Skip to main content
SpringerLink
Log in

Low-dose β-lactam plus amikacin in febrile neutropenia: cefepime vs. piperacillin/tazobactam, a randomized trial

  • Article
  • Published:
European Journal of Clinical Microbiology & Infectious Diseases Aims and scope Submit manuscript

Abstract

Patients with fever and granulocytopenia are at risk of developing severe infection. We performed a prospective, randomized trial to evaluate the efficacy of low-dose cefepime plus amikacin (C-A) compared to low-dose piperacillin/tazobactam plus amikacin (PT-A). Patients received cefepime (2 g/12 h) plus amikacin (15 mg/kg/day) or piperacillin/tazobactam (4 g/500 mg/8 h) plus amikacin. A total of 317 episodes of febrile granulocytopenia in 190 patients were studied (152 in the C-A group, 165 in the PT-A group). A microbiologically documented infection was present in 53 (35%) episodes in the C-A group and 41 (25%) episodes in the PT-A group (p = ns); a clinically documented infection was observed in 39 (26%) and 47 (28%) episodes, respectively. Toxicity was observed in 6 (4%) episodes in the C-A group and in 5 (3%) episodes in the PT-A group. The antibiotic success rate (no change or addition of antibiotics) was recorded in 89 (59%) and 105 (64%) cases, respectively (p = ns). Mortality related to infection was similar in each arm (3.9% vs. 3.6%). Combination therapy of low-dose β-lactam with an aminoglycoside achieves very good response rates and low rates of toxicity. It might be an attractive option in an environment of increasing resistance among gram-negative bacteria.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bodey GP, Buckley M, Sathe YS, Freireich EJ (1966) Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 64:328–340

    CAS  PubMed  Google Scholar 

  2. Wade JC, Schimpff SC, Newman KA, Fortner CL, Standiford HC, Wiernik PH (1981) Piperacillin or ticarcillin plus amikacin. A double-blind prospective comparison of empiric antibiotic therapy for febrile granulocytopenic cancer patients. Am J Med 71:983–990

    Article  CAS  PubMed  Google Scholar 

  3. EORTC (1987) Ceftazidime combined with a short or long course of amikacin for empirical therapy of gram-negative bacteremia in cancer patients with granulocytopenia. N Engl J Med 317:1692–1698

    Google Scholar 

  4. Cordonnier C, Herbrecht R, Pico JL, Gardembas M, Delmer A, Delain M et al (1997) Cefepime/amikacin versus ceftazidime/amikacin as empirical therapy for febrile episodes in neutropenic patients: a comparative study. Clin Infect Dis 24:41–51

    CAS  PubMed  Google Scholar 

  5. Leyland MJ, Bayston KF, Cohen J, Warren R, Newland AC, Bint AJ et al (1992) A comparative study of imipenem versus piperacillin plus gentamicin in the initial management of febrile neutropenic patients with haematological malignancies. J Antimicrob Chemother 30:843–854

    Article  CAS  PubMed  Google Scholar 

  6. Eggimann P, Glauser MP, Aoun M, Meunier F, Calandra T (1993) Cefepime monotherapy for the empirical treatment of fever in granulocytopenic cancer patients. J Antimicrob Chemother 32(Suppl B):151–163

    PubMed  Google Scholar 

  7. Freifeld AG, Walsh T, Marshall D, Gress J, Steinberg SM, Hathorn J et al (1995) Monotherapy for fever and neutropenia in cancer patients: a randomized comparison of ceftazidime versus imipenem. J Clin Oncol 13:165–176

    CAS  PubMed  Google Scholar 

  8. Cometta A, Calandra T, Gaya H, Zinner SH, de Bock R, del Favero A et al (1996) Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. Antimicrob Agents Chemother 40:1108–1115

    CAS  PubMed  Google Scholar 

  9. Biron P, Fuhrmann C, Cure H, Viens P, Lefebvre D, Thyss A et al (1998) Cefepime versus imipenem–cilastatin as empirical monotherapy in 400 febrile patients with short duration neutropenia. J Antimicrob Chemother 42:511–518

    Article  CAS  PubMed  Google Scholar 

  10. Bratu S, Landman D, Alam M, Tolentino E, Quale J (2005) Detection of KPC carbapenem-hydrolyzing enzymes in Enterobacter spp. from Brooklyn, New York. Antimicrob Agents Chemother 49(2):776–778

    Article  CAS  PubMed  Google Scholar 

  11. Woodford N, Tierno PM Jr, Young K, Tysall L, Palepou MF, Ward E et al (2004) Outbreak of Klebsiella pneumoniae producing a new carbapenem-hydrolyzing class A beta-lactamase, KPC-3, in a New York Medical Center. Antimicrob Agents Chemother 48(12):4793–4799

    Article  CAS  PubMed  Google Scholar 

  12. Navon-Venezia S, Chmelnitsky I, Leavitt A, Schwaber MJ, Schwartz D et al (2006) Plasmid-mediated imipenem-hydrolyzing enzyme KPC-2 among multiple carbapenem-resistant Escherichia coli clones in Israel. Antimicrob Agents Chemother 50(9):3098–3101

    Article  CAS  PubMed  Google Scholar 

  13. Bratu S, Landman D, Haag R, Recco R, Eramo A, Alam M et al (2005) Rapid spread of carbapenem-resistant Klebsiella pneumoniae in New York City: a new threat to our antibiotic armamentarium. Arch Intern Med 165(12):1430–1435

    Article  CAS  PubMed  Google Scholar 

  14. Hossain A, Ferraro MJ, Pino RM, Dew RB 3rd, Moland ES, Lockhart TJ et al (2004) Plasmid-mediated carbapenem-hydrolyzing enzyme KPC-2 in an Enterobacter sp. Antimicrob Agents Chemother 48(11):4438–4440

    Article  CAS  PubMed  Google Scholar 

  15. Bratu S, Brooks S, Burney S, Kochar S, Gupta J, Landman D et al (2007) Detection and spread of Escherichia coli possessing the plasmid-borne carbapenemase KPC-2 in Brooklyn, New York. Clin Infect Dis 44(7):972–975

    Article  PubMed  Google Scholar 

  16. Drusano GL, Ambrose PG, Bhavnani SM, Bertino JS, Nafziger AN, Louie A (2007) Back to the future: using aminoglycosides again and how to dose them optimally. Clin Infect Dis 45:753–760

    Article  CAS  PubMed  Google Scholar 

  17. Figuera A, Rivero N, Pajuelo F, Font P, Leyra F, de la Cámara R et al (2001) Comparative study of piperacillin/tazobactam versus imipenem/cilastatin in febrile neutropenia (1994–1996). Med Clin (Barc) 116:610–611

    CAS  Google Scholar 

  18. Sanz MA, López J, Lahuerta JJ, Rovira M, Batlle M, Pérez C et al (2002) Cefepime plus amikacin versus piperacillin–tazobactam plus amikacin for initial antibiotic therapy in haematology patients with febrile neutropenia: results of an open, randomized, multicentre trial. J Antimicrob Chemother 50(1):79–88

    Article  CAS  PubMed  Google Scholar 

  19. Montalar J, Segura A, Bosch C, Galán A, Juan O, Molins C et al (2002) Cefepime monotherapy as an empirical initial treatment of patients with febrile neutropenia. Med Oncol 19(3):161–166

    Article  CAS  PubMed  Google Scholar 

  20. Raad II, Escalante C, Hachem RY, Hanna HA, Husni R, Afif C et al (2003) Treatment of febrile neutropenic patients with cancer who require hospitalization: a prospective randomized study comparing imipenem and cefepime. Cancer 98:1039–1047

    Article  CAS  PubMed  Google Scholar 

  21. Del Favero A, Menichetti F, Martino P, Bucaneve G, Micozzi A, Gentile G et al (2001) A multicenter, double-blind, placebo-controlled trial comparing piperacillin–tazobactam with and without amikacin as empiric therapy for febrile neutropenia. Clin Infect Dis 33:1295–1301

    Article  PubMed  Google Scholar 

  22. Tamura K, Imajo K, Akiyama N, Suzuki K, Urabe A, Ohyashiki K et al (2004) Randomized trial of cefepime monotherapy or cefepime in combination with amikacin as empirical therapy for febrile neutropenia. Clin Infect Dis 39:S15–S24

    Article  CAS  PubMed  Google Scholar 

  23. Schentag JJ, Strenkoski-Nix LC, Nix DE, Forrest A (1998) Pharmacodynamic interactions of antibiotics alone and in combination. Clin Infect Dis 27:40–46

    Article  CAS  PubMed  Google Scholar 

  24. Feld R (1998) Criteria for response in patients in clinical trials of empiric antibiotic regimens for febrile neutropenia. Is there agreement? Support Care Cancer 6:444–448

    Article  CAS  PubMed  Google Scholar 

  25. World Health Organization (1979) WHO handbook for reporting results of cancer treatment. World Health Organization, Geneva, pp 16–21

    Google Scholar 

  26. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T et al (2002) 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 34:730–751

    Article  PubMed  Google Scholar 

  27. Jándula BM, Martino R, Gurgi M, Manteiga R, Sierra J (2001) Treatment of febrile neutropenia with cefepime monotherapy. Chemotherapy 47(3):226–231

    Article  PubMed  Google Scholar 

  28. Cherif H, Björkholm M, Engervall P, Johansson P, Ljungman P, Hast R et al (2004) A prospective, randomized study comparing cefepime and imipenem–cilastatin in the empirical treatment of febrile neutropenia in patients treated for haematological malignancies. Scand J Infect Dis 36:593–600

    Article  CAS  PubMed  Google Scholar 

  29. Cornely OA, Bethe U, Seifert H, Breuer K, Schütt-Gerowitt H, Salzberger B et al (2002) A randomized monocentric trial in febrile neutropenic patients: ceftriaxone and gentamicin vs cefepime and gentamicin. Ann Hematol 81(1):37–43

    Article  CAS  PubMed  Google Scholar 

  30. Bow EJ, Rotstein C, Noskin GA, Laverdière M, Schwarer AP, Segal BH et al (2006) A randomized, open-label, multicenter comparative study of the efficacy and safety of piperacillin–tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies. Clin Infect Dis 43:447–459

    Article  CAS  PubMed  Google Scholar 

  31. Gorschlüter M, Hahn C, Fixson A, Mey U, Ziske C, Molitor E et al (2003) Piperacillin–tazobactam is more effective than ceftriaxone plus gentamicin in febrile neutropenic patients with hematological malignancies: a randomized comparison. Support Care Cancer 11(6):362–370

    PubMed  Google Scholar 

  32. Cappelletty DM (1999) Evaluation of several dosing regimens of cefepime, with various simulations of renal function, against clinical isolates of Pseudomonas aeruginosa in a pharmacodynamic infection model. Antimicrob Agents Chemother 43(1):129–133

    Article  CAS  PubMed  Google Scholar 

  33. 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 57:176–189

    Article  CAS  PubMed  Google Scholar 

  34. Yahav D, Paul M, Fraser A, Sarid N, Leibovici L (2007) Efficacy and safety of cefepime: a systematic review and meta-analysis. Lancet Infect Dis 7(5):338–348

    Article  CAS  PubMed  Google Scholar 

  35. Gomez L, Estrada C, Gomez I, Marquez M, Dalmau D, Estany C et al. Cefepime plus amikacin versus piperacillin–tazobactam plus amikacin in the treatment of patients with fever and granulocytopenia. In: Proceedings of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 16-19 December 2001. Abstract no. L-771

  36. Nguyen TD, Williams B, Trang E (2009) Cefepime therapy and all-cause mortality. Clin Infect Dis 48:902–904

    Article  CAS  Google Scholar 

  37. Cefepime (marketed as Maxipime) Update of Ongoing Safety Review. FDA alert (06/17/2009)

  38. Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R et al (2000) The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 18(16):3038–3051

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Infectious Diseases Unit, Hospital Universitari Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain

    L. Gómez, C. Estrada, I. Gómez, M. Márquez & J. Garau

  2. Service of Hematology, Hospital Universitari Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain

    C. Estany & J. M. Martí

  3. Service of Oncology, Hospital Universitari Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain

    R. Bastús & L. Cirera

  4. Intensive Care Unit, Hospital Universitari Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain

    S. Quintana

Authors
  1. L. Gómez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Estrada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. Gómez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Márquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Estany
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. M. Martí
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Bastús
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. Cirera
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S. Quintana
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J. Garau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. Gómez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gómez, L., Estrada, C., Gómez, I. et al. Low-dose β-lactam plus amikacin in febrile neutropenia: cefepime vs. piperacillin/tazobactam, a randomized trial. Eur J Clin Microbiol Infect Dis 29, 417–427 (2010). https://doi.org/10.1007/s10096-010-0879-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10096-010-0879-1

Keywords

Search

Navigation