of meropenem in patients with febrile neutropenia. Jpn J Infect Dis 65(4):271–287Google Scholar
  15. 15.
    [Finibax] (2011) Clinical phase 3 study of high dosage [CTD, common technical document]. Pharmaceuticals and Medical Devices Agency, Japan http://www.pmda.go.jp/drugs/2011/P201100084/34001800_21700AMZ00695_K100_1.pdf. Published in Japanese. Accessed 24 January 2019Google Scholar
  16. 16.
    de la Camara R, Figuera A, Sureda A, Hermida G, Verge G, Olalla I, Ranada JMF, Albos AD (1997) Meropenem versus ceftazidime plus amikacin in the treatment of febrile episodes in neutropenic patients: a randomized study. Haematologica 82(6):668–675Google Scholar
  17. 17.
    Feld R, DePauw B, Berman S, Keating A, Ho W (2000) Meropenem versus ceftazidime in the treatment of cancer patients with febrile neutropenia: a randomized, double-blind trial. J Clin Oncol 18(21):3690–3698CrossRefGoogle Scholar
  18. 18.
    Montassier E, Batard E, Gastinne T, Potel G, de La Cochetière MF (2013) Recent changes in bacteremia in patients with cancer: a systematic review of epidemiology and antibiotic resistance. Eur J Clin Microbiol 32(7):841–850CrossRefGoogle Scholar
  19. 19.
    Chong Y, Yakushiji H, Ito Y, Kamimura T (2011) Clinical impact of fluoroquinolone prophylaxis in neutropenic patients with hematological malignancies. Int J Infect Dis 15(4):e277–e281CrossRefGoogle Scholar
  20. 20.
    Paul M, Borok S, Fraser A, Vidal L, Leibovici L (2005) Empirical antibiotics against gram-positive infections for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 55(4):436–444CrossRefGoogle Scholar
  21. 21.
    Zhanel GG, Wiebe R, Dilay L, Thomson K, Rubinstein E, Hoban DJ, Noreddin AM, Karlowsky JA (2007) Comparative review of the carbapenems. Drugs 67(7):1027–1052CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Tatsuo Oyake
    • 1
    Email author
  • Yuka Takemasa-Fujisawa
    • 1
  • Norifumi Sugawara
    • 2
  • Takahiro Mine
    • 3
  • Yasuhiko Tsukushi
    • 4
  • Ichiro Hanamura
    • 5
  • Yukiteru Fujishima
    • 1
  • Yusei Aoki
    • 1
  • Shugo Kowata
    • 1
  • Shigeki Ito
    • 6
  • Yoji Ishida
    • 1
  1. 1.Division of Hematology and Oncology, Department of Internal MedicineIwate Medical University School of MedicineMorioka CityJapan
  2. 2.Division of Hematology, Department of Internal MedicineIwate Prefectural Chubu HospitalKitakamiJapan
  3. 3.Division of Hematology, Department of Internal MedicineMorioka Red Cross HospitalMoriokaJapan
  4. 4.Division of Hematology, Department of Internal MedicineHachinohe Red Cross HospitalHachinoheJapan
  5. 5.Division of Hematology, Department of Internal MedicineAichi Medical University School of MedicineNagoyaJapan
  6. 6.Department of Clinical OncologyIwate Medical University School of MedicineMoriokaJapan

Personalised recommendations