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Meta-Analysis
. 2013 Jun 29;2013(6):CD003038.
doi: 10.1002/14651858.CD003038.pub2.

Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropenia

Mical Paul  1 , Yaakov Dickstein, Agata Schlesinger, Simona Grozinsky-Glasberg, Karla Soares-Weiser, Leonard Leibovici
Affiliations
Meta-Analysis

Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropenia

Mical Paul et al. Cochrane Database Syst Rev. .

Abstract

Background: Continued controversy surrounds the optimal empirical treatment for febrile neutropenia. New broad-spectrum beta-lactams have been introduced as single treatment, and classically, a combination of a beta-lactam with an aminoglycoside has been used.

Objectives: To compare beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy for cancer patients with fever and neutropenia.

Search methods: The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 7, 2012), LILACS (August 2012), MEDLINE and EMBASE (August 2012) and the Database of Abstracts of Reviews of Effects (DARE) (Issue 3, 2012). We scanned references of all included studies and pertinent reviews and contacted the first author of each included trial, as well as the pharmaceutical companies.

Selection criteria: Randomised controlled trials (RCTs) comparing any beta-lactam antibiotic monotherapy with any combination of a beta-lactam and an aminoglycoside antibiotic, for the initial empirical treatment of febrile neutropenic cancer patients. All cause mortality was the primary outcome assessed.

Data collection and analysis: Data concerning all cause mortality, infection related mortality, treatment failure (including treatment modifications), super-infections, adverse effects and study quality measures were extracted independently by two review authors. Risk ratios (RRs) with their 95% confidence intervals (CIs) were estimated. Outcomes were extracted by intention-to-treat (ITT) analysis whenever possible. Individual domains of risk of bias were examined through sensitivity analyses. Published data were complemented by correspondence with authors.

Main results: Seventy-one trials published between 1983 and 2012 were included. All cause mortality was lower with monotherapy (RR 0.87, 95% CI 0.75 to 1.02, without statistical significance). Results were similar for trials comparing the same beta-lactam in both trial arms (11 trials, 1718 episodes; RR 0.74, 95% CI 0.53 to 1.06) and for trials comparing different beta-lactams－usually a broad-spectrum beta-lactam compared with a narrower-spectrum beta-lactam combined with an aminoglycoside (33 trials, 5468 episodes; RR 0.91, 95% CI 0.77 to 1.09). Infection related mortality was significantly lower with monotherapy (RR 0.80, 95% CI 0.64 to 0.99). Treatment failure was significantly more frequent with monotherapy in trials comparing the same beta-lactam (16 trials, 2833 episodes; RR 1.11, 95% CI 1.02 to 1.20), and was significantly more frequent with combination therapy in trials comparing different beta-lactams (55 trials, 7736 episodes; RR 0.92, 95% CI 0.88 to 0.97). Bacterial super-infections occurred with equal frequency, and fungal super-infections were more common with combination therapy. Adverse events were more frequent with combination therapy (numbers needed to harm 4; 95% CI 4 to 5). Specifically, the difference with regard to nephrotoxicity was highly significant. Adequate trial methods were associated with a larger effect estimate for mortality and smaller effect estimates for failure. Nearly all trials were open-label. No correlation was noted between mortality and failure rates and these trials.

Authors' conclusions: Beta-lactam monotherapy is advantageous compared with beta-lactam-aminoglycoside combination therapy with regard to survival, adverse events and fungal super-infections. Treatment failure should not be regarded as the primary outcome in open-label trials, as it reflects mainly treatment modifications.

PubMed Disclaimer

Conflict of interest statement

None known.

Figures

1
1
All cause mortality.
2
2
Failure‐same BL.
3
3
Failure‐different BL.
1.1
1.1. Analysis
Comparison 1 Overall effectiveness, Outcome 1 All cause mortality.
1.2
1.2. Analysis
Comparison 1 Overall effectiveness, Outcome 2 Infection‐related mortality.
1.3
1.3. Analysis
Comparison 1 Overall effectiveness, Outcome 3 Treatment failure.
2.1
2.1. Analysis
Comparison 2 Superinfections, Outcome 1 Bacterial superinfections.
2.2
2.2. Analysis
Comparison 2 Superinfections, Outcome 2 Fungal superinfections.
3.1
3.1. Analysis
Comparison 3 Adverse events, Outcome 1 Any adverse event (monotherapy).
3.2
3.2. Analysis
Comparison 3 Adverse events, Outcome 2 Discontinuation due to adverse event.
3.3
3.3. Analysis
Comparison 3 Adverse events, Outcome 3 Any nephrotoxicity ‐ Ag dosing regimen.
3.4
3.4. Analysis
Comparison 3 Adverse events, Outcome 4 Severe nephrotoxicity ‐ Ag dosing regimen.
4.1
4.1. Analysis
Comparison 4 Documented infections (subgroup analysis), Outcome 1 All cause mortality.
4.2
4.2. Analysis
Comparison 4 Documented infections (subgroup analysis), Outcome 2 Treatment failure.
5.1
5.1. Analysis
Comparison 5 Bacteraemia (subgroup analysis), Outcome 1 All cause mortality.
5.2
5.2. Analysis
Comparison 5 Bacteraemia (subgroup analysis), Outcome 2 Treatment failure.
6.1
6.1. Analysis
Comparison 6 Gram‐negative infections (subgroup analysis), Outcome 1 All cause mortality.
6.2
6.2. Analysis
Comparison 6 Gram‐negative infections (subgroup analysis), Outcome 2 Treatment failure.
7.1
7.1. Analysis
Comparison 7 Pseudomonas infections (subgroup analysis), Outcome 1 All cause mortality.
7.2
7.2. Analysis
Comparison 7 Pseudomonas infections (subgroup analysis), Outcome 2 Treatment failure.
8.1
8.1. Analysis
Comparison 8 Haematological cancer patients (subgroup analysis), Outcome 1 All cause mortality.
8.2
8.2. Analysis
Comparison 8 Haematological cancer patients (subgroup analysis), Outcome 2 Treatment failure.
9.1
9.1. Analysis
Comparison 9 Severe neutropenia (subgroup analysis), Outcome 1 All cause mortality.
9.2
9.2. Analysis
Comparison 9 Severe neutropenia (subgroup analysis), Outcome 2 Treatment failure.
10.1
10.1. Analysis
Comparison 10 Monotherapy, Outcome 1 All cause mortality.
10.2
10.2. Analysis
Comparison 10 Monotherapy, Outcome 2 Treatment failure.
11.1
11.1. Analysis
Comparison 11 Adults vs. children, Outcome 1 All cause mortality.
11.2
11.2. Analysis
Comparison 11 Adults vs. children, Outcome 2 Treatment failure.
12.1
12.1. Analysis
Comparison 12 Sensitivity analysis (outcome in parenthesis), Outcome 1 Allocation concealment (mortality).
12.2
12.2. Analysis
Comparison 12 Sensitivity analysis (outcome in parenthesis), Outcome 2 Intention‐to‐treat vs. efficacy analysis (mortality).
12.3
12.3. Analysis
Comparison 12 Sensitivity analysis (outcome in parenthesis), Outcome 3 Unit of randomisation (mortality).
12.4
12.4. Analysis
Comparison 12 Sensitivity analysis (outcome in parenthesis), Outcome 4 Publication status (mortality).
12.5
12.5. Analysis
Comparison 12 Sensitivity analysis (outcome in parenthesis), Outcome 5 Trial size (mortality).
12.6
12.6. Analysis
Comparison 12 Sensitivity analysis (outcome in parenthesis), Outcome 6 Allocation concealment (failure).
12.7
12.7. Analysis
Comparison 12 Sensitivity analysis (outcome in parenthesis), Outcome 7 Intention to treat vs. efficacy analysis (failure).
12.8
12.8. Analysis
Comparison 12 Sensitivity analysis (outcome in parenthesis), Outcome 8 Intention to treat vs. efficacy analysis, assuming dropouts=failures (failure).
12.9
12.9. Analysis
Comparison 12 Sensitivity analysis (outcome in parenthesis), Outcome 9 Trial size (failure).
12.10
12.10. Analysis
Comparison 12 Sensitivity analysis (outcome in parenthesis), Outcome 10 Unit of randomisation (failure).
12.11
12.11. Analysis
Comparison 12 Sensitivity analysis (outcome in parenthesis), Outcome 11 Blinding (failure).
12.12
12.12. Analysis
Comparison 12 Sensitivity analysis (outcome in parenthesis), Outcome 12 Publication status (failure).
See this image and copyright information in PMC

Update of

References

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Novakova 1990 {published data only}
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Novakova 1991 {published data only}
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Ozyilkan 1999 {published and unpublished data}
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Papachristodoulou 96 {published data only}
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Pegram 1984 {published data only}
    1. Pegram SP, Muss HB, McGall CE, Cooper RM, White DR, Richards F, et al. A comparative study of moxalactam vs. ticarcillin and tobramycin in febrile, neutropenic cancer patients. Proceedings of the Annual Meetings of the American Society of Clinical Oncology; Abstract No. 255. 1982.
    1. Pegram SP, Muss HB, McGall CE, Cooper RM, White DR, Richards T, et al. A comparative study of moxalactam vs. ticarcillin and tobramycin in febrile, neutropenic cancer patients. Proceedings of the Annual Meetings of the American Society of Clinical Oncology; Abstract No. 391. 1984.
Pellegrin 1988 {published data only}
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Pereira 2009 {published data only (unpublished sought but not used)}
    1. Pereira CAP, Petrilli AS, Carlesse FA, Luisi FAV, Silva KVTB, Lee MLM. Cefepime monotherapy is as effective as ceftriaxone plus amikacin in pediatric patients with cancer and high‐risk febrile neutropenia in a randomized comparison. Journal of Microbiology, Immunology and Infection 2009;42(2):141‐7. - PubMed
Perez 1995 {published data only}
    1. Perez C, Sirham M, Labarca J, Grebe G, Lira P, Oliva J, et al. [Imipenem/cilastatin versus ceftazidime‐amikacin in the treatment of febrile neutropenic patients] [Imipenem/cilastatina versus ceftazidima‐amikacina para el tratmiento de pacientes neutropenicos febriles]. Revista Medica de Chile 1995;123(3):312‐20. - PubMed
Petrilli 2003 {published and unpublished data}
    1. Petrilli AS, Cypriano M, Dantas LS, Lee LM, Vercillo Luisi MF, Torres B, et al. Evaluation of ticarcillin/clavulanic acid versus ceftriaxone plus amikacin for fever and neutropenia in pediatric patients with leukemia and lymphoma.. Brazilian Journal of Infectious Diseases 2003;7(2):111‐20. - PubMed
Piccart 1984 {published data only}
    1. Piccart M, Klastersky J, Meunier F, Lagast H, Laethem Y, Weerts D. Single‐drug versus combination empirical therapy for gram‐negative bacillary infections in febrile cancer patients with and without granulocytopenia. Antimicrobial Agents and Chemotherapy 1984;26(6):870‐5. - PMC - PubMed
Pickard 1983 {published and unpublished data}
    1. Pickard W, Durack D, Gallis H. A randomized trial of empiric therapy with moxalactam versus tobramycin plus ticarcillin in febrile, neutropenic patients. Current Choices in Antibiotic Therapy for Febrile Episodes in Neutropenic Patients. 1983.
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    1. Pickard W, Gallis HA, Durack DT. A randomized trial of empiric therapy with moxalactam versus tobramycin plus ticarcillin in febrile neutropenic patients. Proceedings of the Second International Symposium in Infections in the Immunocompromised Host. 1982.
Piguet 1988 {published data only}
    1. Piguet H, Pappo M. First‐line treatment of febrile episodes in leukemia in adults: randomized, multicenter study of ceftazidime in single antibiotic therapy versus a cefotaxime‐amikacin combination [Traitment de premiere intention des episodes febriles des leucemies de l'adulte. Etude randomisee, multicentrique de la ceftazidime en monoantibiotherapie versus l'association cefotaxime‐amikacine]. Presse Med 1988;17(37):1954‐9. - PubMed
Rodjer 1987 {published data only}
    1. Rodjer S, Alestig K, Bergmark J, Bergstrom T, Hultberg B, Jagenburg R, et al. Treatment of septicaemia in immunocompromised patients with ceftazidime or with tobramycin and cefuroxime, with special reference to renal effects. Journal of Antimicrobial Chemotherapy 1987;20(1):109‐16. - PubMed
Rodriguez 1995 {published data only}
    1. Rodriguez W, Gomez H, Silva ME, Vallejos C, Valdivia S, Casanova L, et al. Cefotaxime vs cephalotin‐gentamicin in the first febrile episode of patients having solid tumors and short‐term neutropenia. Acta Cancer 1995;25:61‐8.
Rolston 1992 {published data only}
    1. 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. Archives of Internal Medicine 1992;152(2):283‐91. - PubMed
Schuchter 1988 {published data only}
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Smith 1990 {published and unpublished data}
    1. Smith L, Will AM, Williams RF, Stevens RF. Ceftriaxone vs. azlocillin and netilmicin in the treatment of febrile neutropenic children. The Journal of Infection 1990;20(3):201‐6. - PubMed
Tamura 2002 {published and unpublished data}
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Tamura 2004 {published and unpublished data}
    1. 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. Clinical Infectious Diseases 2004;39:S15‐24. - PubMed
Wade 1987 {published data only}
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    1. Wade JC, Delin A, Finely R, Drusano G, Thompson B. Imipenem versus piperacillin plus amikacin, empiric therapy for febrile neutropenic patients: a double blind trial. Proceedings of the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1987:Abstract No. 1251.
Wrzesien‐Kus 2001 {published and unpublished data}
    1. Wrzesien‐Kus 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.
Yamamura 1997 {published and unpublished data}
    1. Ramphal R, Gucalp R, Rotstein C, Cimino M, Oblon D. Clinical experience with single agent and combination regimens in the management of infection in the febrile neutropenic patient. American Journal of Medicine 1996;100(6a):83s‐9s. - PubMed
    1. Yamamura D, Gucalp R, Carlisle P, Cimino M, Roberts J, Rotstein C. Open randomized study of cefepime versus piperacillin‐gentamicin for treatment of febrile neutropenic cancer patients. Antimicrobial Agents and Chemotherapy 1997;41(8):1704‐8. - PMC - PubMed
Yildirim 2008 {published data only (unpublished sought but not used)}
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Zengin 2011 {published and unpublished data}
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References to studies excluded from this review

Berezin 2003 {published data only}
    1. Berezin EN, Almeida FJ, Santos AG, Arnoni M, Safadi M, Peixoto F, et al. Asessment of cefepime monotherapy versus combined therapy with ceftriaxone and aminoglycoside in oncologic children and adolescents with febrile neutropenia. Proceedings of the 13th European Congress of Clinical Microbiology and Infectious Diseases. 2003:UK. Poster 836. [MEDLINE: ]
Bodey 1976 {published data only}
    1. Bodey GP, Feld R, Burgess MA. Beta‐lactam antibiotics alone or in combination with gentamicin for therapy of gram‐negative bacillary infections in neutropenic patients. American Journal of Medicine 1976;271(2):179‐86. - PubMed
Bru 1986 {published data only}
    1. Bru JP, Michallet M, Legrand C, Swierz P, Stahl JP, Leautet JB, et al. A prospective randomized study comparing the efficacy of timentin alone or in combination with amikacin in the treatment of febrile neutropenic patients. Journal of Antimicrobial Chemotherapy 1986;17:Suppl C:203‐9. - PubMed
Cetto 1983 {published data only}
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D'Antonio 1992 {published data only}
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Drusano 1985 {published data only}
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Hauer 1990 {published data only}
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Hazel 1998 {published data only}
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Hoepelman 1988 {published data only}
    1. Hoepelman IM, Rozenberg‐Arska M, Verhoef J. Comparative study of ceftriaxone monotherapy versus a combination regimen of cefuroxime plus gentamicin for treatment of serious bacterial infections: the efficacy, safety and effect on fecal flora. Chemotherapy 1988;34:Suppl 1:21‐9. - PubMed
    1. Hoepelman IM, Rozenberg‐Arska M, Verhoef J. Comparison of once daily ceftriaxone with gentamicin plus cefuroxime for treatment of serious bacterial infections. Lancet 1988;1(8598):1305‐9. - PubMed
Karthaus 1998 {published data only}
    1. Karthaus M, Wolf H, Egerer G, Kampfe D, Suedhoff T, Ritter J, et al. Ceftriaxone in the treatment of solid tumour patients with febrile neutropenia. Onkologie 1998;21:212‐6.
Moreno‐Sanchez 1992 {published data only}
    1. Moreno‐Sanchez FGR, Lazaro RM, Tellez E, Torres E. Monotherapy in patients with neutropenic fever. Proceedings of the American Society for Clinical Oncology. 1992:Abstract No. 1364.
Moroni 1987 {published data only}
    1. Moroni C, Viscoli C, Boni L, Garaventa A, Dini G, Haupt R, et al. A randomized study of the empirical antibiotic therapy of the infections in neutropenic patients, affected by neoplastic diseases in paediatric age and under a fever attack. Giornale di Malattie Infettive e Parassitarie (Journal of Infectious and Parasitic Dieases) 1987;39:1194‐8.
Pegram 1989 {published data only}
    1. Pegram PS, Phair JP, McMahan R, Murphy RL, Gordon LI, Washton H, et al. Prospective comparative trial of short course (four day) and continuous tobramycin in combination with cefoperazone or mezlocillin in febrile, granulocytopenic patients. Journal of Antimicrobial Chemotherapy 1989;24(4):591‐604. - PubMed
Petrilli 1991 {published data only}
    1. Petrilli AS, Melarango R, Bianchi A, Kussano E, Barros KVT, Silva AAM. Fever and neutropenia in children: a new therapeutic proposal. Revista da Associação Médica Brasileira 1991;37(4):173‐80. - PubMed
Pizzo 1986 {published data only}
    1. Pizzo PA, Hathorn JW, Hiemenz J, Browne M, Commers J, Cotton D, et al. A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. New England Journal of Medicine 1986;315:552‐8. - PubMed
Reilly 1983 {published data only}
    1. Reilly JT, Brada M, Bellingham AJ, Hart CA, Bennet C. Ceftazidime compared to tobramycin and ticarcillin in immunocompromised haematological patients. Journal of Antimicrobial Chemotherapy 1983;12:Suppl A:89‐92. - PubMed
Sampi 1987 {published data only}
    1. Sampi K, Kumai R, Maseki N, Sakurai M, Kaneko Y, Hattori M. Cefmenoxime or piperacillin plus amikacin: a prospective randomized comparison of empiric antibiotic therapy of febrile granulocytopenic cancer patients. Gan to Kagaku Ryoho Cancer & Chemotherapy 1987;14:674‐9. - PubMed
Sanz 2005 {published data only}
    1. Sanz MA, Bermudez A, Rovira M, Besalduch J, Pascual MJ, Nocea G, et al. Imipenem/cilastatin versus piperacillin/tazobactam plus amikacin for empirical therapy in febrile neutropenic patients: results of the COSTINE study.. Current Medical Research and Opinion 2005;21(5):645‐55. - PubMed
Sawae 1996 {published data only}
    1. Sawae Y, Niho Y, Okamura T, Gondo H, Kozuru M, Uike N, et al. [Comparison between monotherapy with imipenem/cilastatin sodium (IPM/CS) and combinations of IPM/CS and other drugs for treating bacterial infections in patients with hematopoietic disorders]. [Japanese]. Jpn J Antibiot 1996;49(12):1049‐61. - PubMed
Wrzesien‐Kus 2000 {published data only}
    1. Wrzesien‐Kus AL‐ME, Robak T. Cefepime or ceftazidime in combination with amikacin as the empirical treatment of febrile neutropenic patients. Acta Haematologica Polonica 2000;31(1):79‐85.

References to studies awaiting assessment

Li 1998 {published data only}
    1. Li HC, Zhang M, Ye X. Evidence of treating febrile neutropenia with netilmicin‐ceftazidime. Clinical Assembly 1998;13(23):1057‐8.

References to ongoing studies

Bilgir 2005 {published data only}
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Publication types