Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2015;16(Suppl 1):e6379 doi: 10.5867/medwave.2016.6379
Is the addition of aminoglycosides to beta-lactams in cancer patients with febrile neutropenia needed?
Valeria Contreras, Sebastián Sepúlveda, Ana Heredia
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Abstract

It is still controversial if the combined use of beta-lactam antibiotics and aminoglycosides has advantages over broad-spectrum beta-lactam monotherapy for the empirical treatment of cancer patients with febrile neutropenia. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified three systematic reviews including 14 pertinent randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded the combination of beta-lactam antibiotics and aminoglycosides increases nephrotoxicity and it might increase mortality in febrile neutropenic cancer patients.


 
Problem

Patients with cancer have predisposition to infections that increase morbidity and mortality. Many factors contribute to this risk, including neutropenia and the anatomic barrier disruption due to the underlying disease or its treatment. This has led to the use of empirical antibiotics when infection is suspected in patients with fever, before isolating the pathogen or determining its sensitivity.

The combination of beta-lactams and aminoglycosides has been one of the most widely used treatment options. It aims to increase antimicrobial spectrum, and a synergistic effect has been proposed too, preventing the appearance of intra-treatment resistance. Currently, there are alternatives for beta-lactam monotherapy with wide coverage over gram positive and negative bacteria, which can be used to replace combinations.  Furthermore, the addition of aminoglycosides increases adverse effects risk, mainly renal toxicity.

Methods

We used Epistemonikos database, which is maintained by screening more than 30 databases, to identify systematic reviews and their included primary studies. With this information, we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

  • The addition of aminoglycosides to beta-lactams in cancer patients with febrile neutropenia reduces treatment failure but increases nephrotoxicity and it might increase mortality.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found three systematic reviews [1],[2],[3], including 14 randomized controlled trials reported in 17 references [4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14]
[15],[16],[17],[18],[19],[20].

What types of patients were included

Eleven studies [6],[7],[10],[11],[14],[15],[16],[17],[18]
[19],[20] included adult population only and three studies [4],[8],[9] included adults and children.

Six studies [6],[7],[8],[9],[14],[18] included patients with hematologic malignancy, one study [10] included patients with solid tumors and six studies [4],[11],[15],[17],[19],[20], included both. In three studies [4],[8],[14] patients with bone marrow transplantation were included.

Most of the studies considered patients with moderate neutropenia (<1000 leukocytes/mm3) and five studies [4],[6],[8],[9],[11] included patients with severe neutropenia.

What types of interventions were included

All included studies compared combination therapy (beta-lactam plus aminoglycosides) versus monotherapy with the same beta-lactam. All studies used a beta-lactam with antipseudomonic activity (piperaciline-tazobactam, cefepime, ceftazidime, cefoperazone and imipenem) and 12 of 14 studies [4],[6],[7],[10],[11],[14],[15],[16],[17],
[18],[19],[20], used amikacine as aminoglycoside.

What types of outcomes
were measured

The main outcomes were overall mortality, mortality related to infection, treatment failure and nephrotoxicity.

We found three systematic reviews [5], [6], [7], including 14 studies   reported in 21 references [8], [9], [10], [11], [12], [13], [14], [15], [16],   [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]. Eight   studies correspond to randomized controlled trials (15 references [9], [10],   [11], [12], [13], [14], [16], [17], [19], [21], [22], [23], [24], [26], [27]).   This table and the summary in general are based on the latter. One study [15]   did not contribute data to any of the outcomes of interest.

Summary of findings

The information about the effects of the association between aminoglycosides and beta-lactams in cancer patients with febrile neutropenia is based on 14 randomized controlled trials that included 2670 patients. Fourteen studies reported treatment failure, ten studies overall mortality [4],[6],[7],[9],[14],[15],[16],[18],[19],[20], seven studies measured mortality related to infection [4],[6],[9],[14],[15],[16],[18],[20] and eight studies reported nephrotoxicity [6],[7],[10],[11],[14],[17],[18],[19].

  • The addition of aminoglycosides to beta-lactams in cancer patients with febrile neutropenia reduces treatment failure. The certainty of the evidence is high.
  • The addition of aminoglycosides to beta-lactams in cancer patients with febrile neutropenia increases nephrotoxicity. The certainty of the evidence is high.
  • The addition of aminoglycosides to beta-lactams in cancer patients with febrile neutropenia probably increases mortality, compared to monotherapy with the same beta- lactam. The certainty of the evidence is low. 


Other considerations for decision-making

To whom this evidence does and does not apply

  • The evidence presented applies to adult population with cancer and febrile neutropenia secondary to chemotherapy or bone marrow transplantation. Most studies included severe febrile neutropenic inpatients.
About the outcomes included in this summary
  • Critical for decision-making outcomes included in this summary were selected according to the opinion of the authors.
Balance between benefits and risks, and certainty of the evidence
  • Treatment failure and nephrotoxicity are outcomes that could change mortality, being the latter the most critical outcomes for decision-making. The addition of aminoglycosides would increase it, but the certainty of the evidence is low.
Resource considerations
  • It is a low cost intervention for patients and health systems. However, adverse effects could increase the costs. It is not possible to make a proper balance without better certainty about the effects on mortality.

Differences between this summary and other sources

  • The conclusions of this summary are consistent with the systematic reviews identified.
  • This summary partially agrees with the guideline of the Infectious Disease Society of America [21], which recommends use of combined therapy in cases of hemodynamic instability, gram-negative bacteria confirmed in blood culture and in patients that received antibiotics in the last 90 days.
Could this evidence change in the future?
  • The probability that new studies change the conclusions about the effects of combined therapy on mortality in patients with febrile neutropenia is high because of the low certainty of the evidence.
  • We did not find ongoing trials that could properly answer the clinical question of this summary.

How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Beta‐lactam versus the same beta‐lactam plus aminoglycoside for febrile neutropenic cancer patients

 

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

We concluded the combination of beta-lactam antibiotics and aminoglycosides probably does not lead to a reduced mortality in febrile neutropenic cancer patients and it might increase nephrotoxicity.

We concluded the combination of beta-lactam antibiotics and aminoglycosides increases nephrotoxicity and it might increase mortality in febrile neutropenic cancer patients.

Authors: Valeria Contreras[1,2], Sebastián Sepúlveda[1,2], Ana Heredia[2,3]

Affiliation:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Servicio de Medicina Interna, Complejo Asistencial “Doctor Sótero del Río”, Santiago, Chile

E-mail: amherediac@gmail.com

Author address:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63
Santiago Centro
Chile

Citation: Contreras V, Sepúlveda S, Heredia A. Is the addition of aminoglycosides to beta-lactams in cancer patients with febrile neutropenia needed?. Medwave 2015;16(Suppl 1):e6379 doi: 10.5867/medwave.2016.6379

Publication date: 24/2/2016

PubMed record

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  1. Furno P, Bucaneve G, Del Favero A. Monotherapy or aminoglycoside-containing combinations for empirical antibiotic treatment of febrile neutropenic patients: a meta-analysis. Lancet Infect Dis. 2002 Apr;2(4):231-42. | PubMed |
  2. Paul M, Dickstein Y, Schlesinger A, Grozinsky-Glasberg S, Soares-Weiser K, Leibovici L. Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane Database Syst Rev. 2013 Jun 29;6:CD003038. | CrossRef | PubMed |
  3. Paul M, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ. 2003 May 24;326(7399):1111. | PubMed |
  4. Del Favero A, Menichetti F, Martino P, Bucaneve G, Micozzi A, Gentile G, et al. A multicenter, double-blind, placebo-controlled trial comparing piperacillin-tazobactam with and without amikacin as empiric therapy for febrile neutropenia. Clin Infect Dis. 2001 Oct 15;33(8):1295-301. | PubMed |
  5. Del Favero A, Menichetti F, Micozzi A, Bucaneve G, Martino P. Double-blind, randomized clinical trial comparing monotherapy with piperacillin-tazobactam vs. piperacillin-tazobactam plus amikacin as empiric therapy for febrile neutropenic cancer patients. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA; 1999: 722. | Link |
  6. Doyen C, Tepatondele JM, Wauters G, Michaux JL. A randomized therapeutic trial for ceftazidime versus ceftazidime and amikacin in febrile granulopenic patients. International Congress of Chemotherapy (13th : 1983: Vienna: Spitzy KH); 1983: 26-9. | Link |
  7. Esteve J, Nomdedeu B, Mensa J, Guardia R, Marco F, Montserrat E. Piperacillin/tazobactam vs. piperacillin/tazobactam plus amikacin as empiric therapy for fever in neutropenic patients. Blood. 1997;90(Suppl 1):229b. | Link |
  8. Kiehl MG, Bischoff M, Basara N, Guenzelmann S, Fauser A. A prospective randomized trial comparing the efficacy and safety of piperacillin/tazobactam versus piperacillin/tazobactam plus netilmicin in the treatment of febrile neutropenia in allogeneic stem cell recipients. Abstracts Of The Interscience Conference On Antimicrobial Agents & Chemotherapy. 2001 2001(41):267. | Link |
  9. Kinsey SE, Machin SJ, Goldstone AH. Ceftazidime monotherapy is as effective as ceftazidime combined with gentamicin in the treatment of febrile neutropenic patients. J Hosp Infect. 1990 Apr;15 Suppl A:49-53. | PubMed |
  10. Kojima A, Shinkai T, Soejima Y, Okamoto H, Eguchi K, Sasaki Y, et al. A randomized prospective study of imipenem-cilastatin with or without amikacin as an empirical antibiotic treatment for febrile neutropenic patients. Am J Clin Oncol. 1994 Oct;17(5):400-4. | PubMed |
  11. Marie JP, Pico J, Lapierre V, Maulard C, Pappo M, Chiche D, et al. Comparative trial of ceftazidime alone, ceftazidime + amikacin and ceftazidime + vancomycin as empiric therapy of febrile cancer patients with induced prolonged neutropenia. Médecine et Maladies Infectieuses. 1991 7;21(7):386-8.
  12. Marie JP, Vekhoff A, Pico JL, Guy H, Andremont A, Richet H. Neutropenic infections: a review of the French Febrile Aplasia Study Group trials in 608 febrile neutropenic patients. J Antimicrob Chemother. 1998 Jun;41 Suppl D:57-64. | PubMed |
  13. Micozzi A, Bucaneve G, Menichetti F, Martino P, Del Favero A, Program GI. Double blind, randomized, clinical trial comparing monotherapy with piperacillin-tazobactam versus piperacillin-tazobactam plus amikacin as empiric therapy for febrile neutropenic cancer patients. Supportive care in cancer. 2000;8 (Suppl:160). | Link |
  14. Nováková IR, Donnelly JP, de Pauw BE. Ceftazidime with or without amikacin for the empiric treatment of localized infections in febrile, granulocytopenic patients. Ann Hematol. 1991 Oct;63(4):195-200. | PubMed |
  15. Papachristodoulou A, Vaslamatzis M, Xynogalos S, Papacharalambous A, Alexopoulos CG. Ceftazidime (CFZ) monotherapy as empirical initial treatment of febrile neutropenia cancer patients (Pts). Ann of Oncol. 1996;7(suppl 5):146. | CrossRef |
  16. Piccart M, Klastersky J, Meunier F, Lagast H, Van Laethem Y, Weerts D. Single-drug versus combination empirical therapy for gram-negative bacillary infections in febrile cancer patients with and without granulocytopenia. Antimicrob Agents Chemother. 1984 Dec;26(6):870-5. | PubMed |
  17. Rolston KV, Berkey P, Bodey GP, Anaissie EJ, Khardori NM, Joshi JH, et al. A comparison of imipenem to ceftazidime with or without amikacin as empiric therapy in febrile neutropenic patients. Arch Intern Med. 1992 Feb;152(2):283-91. | PubMed |
  18. Tamura K, Imajo K, Akiyama N, Suzuki K, Urabe A, Ohyashiki K, et al. Randomized trial of cefepime monotherapy or cefepime in combination with amikacin as empirical therapy for febrile neutropenia. Clin Infect Dis. 2004 Jul 15;39 Suppl 1:S15-24. | PubMed |
  19. Tamura K, Matsuoka H, Tsukada J, Masuda M, Ikeda S, Matsuishi E, et al. Cefepime or carbapenem treatment for febrile neutropenia as a single agent is as effective as a combination of 4th-generation cephalosporin + aminoglycosides: comparative study. Am J Hematol. 2002 Dec;71(4):248-55. | PubMed |
  20. Wrzesień-Kuś A, Jamroziak K, Wierzbowska A, Robak T. Cefepime in monotherapy or in combination with amikacine as the empirical treatment of febrile neutropenic patients. Acta Haematologica Polonica. 2001;32(2):165-72. | Link |
  21. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. 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. 2011 Feb 15;52(4):427-31. | CrossRef | PubMed |
Furno P, Bucaneve G, Del Favero A. Monotherapy or aminoglycoside-containing combinations for empirical antibiotic treatment of febrile neutropenic patients: a meta-analysis. Lancet Infect Dis. 2002 Apr;2(4):231-42. | PubMed |

Paul M, Dickstein Y, Schlesinger A, Grozinsky-Glasberg S, Soares-Weiser K, Leibovici L. Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane Database Syst Rev. 2013 Jun 29;6:CD003038. | CrossRef | PubMed |

Paul M, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ. 2003 May 24;326(7399):1111. | PubMed |

Del Favero A, Menichetti F, Martino P, Bucaneve G, Micozzi A, Gentile G, et al. A multicenter, double-blind, placebo-controlled trial comparing piperacillin-tazobactam with and without amikacin as empiric therapy for febrile neutropenia. Clin Infect Dis. 2001 Oct 15;33(8):1295-301. | PubMed |

Del Favero A, Menichetti F, Micozzi A, Bucaneve G, Martino P. Double-blind, randomized clinical trial comparing monotherapy with piperacillin-tazobactam vs. piperacillin-tazobactam plus amikacin as empiric therapy for febrile neutropenic cancer patients. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA; 1999: 722. | Link |

Doyen C, Tepatondele JM, Wauters G, Michaux JL. A randomized therapeutic trial for ceftazidime versus ceftazidime and amikacin in febrile granulopenic patients. International Congress of Chemotherapy (13th : 1983: Vienna: Spitzy KH); 1983: 26-9. | Link |

Esteve J, Nomdedeu B, Mensa J, Guardia R, Marco F, Montserrat E. Piperacillin/tazobactam vs. piperacillin/tazobactam plus amikacin as empiric therapy for fever in neutropenic patients. Blood. 1997;90(Suppl 1):229b. | Link |

Kiehl MG, Bischoff M, Basara N, Guenzelmann S, Fauser A. A prospective randomized trial comparing the efficacy and safety of piperacillin/tazobactam versus piperacillin/tazobactam plus netilmicin in the treatment of febrile neutropenia in allogeneic stem cell recipients. Abstracts Of The Interscience Conference On Antimicrobial Agents & Chemotherapy. 2001 2001(41):267. | Link |

Kinsey SE, Machin SJ, Goldstone AH. Ceftazidime monotherapy is as effective as ceftazidime combined with gentamicin in the treatment of febrile neutropenic patients. J Hosp Infect. 1990 Apr;15 Suppl A:49-53. | PubMed |

Kojima A, Shinkai T, Soejima Y, Okamoto H, Eguchi K, Sasaki Y, et al. A randomized prospective study of imipenem-cilastatin with or without amikacin as an empirical antibiotic treatment for febrile neutropenic patients. Am J Clin Oncol. 1994 Oct;17(5):400-4. | PubMed |

Marie JP, Pico J, Lapierre V, Maulard C, Pappo M, Chiche D, et al. Comparative trial of ceftazidime alone, ceftazidime + amikacin and ceftazidime + vancomycin as empiric therapy of febrile cancer patients with induced prolonged neutropenia. Médecine et Maladies Infectieuses. 1991 7;21(7):386-8.

Marie JP, Vekhoff A, Pico JL, Guy H, Andremont A, Richet H. Neutropenic infections: a review of the French Febrile Aplasia Study Group trials in 608 febrile neutropenic patients. J Antimicrob Chemother. 1998 Jun;41 Suppl D:57-64. | PubMed |

Micozzi A, Bucaneve G, Menichetti F, Martino P, Del Favero A, Program GI. Double blind, randomized, clinical trial comparing monotherapy with piperacillin-tazobactam versus piperacillin-tazobactam plus amikacin as empiric therapy for febrile neutropenic cancer patients. Supportive care in cancer. 2000;8 (Suppl:160). | Link |

Nováková IR, Donnelly JP, de Pauw BE. Ceftazidime with or without amikacin for the empiric treatment of localized infections in febrile, granulocytopenic patients. Ann Hematol. 1991 Oct;63(4):195-200. | PubMed |

Papachristodoulou A, Vaslamatzis M, Xynogalos S, Papacharalambous A, Alexopoulos CG. Ceftazidime (CFZ) monotherapy as empirical initial treatment of febrile neutropenia cancer patients (Pts). Ann of Oncol. 1996;7(suppl 5):146. | CrossRef |

Piccart M, Klastersky J, Meunier F, Lagast H, Van Laethem Y, Weerts D. Single-drug versus combination empirical therapy for gram-negative bacillary infections in febrile cancer patients with and without granulocytopenia. Antimicrob Agents Chemother. 1984 Dec;26(6):870-5. | PubMed |

Rolston KV, Berkey P, Bodey GP, Anaissie EJ, Khardori NM, Joshi JH, et al. A comparison of imipenem to ceftazidime with or without amikacin as empiric therapy in febrile neutropenic patients. Arch Intern Med. 1992 Feb;152(2):283-91. | PubMed |

Tamura K, Imajo K, Akiyama N, Suzuki K, Urabe A, Ohyashiki K, et al. Randomized trial of cefepime monotherapy or cefepime in combination with amikacin as empirical therapy for febrile neutropenia. Clin Infect Dis. 2004 Jul 15;39 Suppl 1:S15-24. | PubMed |

Tamura K, Matsuoka H, Tsukada J, Masuda M, Ikeda S, Matsuishi E, et al. Cefepime or carbapenem treatment for febrile neutropenia as a single agent is as effective as a combination of 4th-generation cephalosporin + aminoglycosides: comparative study. Am J Hematol. 2002 Dec;71(4):248-55. | PubMed |

Wrzesień-Kuś A, Jamroziak K, Wierzbowska A, Robak T. Cefepime in monotherapy or in combination with amikacine as the empirical treatment of febrile neutropenic patients. Acta Haematologica Polonica. 2001;32(2):165-72. | Link |

Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. 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. 2011 Feb 15;52(4):427-31. | CrossRef | PubMed |