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

  1. Mical Paul1,*,
  2. Yaakov Dickstein2,
  3. Agata Schlesinger3,
  4. Simona Grozinsky-Glasberg4,
  5. Karla Soares-Weiser5,
  6. Leonard Leibovici3

Editorial Group: Cochrane Gynaecological Cancer Group

Published Online: 29 JUN 2013

Assessed as up-to-date: 7 JUN 2013

DOI: 10.1002/14651858.CD003038.pub2

How to Cite

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 of Systematic Reviews 2013, Issue 6. Art. No.: CD003038. DOI: 10.1002/14651858.CD003038.pub2.

Author Information

  1. 1

    Rambam Health Care Campus and the Technion-Israel Institute of Technology, Division of Infectious Diseases, Haifa, Israel

  2. 2

    Rambam Health Care Center, Medicine A and Unit of Infectious Diseases, Haifa, Israel

  3. 3

    Beilinson Hospital, Rabin Medical Center, Department of Medicine E, Petah Tikva, Israel

  4. 4

    Dept of Medicine, Hadassah-Hebrew University Medical Center, Neuroendocrine Tumors Unit, Endocrinology & Metabolism Service, Jerusalem, Israel

  5. 5

    Enhance Reviews Ltd, Wantage, UK

*Mical Paul, Division of Infectious Diseases, Rambam Health Care Campus and the Technion-Israel Institute of Technology, 6 Ha'Aliya Street, Haifa, 31096, Israel. paulm@post.tau.ac.il. mica@zahav.net.il; MichalP2@clalit.org.il; paulm@post.tau.ac.il.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 29 JUN 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

 
Summary of findings for the main comparison. beta-lactam monotherapy compared to beta-lactam-aminoglycoside combination therapy for Febrile neutropenic cancer patients

Beta-lactam monotherapy compared with beta-lactam-aminoglycoside combination therapy for febrile neutropenic cancer patients

Patient or population: febrile neutropenic cancer patients.
Settings:
Intervention: beta-lactam monotherapy.
Comparison: beta-lactam-aminoglycoside combination therapy.

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Beta-lactam-aminoglycoside combination therapyBeta-lactam monotherapy

All cause mortalityStudy populationRR 0.87
(0.75 to 1.02)
7186
(44 studies)
⊕⊕⊕⊕
high

83 per 100072 per 1000
(62 to 85)

Moderate

68 per 100059 per 1000
(51 to 69)

Any nephrotoxicity - Ag dosing regimen (Copy)Study populationRR 0.45
(0.35 to 0.57)
6608
(39 studies)
⊕⊕⊕⊕
high

57 per 100026 per 1000
(20 to 33)

Moderate

29 per 100013 per 1000
(10 to 17)

Treatment failure - same beta-lactamStudy populationRR 1.11
(1.02 to 1.2)
2833
(16 studies)
⊕⊕⊕⊝
moderate1

405 per 1000449 per 1000
(413 to 485)

Moderate

398 per 1000442 per 1000
(406 to 478)

Treatment failure - different beta-lactamStudy populationRR 0.92
(0.88 to 0.97)
7736
(55 studies)
⊕⊕⊝⊝
low1,2,3,4

426 per 1000392 per 1000
(375 to 413)

Moderate

432 per 1000397 per 1000
(380 to 419)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Outcome determined mainly by treatment modifications. Poor correlation with all cause mortality, the ultimate target of treating cancer patients.
2 Differences decreased with low risk of bias regarding allocation concealment.
3 Differences in effects between published and unpublished trials.
4 No explanation was provided.&&

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

Cancer patients are prone to infection. Low blood cell count (neutropenia) and disruption of normal barriers to infection, such as skin and mucous membranes, are caused by chemotherapy or underlying malignancy. Both disrupt the normal immune response and predispose patients to infection (Bodey 1966). Pathogens implicated in these infections are Gram-negative bacteria, including Pseudomonas aeruginosa, Gram-positive bacteria and fungi (Chow 1991; Hughes 1997). The considerable morbidity and mortality associated with these infections in neutropenic patients led to the routine use of empirical antibiotic treatment, which is given upon suspicion of infection (e.g. fever), before the causative pathogen/s or their susceptibilities are identified (Hughes 1997; Schimpff 1986).

Initial effective empirical treatment for patients with fever and neutropenia consisted of combinations of antibiotics, including double beta-lactam regimens and, more recently, aminoglycoside-beta-lactam combinations (Hughes 1990; Hughes 1997; Schimpff 1971). In the 1980s, third-generation cephalosporins and carbapenems having bactericidal activity against Enterobacteriaceae, Pseudomonas aeruginosa and many Gram-positive organisms became available, making monotherapy a reasonable alternative to combination therapy. Neither combination therapy nor monotherapy provides full coverage for the spectrum of infections encountered among neutropenic patients. Notably, resistant Gram-positive bacteria and fungi are left untreated. Nevertheless, current guidelines recommend beta-lactam monotherapy in clinically stable patients (Freifeld 2011; Tam 2011).

An evident advantage of combination therapy over monotherapy is the higher probability that the infecting pathogen will be covered by at least one of the components of the regimen. Furthermore, the interaction between two antibiotics may be synergistic, resulting in enhanced bacterial kill activity compared with the additive activities of the antibiotics when assessed separately (Giamarellou 1984; Giamarellou 1986; Klastersky 1976; Klastersky 1982). Finally, use of combination therapy has been claimed to suppress the emergence of resistant subpopulations of bacteria (Allan 1985; Milatovic 1987; Wade 1989). On the other hand, benefits of monotherapy may include a lower probability of adverse effects and narrower-spectrum treatment, possibly reducing the chance of developing a super-infection with resistant bacteria (Weistein 1985). Adverse effects may be related to administration of aminoglycosides per se (e.g. nephrotoxicity) or to interactions between antibiotic and underlying disease and/or other drugs. Neutropaenic participants not responding to the initial antibiotic regimen will be given modified treatment, which usually includes vancomycin to cover resistant Gram-positive bacteria and/or amphotericin-based preparations or azoles to treat fungal infection (Hughes 1997), thus increasing the chance for adverse events and drug interactions.

Although neutropenia itself is the single most important risk factor for infection, other factors can alter the risk. The probability and severity of infection are inversely proportional to the absolute neutrophil count, and patients with neutrophil counts below 100/mm³ are at highest risk for severe infection (Bodey 1966; Schimpff 1986). Underlying malignancy may affect outcome. Patients with acute leukaemia and other haematological malignancies have a worse prognosis than solid tumour patients (Rolston 1992; Rossini 1994; Talcott 1992). The severity and nature of the infection (e.g. bacteraemia, Gram-positive and Pseudomonas aeruginosa infections, resistant organisms) as well as the patient's age may underlie heterogeneity (Elting 1997; Hann 1997; Rolston 1992). More recent guidelines for empirical treatment of febrile neutropenia have emphasized the importance of risk stratification, both for deciding on the setting of therapy (out-patient versus hospitalisation) and for choosing among empirical antibiotics (monotherapy versus combination therapy) (Freifeld 2011; Tam 2011).

We undertook this systematic review to assess the evidence for combination therapy versus monotherapy in patients with febrile neutropenia in clinical trials. In 2002, the first version of this review was published. Results showed no advantage of combination therapy with regard to all cause mortality, the primary outcome assessed and an increased rate of nephrotoxicity with the combined regimen. Most trials compared a broad-spectrum beta-lactam with an older beta-lactam combined with an aminoglycoside; however comparisons performed to directly assess our research question, that is, trials comparing the same beta-lactam with or without an aminoglycoside, were rare. We called for further studies assessing directly the clinical implications of synergism, and further trials comparing different beta-lactams were discouraged in our recommendations (Paul 2003). In 2008 we updated our systematic review with new evidence that had accumulated since publication of the first version of our review; no significant differences were presented in terms of outcomes or subsequent recommendations. At present we are undertaking to update the review to include new evidence that has accumulated since the previous version.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

To compare the effectiveness of beta-lactam monotherapy versus that of beta-lactam-aminoglycoside combination therapy in febrile neutropenic cancer patients. In addition, to compare the effectiveness of the two treatment modalities in the following subgroups of neutropenic participants:

  • Participants with an absolute neutrophil count of less than 100/mm³
  • Participants with microbiologically documented infection
  • Participants with documented Pseudomonas aeruginosa infection
  • Bacteraemic participants
  • Participants with an underlying haematological malignancy or bone marrow transplantation

The following hypotheses were tested for the comparison between participants treated with beta-lactam monotherapy and those treated with beta-lactam-aminoglycoside combination therapy:

  • There is no difference in the number of deaths in febrile neutropenic patients
  • There is no difference in the number of deaths in the above subgroups of febrile neutropenic patients
  • There is no difference in the number of treatment failures in all febrile neutropenic patients and in the defined subgroups
  • There is no difference in the number and severity of adverse effects among all patients
  • There is no difference in the rate of resistant colonisation and super-infection among all neutropenic patients

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised or quasi-randomised trials comparing any beta-lactam antibiotic monotherapy with any combination of a beta-lactam and an aminoglycoside antibiotic, for the treatment of febrile neutropenia in cancer patients. Allocation to these regimens had to occur initially, before administration of any other antibiotics for the specific febrile episode and, empirically, before detection of pathogen/s or their susceptibilities.

Trials with randomly assigned participants with microbiologically documented infection (e.g. Pseudomonas aeruginosa infection, Gram-negative bacteraemia) were excluded, as were trials comparing short versus long courses of aminoglycoside treatment, because in both cases randomisation to combination treatment versus monotherapy did not occur empirically (referred to as semi-empirical studies).

 

Types of participants

Febrile cancer patients with neutropenia, as defined in the study, induced by chemotherapy or bone marrow transplantation. Neonates and preterm babies were excluded.

 

Types of interventions

The following antibiotic regimens were compared:

  • Intravenous beta-lactam antibiotic given as monotherapy, including:

    • Antipseudomonal carboxy-penicillins or ureido-penicillins ± beta-lactamase inhibitor (piperacillin, piperacillin/clavulanate, ticarcillin-clavulanate, azlocilin, mezlocillin)
    • Cephalosporins (ceftazidime, ceftriaxone, cefoperazone, cefoxitin, cefuroxime, cefepime, cefpiramide)
    • Carbapenems (imipenem/cilastatin, meropenem)

Studies comparing the same beta-lactam, with the addition of an aminoglycoside to one arm ('same beta-lactam'), were analysed separately from studies comparing different beta-lactams ('different beta-lactam').

  • Combination duotherapy of an intravenous beta-lactam antibiotic (as specified) with one of the following aminoglycosides given intravenously:

    • Gentamicin
    • Tobramycin
    • Amikacin
    • Netilmicin
    • Kanamycin

 

Types of outcome measures

 

Primary outcomes

Death at end of follow-up for the infectious episode, up to 30 days (all cause mortality).

 

Secondary outcomes

  • Treatment failure: a composite end point comprising one or more of the following: death; persistence, recurrence or worsening of clinical signs or symptoms of presenting infection; any modification of the assigned empirical antibiotic treatment.
  • Infection related mortality, as reported in the study.
  • Duration of hospital stay.
  • Dropouts before end of study.
  • Super-infection: new, persistent or worsening symptoms and/or signs of infection associated with the isolation of a new pathogen (different, or different susceptibilities) or the development of a new site of infection.
  • Colonisation: isolation during or after therapy of Gram-negative bacteria resistant to the beta-lactam included in the empirical regimen, without symptoms or signs of infection.

 
Adverse effects

  • Life threatening or associated with permanent disability.
  • Serious-requiring discontinuation of therapy.
  • Any other.

 

Search methods for identification of studies

 

Electronic searches

Relevant randomised trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 7, 2012), LILACS to August 2012, Database of Abstracts of Reviews of Effects (DARE) (Issue 3, 2012) and MEDLINE and EMBASE to August 2012. We conducted a wide search targeting all randomised trials for the treatment of infection in neutropenic patients for this and other systematic reviews conducted by our group. The detailed search strategies for each database are provided in Appendix 1, Appendix 2 and Appendix 3.

 

Searching other resources

References of all identified studies as well as major reviews were inspected for more studies. We checked the conference proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) 1995 to 2011, the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2001 to 2012) and the American Society of Hematology (ASH) 2003 to 2011. Letters, abstracts and unpublished trials were accepted to reduce the influence of publication bias. Additionally, the first or corresponding author of each included study and pharmaceutical companies were contacted for complementary information or information regarding unpublished trials.

 

Data collection and analysis

 

Selection of studies

One review author inspected the abstract of each reference identified by the search and applied inclusion criteria. For possibly relevant articles, the full article was obtained and inspected by two review authors.

 

Data extraction and management

Two review authors independently extracted data from included trials. In cases of disagreement between the two review authors, a third review author extracted the data. In addition the third review author extracted 10% of the studies, selected randomly. Data extractions were discussed, decisions documented and all authors of included studies contacted for clarification. Justification for excluding studies from the review was also documented. Differences in the data extracted were resolved by discussion. All data were collected on an intention-to-treat (ITT) basis whenever possible.

 

Assessment of risk of bias in included studies

Trials fulfilling the review inclusion criteria were assessed for risk of bias by two review authors working independently. For the 2012 update, this was done using the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We primarily assessed the effect of allocation concealment on results, based on the evidence of a strong association between poor allocation concealment and overestimation of effect (Schulz 1995), as defined below:

  • Low risk of bias (adequate allocation concealment).
  • Moderate risk of bias (uncertainty regarding allocation concealment).
  • High risk of bias (inadequate allocation concealment).

In addition to the adequacy of allocation concealment, methods of allocation generation, blinding, incomplete outcome data, selective reporting, the unit of randomisation (patient or febrile episode) and publication status were recorded independently by the two review authors.

 

Assessment of heterogeneity

Heterogeneity in the results of the trials was initially graphically inspected and assessed by calculating a test of heterogeneity (Chi-square). We anticipated between-trial variation in estimation of morbidity and mortality for studies comparing the same beta-lactam and studies comparing different beta-lactams (Elphick 2001). These were separated when heterogeneity was observed. Further heterogeneity was explored through subgroup analysis, assessing the above-defined patient subgroups (Objectives).

A funnel plot estimating the precision of trials (plots of the log of the risk ratio for efficacy against the sample size) was examined to estimate potential selection bias (such as publication bias) and to assess whether effect estimates are associated with study size.

Adjusted means were calculated and corrected by the inverse of the variance. We searched for the correlation between mortality and treatment failure, to assess the clinical relevance of treatment failure and infection related mortality outcomes in these studies. Correlations were tested for significance using a non-parametric test (Spearman) using the Statistical Package for the Social Sciences (SPSS) version 14.0. Numbers needed to treat or harm were calculated as 1/(CER-CER*RR), where CER is the control event rate and RR is the risk ratio.

 

Data synthesis

Dichotomous data were analysed by calculating the risk ratio (RR) for each trial with the uncertainty in each result expressed with the use of 95% confidence intervals (CIs). A fixed-effect model was used throughout the review, unless significant heterogeneity was observed (P < 0.1 or I2 > 50%) where the random-effects model was used.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Description of studies

The computerised search strategy identified a large number of randomised trials assessing the treatment of febrile neutropenia-not all of which were relevant for the present review. These were screened for trials assessing beta-lactam-aminoglycoside combination therapy versus beta-lactam monotherapy. Ninety-five publications of RCTs were considered eligible for this review.

Twenty-three publications of 22 trials were excluded (Characteristics of excluded studies). Allocation to monotherapy versus combination therapy was non-random in five studies, randomisation to monotherapy versus combination therapy was semi-empirical in three trials (Bodey 1976; EORTC 1987; Pegram 1989), the comparator regimens were incompatible with our inclusion criteria in nine trials, and non-neutropenic patients were included in three trials (D'Antonio 1992; Fainstein 1983; Hoepelman 1988), in which results for neutropenic patients only could not be extracted. One trial randomly assigned participants to treatment with ticarcillin-clavulanate versus ticarcillin-clavulanate+amikacin; however participants who had undergone bone marrow transplantation were allocated to combination therapy only, over-riding the random allocation (Bru 1986); another trial comparing imipenem versus ceftazidime versus amikacin was excluded, because it was presented as an ongoing study in a conference in 1986, no further publication of the study was found and we were not able to contact the authors (Moreno-Sanchez 1992).

We could not yet obtain the full text of one trial, which is awaiting assessment (Li 1998). Another trial was presented at a conference in 2005 and is listed as ongoing (Bilgir 2005).

Seventy-one trials described in 89 publications are included in the review (Characteristics of included studies; secondary publications are listed under their primary reference). The trials were published between 1983 and 2012. Three trials were added since the previous version of this review, all published between 2007 and 2012. Forty-three trials reported data on all cause mortality and 41 reported on infection related mortality. Data regarding treatment failure were available for all trials. Thirty-one trials contained usable information for super-infections, and 49 trials are included in the adverse event analysis.

Eight included trials, presented in conference proceedings between 1987 and 2002, were published in abstract form only. Supplementary data from the authors were available for two of these (Cornely 2001, Hense 2000). Additional information on trial methods and/or on mortality was available from 24 full-text publications ('unpublished data' in the reference description).

 

Patient and infection characteristics

Most trials included adult cancer patients. Fourteen trials included only children, and another 14 trials included both adults and children. Most trials included participants with haematological cancer: 35 trials included only patients with haematological malignancies, and in another 32 trials most patients had haematological cancer. Bone marrow transplant patients were excluded from three trials. Patients with septic shock were specifically excluded from four trials; most trials did not refer to patients with septic shock, and in the few trials that did report patients with septic shock, only a few patients were included (1% to 6% of patients in five trials reporting the number of patients with shock on admission).

The ratio between Gram-negative and Gram-positive bacteria among all included studies was 0.69. The adjusted mean rate of infection caused by Gram-negative bacteria was 11.5% of participants. Pseudomonas aeruginosa, a commonly implicated pathogen of febrile neutropenia in the past, was isolated in only 1.7% of included participants, constituting 15.3% of all documented Gram-negative isolates.

Surveillance cultures were performed in nine trials.

 

Antibiotic regimens

The same beta-lactam was compared in 16 of 71 included trials. In these trials the beta-lactam was ceftazidime (seven trials), piperacillin-tazobactam (four trials), cefepime (three trials), imipenem (two trials-one of which included four arms and assessed both ceftazidime and imipenem) and cefoperazone (one trial). All other trials compared one beta-lactam (usually a new drug) with a narrower-spectrum beta-lactam combined with an aminoglycoside. The most common mono-combi beta-lactam comparison was between a carbapenem and a cephalosporin (18 trials). Other comparisons included cephalosporin-cephalosporin (11 trials), cephalosporin-penicillin (nine trials), carbapenem-penicillin (nine trials), penicillin-cephalosporin (four trials) and penicillin-penicillin (three trials), respectively.

The most commonly tested aminoglycoside was amikacin (43 trials), followed by tobramycin (14 trials), gentamicin (11 trials) and netilmicin (three trials). Aminoglycosides were administered once daily in 16 trials. Aminoglycosides were administered for the duration of treatment in all trials, except Tamura 2004, where amikacin was administered only for the first 3 days of combination therapy.

Treatment duration was reported as means or medians. The mean treatment duration ranged from 7 to 15 days (most commonly 9 days); median treatment duration varied between 4 and 9 days (most commonly 9 days).

 

Risk of bias in included studies

Adequate allocation concealment, using sealed opaque envelopes or central randomisation, was described in 27 trials (Ahmed 2007; Akova 1999; Alanis 1983; Behre 1998; Cometta 1996; Cornely 2001; De la Camara 1997; Del Favero 2001; De Pauw 1994; Gibson 1989; Gorschluter 2003; Hess 1998; Jimeno 2006; Kinsey 1990; Leyland 1992; Lieschke 1990; Marie 1991; Matsui 1991; Norrby 1987; Novakova 1991; Novakova 1990; Petrilli 1991; Pickard 1983; Tamura 2002; Tamura 2004; Wrzesien-Kus 2001; Yamamura 1997). Allocation generation was adequate in a similar number of studies. These studies used tables of random numbers or computer-generated lists. Allocation concealment was inadequate in two trials describing the randomisation only as consecutive (Corapcioglu 2005; Zengin 2011). Randomisation methods were not described in all other trials. Four trials were double-blinded (Del Favero 2001; Ozyilkan 1999; Schuchter 1988; Wade 1989), four single-blinded (Cometta 1996; Duzova 2001; Leyland 1992; Rolston 1992) and the remainder open-randomised trials.

Intention-to-treat (ITT) analysis was presented in 23 of 68 trials included for treatment failure analysis and in 25 of 47 trials included for mortality analysis. Dropouts were reported by their allocation group in 26 of the 45 trials presenting per protocol analysis for treatment failure, permitting a secondary ITT analysis in which dropouts were assumed to be failures (see later, sensitivity analyses for failure). The number of patients excluded from analysis in studies in which ITT analysis was impossible ranged between 3% and 30% and the median rate of excluded patients was 10%. Twelve trials, mostly presented as conference proceedings, addressed 'treated' or 'evaluated' patients, without specifying a different figure for the number of randomly assigned participants (Agaoglu 2001; Borbolla 2001; Duzova 2001; El Haddad 1995; Esteve 1997; Gaytan-Martinez 2002; Kliasova 2001; Marie 1991; Pegram 1984; Pellegrin 1988; Schuchter 1988; Wade 1987). The analysis presumed for these studies was per-protocol.

A pre-determined, defined follow-up period was available from the publication or through author contact for 14 included trials (Behre 1998; Cometta 1996; De la Camara 1997; Del Favero 2001; Gorschluter 2003; Hess 1998; Kojima 1994; Leyland 1992; Norrby 1987; Ozyilkan 1999; Smith 1990; Tamura 2002; Tamura 2004; Yamamura 1997). Follow-up ranged from 72 hours to 1 month following the end of treatment. The observation time was longer than 1 month in two trials (De la Camara 1997; Ozyilkan 1999), both of which reported the outcomes at 1 month post-therapy. In five trials the time of outcome assessment was described more generally as end of treatment, fever, episode or neutropenia (De Pauw 1994; Erjavec 1994; Lieschke 1990; Matsui 1991; Piguet 1988). Two additional trials reported the average follow-up period of their trials (8 and 14 days) but a fixed time for outcome assessment was not specified (Akova 1999; Rolston 1992).

The unit of randomisation was the patient in 23 of the 71 trials (Characteristics of included studies). Episodes comprised the unit of randomisation in all the other trials, which allowed patient re-entry for recurrent episodes of fever and neutropenia. The number of participating patients was given in 74% of trials analysing episodes, and the mean episode-to-patient ratio in these trials was 1.3 (range 1.02 to 2.07). Trials that allowed repeat randomisation of participants for separate episodes of febrile neutropenia did not adjust their analyses to the 'cluster' effect of episodes within single participants and did not provide an intra-patient correlation estimate to allow for adjusted analyses in the meta-analysis. All trials were included in the main analysis and the effect of episode randomisation was assessed through sensitivity analyses.

 

Effects of interventions

See:  Summary of findings for the main comparison beta-lactam monotherapy compared to beta-lactam-aminoglycoside combination therapy for Febrile neutropenic cancer patients

 

Overall effectiveness

All cause mortality :
All cause mortality was reported in 44 trials, including 7186 episodes. A difference in favour of monotherapy was observed overall (RR 0.87, 95% CI 0.75 to 1.02) ( Analysis 1.1). This difference was not statistically significant, but there was no heterogeneity (P = 0.95, I2 = 0) among trials for this combined effect estimate. Similar results were obtained using the random-effects model (RR 0.88, 95% CI 0.75 to 1.04). Among trials comparing the same beta-lactam, the RR was 0.74 (95% CI 0.53 to 1.06, 11 trials, 1718 episodes). Among trials comparing different beta-lactams, the RR was 0.91 (95% CI 0.77 to 1.09, 33 trials, 5468 episodes). Results were similar for trials comparing same and different beta-lactams with regard to all cause mortality; therefore these trials were combined in all subsequent subgroup and sensitivity analyses for mortality.

No significant differences between monotherapy and combination therapy were observed for the planned subgroups. The trend observed was similar for all comparisons, with RRs favouring monotherapy, with no statistical significance. Moreover, effect estimates favouring monotherapy were larger in subgroups designating participants with a potential worst prognosis:

  • Participants with microbiologically documented infection: 13 trials, 1188 episodes, RR 0.81 (95% CI 0.56 to 1.17) ( Analysis 4.1).
  • Participants with bacteraemia: 14 trials, 676 episodes, RR 0.74 (95% CI 0.46 to 1.18) ( Analysis 5.1).
  • Participants with microbiologically documented Gram-negative infection: 16 trials, 376 episodes, RR 0.64 (95% CI 0.37 to1.11) ( Analysis 6.1).
  • Participants with documented Pseudomonas aeruginosa infection: 9 trials, 71 episodes, RR 0.87 (95% CI 0.34 to 2.24) ( Analysis 7.1).
  • Participants with haematological cancer: 22 trials 3463 episodes, RR 0.88 (95% CI 0.68 to 1.13) ( Analysis 8.1).
  • Participants with severe neutropenia on admission: 6 trials, 737 episodes, RR 0.68 (95% CI 0.37 to 1.24) ( Analysis 9.1).

When the analysis was separated by the monotherapy beta-lactam ( Analysis 10.1), only piperacillin-tazobactam was associated with significantly improved survival compared with combination therapy (RR 0.62, 95% CI 0.40 to 0.96, 5 trials, 1093 episodes). In studies including only children, the RR was 0.80 (95% CI 0.29 to 1.64), and in trials including only adults, the RR was 0.90 (95% CI 0.75 to 1.09) ( Analysis 11.1).

In summary, monotherapy was associated with a trend toward improved survival overall and in all subgroups assessed.

 

Infection related mortality and treatment failure

Infection related mortality was reported in 41 trials ( Analysis 1.2). No deaths related to infection were reported in nine trials (which did not contribute to the meta-analysis). Monotherapy was associated with a significantly lower rate of infection related mortality compared with combination therapy (RR 0.80, 95% CI 0.64 to 0.99). Results were similar for trials comparing same and different beta-lactams. The number of participants needed to treat with monotherapy to prevent one death related to infection was 95 participants, but 95% CIs were large (49 to 1241 participants).

Studies performed in recent years based their definitions for treatment success and failure on recommendations of the Immuncompromised Host Society (Consensus 1990). Treatment failure reported here is the inverse of "success without modification". It should be noted that we defined treatment failure more broadly in our protocol as death, lack of clinical improvement or any modification of the assigned empirical antibiotic treatment (see earlier, outcomes). Death judged as unrelated to infection was not included in the consensus definitions for failure. Thus other than infection related deaths, treatment failure reflected mainly treatment modifications in trials that were open-label in the vast majority.

In trials comparing the same beta-lactam, a significant advantage was seen with combination therapy (RR 1.11, 95% CI 1.02 to 1.20) with minor heterogeneity (I2 = 12%). In trials comparing different beta-lactams, a significant advantage was observed with beta-lactam monotherapy (RR 0.92, 95% CI 0.88 to 0.97, I2 = 16%) ( Analysis 1.3). Results diverged for trials comparing same and different beta-lactams with regard to treatment failure; therefore these data were not pooled for the main and all subsequent analyses of treatment failure.

Subgroup analyses for trials comparing the same beta-lactams ( Analysis 4.2;  Analysis 5.2;  Analysis 6.2;  Analysis 7.2;  Analysis 8.2;  Analysis 9.2) demonstrated significant differences in favour of combination therapy for patients with Gram-negative infection (RR 1.34) and severe neutropenia (RR 1.48). No significant differences were observed for the subgroups of participants with any microbiologically documented infection, Pseudomonas aeruginosa infection, bacteraemia and haematological cancer. No specific beta-lactam monotherapy was associated with increased risk for failure ( Analysis 10.2). All subgroup analyses for trials comparing the same beta-lactam were limited by the paucity of trials and participants included.

Similar subgroup analyses for trials comparing different beta-lactams showed that the significant advantage associated with monotherapy persisted in all tested subgroups, except for cases of documented Pseudomonas aeruginosa infection, severe neutropenia and haematological cancer. Similar RRs in favour of monotherapy were observed with the different specific beta-lactams.

No correlation was noted between rates of treatment failure and all cause or infection related mortality in these studies (r = 0.27, P = 0.11, 38 trials, and r = 0.21, P = 0.27, 30 trials, respectively). As expected, infection related mortality was significantly correlated with all cause mortality (r = 0.63, P < 0.001, 29 trials). No significant correlation was noted between publication year and the RRs for mortality or treatment failure.

 

Super-infections

Twenty-nine trials, including 4961 episodes, reported on the development of bacterial super infections during and after antibiotic treatment ( Analysis 2.1), and 20 trials, including 3437 episodes, reported on fungal super infections ( Analysis 2.2). Equivalence was demonstrated with regard to bacterial super infections (RR 1.02, 95% CI 0.87 to 1.19). Fungal super infections developed more frequently in the combination treatment group (RR 0.70, 95% CI 0.49 to 1.00). Data concerning resistant colonisation were scarce. Five trials supplied data regarding any colonisation (Alanis 1983; Cornelissen 1992; Erjavec 1994; Kojima 1994; Norrby 1987), and comparison of colonisation with resistant Gram-negative bacteria was possible in only two studies (Cornelissen 1992; Norrby 1987). In these studies, resistant Gram-negative bacteria were detected in 5 of 152 participants in the monotherapy group versus 1 of 152 in the combination group. Notably, none of the newer trials included in the updated review performed surveillance cultures, nor did they report on colonisation with resistant bacteria.

 

Adverse events

Adverse events were significantly more frequent in the combination treatment group. The difference was most remarkable when development of renal failure was compared (RR 0.45, 95% CI 0.35 to 0.57) for any nephrotoxicity ( Analysis 3.3) and (RR 0.16, 95% CI 0.05 to 0.49) for severe nephrotoxicity ( Analysis 3.4). Nephrotoxicity was more common in the combination therapy than in the monotherapy arm also in studies using a once-daily dosing regimen for the aminoglycoside (RR 0.31, 95% CI 0.15 to 0.63, 8 trials, 1707 participants). In assessment of any adverse effect in all trials and in studies grouped by their monotherapy ( Analysis 3.1), an advantage of monotherapy was seen overall (RR 0.87, 95% CI 0.81 to 0.94), and with ceftazidime monotherapy (RR 0.64, 95% CI 0.53 to 0.76). Likewise, discontinuation of study medication due to adverse events occurred more often in the combination group ( Analysis 3.2) (RR 0.61, 95% CI 0.40 to 0.93). The number needed to harm with combination therapy was 34 participants (95% CI, 20 to 104) with regard to any adverse event and 31 participants (95% CI, 24 to 42) with regard to nephrotoxicity.

 

Other outcomes

Duration of hospital stay was non-significantly shorter in the monotherapy group in each of the four trials that reported this outcome: mean 24.8 days (standard deviation (SD) 21 to 31) versus 27.3 days (SD 23 to 56) (De la Camara 1997, data availed through personal correspondence), median 8.6 ± 4 versus 11.8 ± 5.6 (Corapcioglu 2005), mean 9.96 versus 11.93 days (Jimeno 2006) and mean 12.6 ± 5.3 versus 10.6 ± 4.7 (Yildirim 2008) for monotherapy versus combination therapy, respectively. The data were not pooled because variable reporting measures were used.

 

Selection bias

Funnel plot analyses were undertaken for the two main comparisons: failure and mortality. The funnel plot for mortality was symmetrical (Figure 1). The funnel plots for trials comparing same and different beta-lactams for failure were separated. Among trials comparing the same beta-lactam, the funnel plot was approximately symmetrical (Figure 2); among trials comparing different beta-lactams, an indication that small trials favouring combination therapy are missing may be present (Figure 3).

 FigureFigure 1. All cause mortality.
 FigureFigure 2. Failure-same BL.
 FigureFigure 3. Failure-different BL.

 

Sensitivity analyses

Sensitivity analyses were performed for the primary outcomes-mortality and failure-to assess the impact of study quality on our results.

For mortality, results from studies with adequate allocation concealment (RR 0.88) were similar to results from studies with unclear allocation concealment (RR 0.87;  Analysis 12.1), as were results for trials reporting ITT (RR 0.87) versus efficacy analysis (RR 0.88;  Analysis 12.2). The effect size was smaller in trials assessing episodes (RR 0.90) compared with trials assessing participants (RR 0.84), although the 95% CI overlapped ( Analysis 12.3). Small and large trials provided similar results, with no study size effect for mortality (comparison 12.5). Unpublished trials and those published only in conference proceedings showed no advantage of monotherapy (RR 1.07, 95% CI 1.07 to 0.72 to 1.59), and trials published in peer reviewed journals showed an advantage of monotherapy (RR 0.84, 95% CI 0.71 to 1.00) ( Analysis 12.4).

For failure among trials comparing the same beta-lactams, no significant differences in the pooled effect estimate were observed for the different methodological measures assessed. In an ITT analysis counting all dropouts as failures, the advantage of combination therapy decreased (RR 1.07;  Analysis 12.8). Analysis by episodes was associated with a larger effect estimate in favour of combination therapy (RR 1.16;  Analysis 12.10). The only double-blinded trial showed similar results for combination therapy versus monotherapy (Del Favero 2001,  Analysis 12.11).

Among trials comparing different beta-lactams, adequate allocation concealment was associated with a smaller effect estimate in favour of monotherapy than was seen with unclear methods (RR 0.94 versus RR 0.87, respectively;  Analysis 12.6). ITT analysis in the publication was associated with a smaller effect estimate than was seen with efficacy analysis (RR 0.80, 95% CI 0.71 to 0.91 versus RR 0.95, 95% CI 0.88 to 1.01, respectively;  Analysis 12.7), and an ITT analysis assuming that all dropouts were failures did not alter results significantly (RR 0.92, 95% CI 0.86 to 0.97;  Analysis 12.8). Analysis by episodes was associated with a smaller effect estimate than analysis by participants (RR 0.95 versus RR 0.89;  Analysis 12.10). Smaller trials were associated with a significantly larger effect estimate than was noted in the bigger trials (RR 0.75, 95% CI 0.67 to 0.84 versus RR 0.98, 95% CI 0.92 to 1.03;  Analysis 12.9), pointing at the same small studies for effects observed in the corresponding funnel plot analysis (Figure 3). No advantage was seen with monotherapy in double-blind trials ( Analysis 12.11).

For trials comparing same and different beta-lactams, unpublished trials showed no difference between monotherapy and combination therapy, but published trials showed a significant difference favouring combination therapy for trials comparing the same beta-lactams, and favouring monotherapy for trials comparing different beta-lactams ( Analysis 12.12).

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

Seventy one trials that included more than 10,000 participants were analysed to compare beta-lactam monotherapy with beta-lactam-aminoglycoside combination therapy for the empirical treatment of febrile neutropenic cancer patients. The same beta-lactam was compared in 16 trials, but all other trials compared a broad-spectrum beta-lactam with a narrower-spectrum beta-lactam combined with an aminoglycoside. Most of the participants included in these trials were haematological cancer patients. We assessed all cause mortality as the primary outcome.

Monotherapy was associated with a statistically non-significant lower all cause mortality rate at end of follow-up (30 days) (RR 0.87, 95% CI 0.75 to 1.02). Results for trials comparing same and different beta-lactams were similar. Appropriate trial methods (adequate allocation concealment, ITT analysis and analysis by participants) were associated with similar effect estimates in favour of monotherapy, and no small studies effect was observed. Mortality attributed in the primary studies to infection was significantly lower with monotherapy (RR 0.80, 95% CI 0.64 to 0.99).

Treatment failure was assessed as the primary outcome in all included trials. By definition, its main addition on the rather subjective outcome of infection related mortality is treatment modifications (Consensus 1990). Among trials comparing the same beta-lactams, treatment failure was significantly more frequent with monotherapy. This difference likely reflects mainly physicians' tendency for treatment modifications in open trials comparing one antibiotic regimen with a broader-spectrum regimen. Among trials comparing different beta-lactams, a significant advantage was seen with monotherapy. Adequate trial methods were associated with smaller effect estimates for both 'same' and 'different' comparisons. Notably, in the single double-blind trial comparing the same beta-lactams, failure was equal with combination treatment and with monotherapy, and in three double-blind trials assessing different beta-lactams, the RRs were in the opposite direction compared with those in the other trials. We detected a small studies effect for trials comparing different beta-lactams. This may reflect a publication bias related to trials that assessed a newer monotherapy without showing its advantage.

Bacterial super infections occurred with equal frequency with monotherapy and combination therapy. Fungal super-infections were more common with combination therapy. All adverse events were more common with combination therapy, with a highly significant difference for nephrotoxicity. The pooled effect estimate translated to a number needed to harm of 34 participants (95% CI 20 to 104 participants).

To explain the advantage of monotherapy with regard to all cause mortality, several of the secondary outcomes may be used. Infection related mortality was significantly lower with monotherapy, and fungal super infections occurred more frequently with combination treatment. Fungal infections developing during neutropenia are highly lethal (Lin 2001). Thus, the improvement in survival may indeed be infection related. On the other hand, nephrotoxicity associated with combination therapy is a risk factor for subsequent adverse outcomes. Given these results and those of the methodological quality assessment, it is likely that the both mechanisms contribute to an unbiased advantage in overall survival with monotherapy.

Several hypotheses underlie the use of beta-lactam-aminoglycoside combination therapy for patients with neutropenia and suspected infection. Synergism is usually claimed as the major reason for combination therapy. Synergism was assessed most directly in trials comparing the same beta-lactam. We did not detect the beneficial effects of synergism. A wider spectrum of coverage may be the incentive for the addition of an aminoglycoside depending on local patterns of resistance. Studies included in the review did not supply enough data to allow determination of whether coverage is indeed improved with combination therapy. However, the efficacy of aminoglycosides alone for the treatment of neutropenic patients is doubtful (Bodey 1972; Klastersky 1986); therefore this potential advantage does not seem substantial. Finally, combination therapy is claimed to prevent emergence of resistant pathogens. Development of resistance after antibiotic treatment is difficult to quantify. We intended to extract data regarding colonisation with resistant pathogens following antibiotic treatment, but these data were rarely available. Resistance was therefore indirectly examined through super infections, under the assumption that infection that develops under antibiotic treatment involves resistant pathogens. No difference was noted in the rate of bacterial super infections between monotherapy and combination therapy, and this analysis resulting in an RR close to 1. Fungal super infections developed more frequently with combination therapy, perhaps as a reflection of increased antibiotic spectrum or burden with combination therapy. Thus we could not show an advantage of combination therapy from this aspect.

We chose all cause mortality as the primary outcome, rather than treatment failure or infection related mortality, and have drawn our conclusions from the analysis for all cause mortality. Only a small part of the variance in mortality is explained by infection and its treatment; however, appropriate randomisation should ensure similar distribution of non–infection related risk factors for death between the study groups. Infection related mortality may be prone to bias in that the cause of death is difficult to determine in severely ill cancer patients. Moreover, ignoring deaths due to treatment-related adverse effects and super infections is inappropriate. Early empirical antibiotic treatment is the standard of practice for febrile neutropenic patients because it has been proven to decrease mortality (Hughes 1997; Schimpff 1986). Survival is indeed the objective when an acute infection is treated in cancer patients. Treatment failure indicates mainly modifications of the initial antibiotic regimen, and possibly a longer time to defervescence. The implications of such an outcome are not clear from the clinical point of view. Finally, deaths are objective, but failures cannot be objective when the trials are open. It is important to note that we could demonstrate in this review that assessing treatment failure is probably inappropriate, because no correlation between failure and mortality could be shown.

Our results are congruent with those of several other analyses of beta-lactam-aminoglycoside combination therapy versus beta-lactam monotherapy, showing no advantage associated with combination therapy. We conducted a similar analysis in non-neutropenic participants with sepsis, showing an advantage of monotherapy in trials comparing different beta-lactams, and no difference in trials comparison the same beta-lactam (Paul 2004; Paul 2006a). In an analysis of all RCTs comparing the same beta-lactam in the combination and monotherapy arms, in both neutropenic and non-neutropenic participants, and including semi-empirical studies, we did not find a significant difference in all cause mortality, but we noted significantly more bacterial super infections and increased renal failure with the addition of aminoglycosides (Marcus 2011). An analysis focusing on the development of resistance did not find an advantage associated with combination therapy (Bliziotis 2005). Finally, an analysis of observational studies focusing onPseudomonas aeruginosa infection (mainly bacteraemia), a pathogen with special relevance to neutropenic cancer patients, did not find an advantage for combination therapy (Vardakas 2013).

The major limitations of this review include the lack of complete data concerning mortality (all cause mortality was available for 44 of 71 included trials, 62%) and the paucity of available data regarding specific patient subgroups, such as those with Pseuomonas aeruginosa infection. Other limitations stem from those of the primary studies. Allocation concealment was at low risk of bias in less than 35% of the trials, and nearly all were non-blinded. Many of the trials did not adhere to the principle of ITT analysis, resulting in incomplete data reporting. Most studies used febrile episodes as the unit of randomisation, although recurrent episodes are not independent for any for the outcomes assessed. Finally, follow-up did not seem pre-determined in many of the studies. Reported mortality may have been biased because the time of assessment was not defined in advance. We included trials regardless of their publication status. The differences detected in our review, namely, the advantage of monotherapy with regard to survival and the divergent advantages with regard to failure, existed with larger effect estimates in trials published in peer reviewed journals. The RRs were close to 1 for these outcomes in unpublished trials, mainly conference proceedings. Their inclusion in the meta-analysis tipped the overall RRs toward equivalence.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

 

Implications for practice

Monotherapy can be regarded as the standard of care for the empirical treatment of febrile neutropenic patients. The addition of an aminoglycoside does not improve survival. On the contrary, it is associated with significant morbidity incurred mainly through aminoglycoside-associated nephrotoxicity.

The monotherapies assessed in recent years have included imipenem, meropenem, ceftazidime, piperacillin-tazobactam and cefepime. These beta-lactams have also been assessed in head-to-head trials comparing different monotherapies and have shown similar efficacies, but for cefepime this was associated with increased all cause mortality (Paul 2006). Thus, individual centres should select the best matching monotherapy according to local epidemiology and susceptibility patterns.

RCTs do not support an advantage of combination therapy for Pseudomonas aeruginosa infection and other more severely ill patient subgroups. However the paucity of data precludes firm conclusions regarding these patient subgroups.

 
Implications for research

Assessment of new beta-lactams for febrile neutropenia should not be performed by comparison with a narrower-spectrum beta-lactam combined with an aminoglycoside. The results of these trials are uniformly unfavourable for patients. Assessment of new beta-lactam monotherapies should be performed by comparison with established monotherapies for febrile neutropenia. This design can and does show the advantages and disadvantages of specific beta-lactams (Paul 2006).

The need for further trials assessing the addition of an aminoglycoside to the same beta-lactam is doubtful given the results of our review, spanning more than two decades of clinical trials in febrile neutropenia and without a change in RRs throughout the years. We can foresee such a need if a reduction in aminoglycoside-related adverse effects is expected, or if new data will point toward drug combinations with a marked synergistic effect-much greater than that observed in current studies. Trials targeting specific patient subgroups, such as those with severe sepsis and septic shock, documented Pseudomonas aeruginosa infection, etc. are warranted.

Future trials should report all cause mortality. The primary outcome used in these studies should be re-defined because with current definitions, no correlation can be noted between failure and the ultimate outcome: survival. This outcome should be defined in a consensus statement and applied universally to permit comparisons and compilation of different studies. The unit of randomisation should be the patient-not the episode. If recurrent episodes are allowed, results for the first randomisation of each patient should be reported separately, or the analysis should be adjusted to the clustering effect of patient episodes. Length of follow-up should be uniform and should be determined before the study is begun.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

We would like to thank warmly the Cochrane Gynaecological Cancer Review Group, for their helpful advice and for their assistance in obtaining articles from abroad.

We would like to express our appreciation to all the authors who responded to our letters and supplied additional information on their studies: Drs. Will (Smith 1990 trial), Wrzesien-Kus, Ahmed, Jimeno, Pettrili, Tamura and Vallejos (Rodriguez 1995), Gibson, Donnelly and De Pauw (De Pauw 1983; De Pauw 1994 trials), Pickard and Rotstein (Yamamura 1997 trial), Kojima, Kinsey, Norrby, Matsui, Ozyilkan, Dincol, Doyen and Michaux (Doyen 1983 trial), Duzova, Agaoglu and Karakas (Agaoglu 2001 trial), Jacobs, De la Camara and Sarper (Zengin 2011), Drs. Glasmacher, Hense and Lieschke, who supplied their full unpublished manuscripts, Drs. Keddie and Wilks of the AstraZeneca Company for supplying their data for the Behre 1998 and De la Camara 1997 trials, Dr. Sawae for clarifying the details of his study, and Dr. Cornelly for supplying full results for his yet unpublished trial (Cornely 2001). We would also like to thank Professor Bodey for his response and comments on the previous version of this review.

In addition we would like to thank the authors who responded even though additional data were unavailable: Drs. Morgan, Piccart, Rehm (Alanis 1983 trial),

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological Cancer Group. 

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
Download statistical data

 
Comparison 1. Overall effectiveness

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All cause mortality447186Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.75, 1.02]

    1.1 same beta-lactam
111718Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.53, 1.06]

    1.2 different beta-lactam
335468Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.77, 1.09]

 2 Infection-related mortality416872Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.64, 0.99]

    2.1 same beta-lactam
81403Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.43, 1.10]

    2.2 different beta-lactam
335469Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.65, 1.06]

 3 Treatment failure71Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 same beta-lactam
162833Risk Ratio (M-H, Fixed, 95% CI)1.11 [1.02, 1.20]

    3.2 different beta-lactam
557736Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.88, 0.97]

 
Comparison 2. Superinfections

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Bacterial superinfections294961Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.87, 1.19]

 2 Fungal superinfections203437Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.49, 1.00]

 
Comparison 3. Adverse events

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Any adverse event (monotherapy)497412Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.81, 0.94]

    1.1 imipenem monotherapy
121429Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.86, 1.13]

    1.2 meropenem monotherapy
92003Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.84, 1.06]

    1.3 ceftazidime monotherapy
91941Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.53, 0.76]

    1.4 moxalactam monotherapy
5421Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.51, 0.97]

    1.5 cefepime monotherapy
81079Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.75, 1.17]

    1.6 other monotherapy
7539Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.61, 1.44]

 2 Discontinuation due to adverse event164051Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.40, 0.93]

 3 Any nephrotoxicity - Ag dosing regimen396608Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.35, 0.57]

    3.1 Once daily
81707Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.15, 0.63]

    3.2 Multiple daily
314901Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.36, 0.61]

 4 Severe nephrotoxicity - Ag dosing regimen204199Risk Ratio (M-H, Fixed, 95% CI)0.16 [0.05, 0.49]

    4.1 Once daily
61526Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.03, 1.14]

    4.2 Multiple daily
142673Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.03, 0.60]

 
Comparison 4. Documented infections (subgroup analysis)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All cause mortality131188Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.56, 1.17]

 2 Treatment failure35Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 same beta-lactam
81043Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.93, 1.19]

    2.2 different beta-lactam
272740Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.82, 0.95]

 
Comparison 5. Bacteraemia (subgroup analysis)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All cause mortality14676Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.46, 1.18]

 2 Treatment failure26Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 same beta-lactam
6395Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.90, 1.23]

    2.2 different beta-lactam
201149Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.78, 0.95]

 
Comparison 6. Gram-negative infections (subgroup analysis)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All cause mortality16376Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.37, 1.11]

 2 Treatment failure29Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 same beta-lactam
7261Risk Ratio (M-H, Fixed, 95% CI)1.34 [1.03, 1.74]

    2.2 different beta-lactam
22603Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.60, 0.90]

 
Comparison 7. Pseudomonas infections (subgroup analysis)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All cause mortality971Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.34, 2.24]

 2 Treatment failure16Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 same beta-lactam
349Risk Ratio (M-H, Fixed, 95% CI)1.41 [0.90, 2.22]

    2.2 different beta-lactam
1399Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.60, 1.31]

 
Comparison 8. Haematological cancer patients (subgroup analysis)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All cause mortality223463Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.68, 1.13]

 2 Treatment failure32Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 same beta-lactam
8778Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.91, 1.20]

    2.2 different beta-lactam
243671Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.88, 1.01]

 
Comparison 9. Severe neutropenia (subgroup analysis)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All cause mortality6737Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.37, 1.24]

 2 Treatment failure11Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 same beta-lactam
2237Risk Ratio (M-H, Fixed, 95% CI)1.48 [1.12, 1.96]

    2.2 different beta-lactam
9871Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.84, 1.10]

 
Comparison 10. Monotherapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All cause mortality43Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 ceftazidime monotherapy
101868Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.70, 1.14]

    1.2 imipenem monotherapy
91164Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.68, 1.50]

    1.3 meropenem monotherapy
91921Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.77, 1.69]

    1.4 moxalactam monotherapy
2140Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.26, 1.06]

    1.5 piperacillin-tazobactam monotherapy
51093Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.40, 0.96]

    1.6 cefepime monotherapy
5802Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.61, 1.93]

    1.7 other monotherapy
4320Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.19, 2.25]

 2 Treatment failure65Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 same BL - ceftazidime
6647Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.94, 1.23]

    2.2 same BL - imipenem
167Risk Ratio (M-H, Fixed, 95% CI)3.05 [0.92, 10.10]

    2.3 same BL - piperacillin-tazobactam
3911Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.92, 1.18]

    2.4 same BL - cefepime
3343Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.84, 1.39]

    2.5 same BL - other monotherapy
144Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.30, 2.33]

    2.6 different BL - ceftazidime
101917Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.05]

    2.7 different BL - imipenem
141964Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.78, 1.01]

    2.8 different BL - meropenem
81542Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.79, 0.98]

    2.9 different BL - moxalactam
5402Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.60, 0.99]

    2.10 different BL - piperacillin-tazobactam
2203Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.53, 1.02]

    2.11 different BL - cefepime
5377Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.77, 1.22]

    2.12 different BL - other
7575Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.83, 1.28]

 
Comparison 11. Adults vs. children

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All cause mortality447186Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.75, 1.02]

    1.1 children
9789Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.64]

    1.2 mixed/ undefined
62089Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.52, 1.04]

    1.3 adults
294308Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.77, 1.12]

 2 Treatment failure68Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 same BL - children
2163Risk Ratio (M-H, Fixed, 95% CI)1.34 [0.95, 1.90]

    2.2 same BL - mixed
3985Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.90, 1.14]

    2.3 same BL - adults
111685Risk Ratio (M-H, Fixed, 95% CI)1.17 [1.04, 1.32]

    2.4 different BL - children
121086Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.87, 1.18]

    2.5 different BL - mixed/ undefined
112263Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.83, 1.04]

    2.6 different BL - adults
294160Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.85, 0.96]

 
Comparison 12. Sensitivity analysis (outcome in parenthesis)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Allocation concealment (mortality)447186Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.75, 1.02]

    1.1 A
245489Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.73, 1.05]

    1.2 B
191625Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.61, 1.24]

    1.3 C
172Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Intention-to-treat vs. efficacy analysis (mortality)447186Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.75, 1.02]

    2.1 efficacy analysis
204432Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.73, 1.06]

    2.2 intention-to-treat analysis
242754Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.66, 1.15]

 3 Unit of randomisation (mortality)447186Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.75, 1.02]

    3.1 patient analysis
193711Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.66, 1.08]

    3.2 episode analysis
253475Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.73, 1.11]

 4 Publication status (mortality)437110Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.75, 1.03]

    4.1 jounal publication
345811Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.71, 1.00]

    4.2 other publication or un-published
91299Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.72, 1.59]

 5 Trial size (mortality)447186Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.75, 1.02]

    5.1 number randomised>median 94p
195438Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.75, 1.07]

    5.2 number randomised<median 94p
251748Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.55, 1.11]

 6 Allocation concealment (failure)6910357Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.93, 1.01]

    6.1 same beta-lactam - A
61310Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.99, 1.22]

    6.2 same beta-lactam - B
91451Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.99, 1.30]

    6.3 same beta-lactam - C
172Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.73, 1.46]

    6.4 different beta-lactam - A
214422Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.88, 1.00]

    6.5 different beta-lactam - B
313052Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.79, 0.96]

    6.6 different beta-lactam - C
150Risk Ratio (M-H, Fixed, 95% CI)0.8 [0.48, 1.34]

 7 Intention to treat vs. efficacy analysis (failure)70Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 same BL - efficacy analysis
121884Risk Ratio (M-H, Random, 95% CI)1.11 [0.98, 1.26]

    7.2 same BL - ITT analysis
4949Risk Ratio (M-H, Random, 95% CI)1.04 [0.91, 1.19]

    7.3 different BL - efficacy analysis
386010Risk Ratio (M-H, Random, 95% CI)0.95 [0.88, 1.01]

    7.4 different BL - ITT analysis
161659Risk Ratio (M-H, Random, 95% CI)0.80 [0.71, 0.91]

 8 Intention to treat vs. efficacy analysis, assuming dropouts=failures (failure)68Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 same BL - efficacy analysis
51238Risk Ratio (M-H, Fixed, 95% CI)1.15 [1.02, 1.29]

    8.2 same BL - ITT analysis
101590Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.96, 1.19]

    8.3 different BL - efficacy analysis
203037Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.04]

    8.4 different BL - ITT analysis
334922Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.86, 0.97]

 9 Trial size (failure)70Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 same BL no. randomised>median
72210Risk Ratio (M-H, Fixed, 95% CI)1.10 [1.01, 1.21]

    9.2 same BL no. randomised<median
9623Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.94, 1.39]

    9.3 different BL no. randomised>median
286032Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.92, 1.03]

    9.4 different BL no. randomised<median
261637Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.67, 0.84]

 10 Unit of randomisation (failure)71Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 same beta-lactam - patient
61212Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.93, 1.19]

    10.2 same beta-lactam - episode
101621Risk Ratio (M-H, Fixed, 95% CI)1.16 [1.04, 1.30]

    10.3 different beta-lactam - patient
203137Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.82, 0.96]

    10.4 different beta-lactam - episode
364656Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.89, 1.01]

 11 Blinding (failure)71Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 same beta-lactam - double blind
1754Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.90, 1.20]

    11.2 same beta-lactam - other
152079Risk Ratio (M-H, Fixed, 95% CI)1.14 [1.04, 1.26]

    11.3 different beta-lactam - double blind
3623Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.83, 1.55]

    11.4 different beta-lactam - other
527113Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.87, 0.96]

 12 Publication status (failure)71Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 same beta-lactam - journal publication
122496Risk Ratio (M-H, Fixed, 95% CI)1.12 [1.02, 1.21]

    12.2 same beta-lactam - other
4337Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.79, 1.41]

    12.3 different beta-lactam - journal publication
445866Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.86, 0.96]

    12.4 different beta-lactam - other
111870Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.89, 1.12]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Appendix 1. MEDLINE search strategy

Medline Ovid

1   exp Neoplasms/
2   Bone Marrow Transplantation/
3   (cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or adenocarcinoma* or leukemia* or leukaemia* or bone marrow transplant*).mp.
4   1 or 2 or 3
5   exp Agranulocytosis/
6   (agranulocytosis or neutropen* or neutropaen* or granulocytopen* or granulocytopaen* or granulopen* or granulopaen*).mp.
7   5 or 6
8   exp beta-Lactams/
9   exp Anti-Bacterial Agents/
10 (beta-lactam* or antibiotic* or antimicrob* or anti-microb* or antibacteria* or anti-bacteria*).mp.
11 8 or 9 or 10
12 exp Aminoglycosides/
13 (aminoglycoside* or gentamicin or gentamycin or amikacin or amikacyn or tobramicin or tobramycin or kanamicin or kanamycin or netilmicin or netilmycin).mp.
14 12 or 13
15 4 and 7 and 11 and 14
16 randomized controlled trial.pt.
17 controlled clinical trial.pt.
18 randomized.ab
19 placebo.ab.
20 drug therapy.fs.
21 randomly.ab.
22 trial.ab.
23 groups.ab.
24 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23
25 15 and 24

key:

mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier, pt=publication type, ab=abstract, sh=subject heading, ti=title

 

 

Appendix 2. EMBASE search strategy

Embase Ovid

1   exp neoplasm/
2   exp bone marrow transplantation/
3   (cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or adenocarcinoma* or leukemia* or leukaemia* or bone marrow transplant*).mp.
4   1 or 2 or 3
5   agranulocytosis/
6   exp neutropenia/
7   (agranulocytosis or neutropen* or neutropaen* or granulocytopen* or granulocytopaen* or granulopen* or granulopaen*).mp.
8   5 or 6 or 7
9   exp antiinfective agent/
10 (beta-lactam* or antibiotic* or antimicrob* or anti-microb* or antibacterial* or anti-bacteria*).mp.
11 9 or 10
12 exp aminoglycoside antibiotic agent/
13 (aminoglycoside* or gentamicin or gentamycin or amikacin or amikacyn or tobramicin or tobramycin or kanamicin or kanamycin or netilmicin or netilmycin).mp.
14 12 or 13
15 4 and 8 and 11 and 14
16 crossover procedure/
17 double-blind procedure/
18 randomized controlled trial/
19 single-blind procedure/
20 random*.mp.
21 factorial*.mp.
22 (crossover* or cross over* or cross-over*).mp.
23 placebo*.mp.
24 (double* adj blind*).mp.
25 (singl* adj blind*).mp.
26 assign*.mp.
27 allocat*.mp.
28 volunteer*.mp.
29 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28
30 15 and 29

key

[mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

 

Appendix 3. CENTRAL search strategy

CENTRAL/DARE

 #1   MeSH descriptor Neoplasms explode all trees
#2   MeSH descriptor Bone Marrow Transplantation, this term only
#3   (cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or adenocarcinoma* or leukemia* or leukaemia* or bone marrow transplant*)
#4   (#1 OR #2 OR #3)
#5   MeSH descriptor Agranulocytosis explode all trees
#6   (agranulocytosis or neutropen* or neutropaen* or granulocytopen* or granulocytopaen* or granulopen* or granulopaen*)
#7   (#5 OR #6)
#8   MeSH descriptor beta-Lactams explode all trees
#9   MeSH descriptor Anti-Bacterial Agents explode all trees
#10  beta-lactam* or antibiotic* or antimicrob* or anti-microb* or antibacterial* or anti-bacteria*
#11  (#8 OR #9 OR #10)
#12  MeSH descriptor Aminoglycosides explode all trees
#13  (aminoglycoside* or gentamicin or gentamycin or amikacin or amikacyn or tobramicin or tobramycin or kanamicin or kanamycin or netilmicin or netilmycin)
#14  (#12 OR #13)
#15  (#4 AND #7 AND #11 AND #14)

 

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

Last assessed as up-to-date: 7 June 2013.


DateEventDescription

26 February 2014AmendedContact details updated.



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

Protocol first published: Issue 2, 2001
Review first published: Issue 2, 2002


DateEventDescription

7 June 2013New citation required but conclusions have not changedNo change to conclusions.

10 April 2013New search has been performedThree new trials identified.

7 November 2007New search has been performedNew studies found and included or excluded: 01/06/07.

Addition of infection-related mortality as a protocol-defined outcome.
Search updated and expanded the search of conference proceedings (ECCMID, ASH).
Deleted the limitation on inclusion of trials with >30% dropouts and assessed the effect of dropouts through sensitivity analyses.
The comparisons of 'same' and 'different' beta-lactams separated throughout the review for the analysis of treatment failure.
Re-wrote results, discussion and implications for further practice and research.

17 April 2003New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

Mical Paul performed the search and article retrieval; applied inclusion and exclusion criteria; performed quality assessment and data extraction; contacted authors; analysed results and wrote the review. Yaakov Dickstein conducted the search for the 2012 update, extracted the data from new trials, entered data into RevMan and wrote the review for the 2012 update. Karla Soares-Weiser applied inclusion and exclusion criteria; performed data extraction; analysed results-all for the previous version of the review and commented on all drafts and final version of the review. Simona Grozinsky-Glasberg assisted with search; retrieved articles; applied inclusion and exclusion criteria and assisted in data extraction-all for the previous version of the review. Leonard Leibovici performed search; applied inclusion and exclusion criteria; performed data extraction; assisted with author correspondence; analysed results; assisted in writing the review and commented on all drafts and final version of the review.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Index terms
 

Internal sources

  • Rabin Medical Center, Beilison Campus, Skidal Foundation, Israel.
  • Tel-Aviv University, Sackler Faculty of Medicine, Israel.

 

External sources

  • EU 5th Framework: TREAT project (grant number: 1999-11459), Not specified.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Agaoglu 2001 {published and unpublished data}
  • Agaoglu L, Devecioglu O, Anak S, Karakas Z, Yalman N, Biner B, et al. Cost-effectiveness of cefepime + netilmicin or ceftazidime + amikacin or meropenem monotherapy in febrile neutropenic children with malignancy in Turkey. Journal of Chemotherapy 2001;13(3):281-7.
Ahmed 2007 {published and unpublished data}
  • Ahmed N, Borollosy N, Beshlawy A, Mahallawy H, Haddad A. Outpatient single dose ceftriaxone and amikacin vs. imipenem/cilastatin monotherapy in the empiric treatment of pediatric patients with high risk fever and neutropenia: a randomized, prospective clinical trial. Proceedings of Meeting of the American Society of Hematology; Abstract No. 887. 2003.
  • Ahmed N, Borollosy N, Beshlawy A, Mahallawy H, Haddad A. Outpatient single dose ceftriaxone and amikacin vs. imipenem/cilastatin monotherapy in the empiric treatment of pediatric patients with high risk fever aneutropenia: a randomized, prospective clinical trial. Proceedings of ASCO Meeting; Abstract No. 8520. 2004.
  • Ahmed N, Mahallawy HA, Ahmed IA, Nassif S, Beshlawy A, Haddad A. Early hospital discharge versus continued hospitalization in febrile pediatric cancer patients with prolonged neutropenia: a randomized, prospective study. Pediatric Blood Cancer 2007;49:786-92.
Akova 1999 {published and unpublished data}
  • Akova M, Akan H, Korten V, Biberoglu K, Hayran M, Unal S, et al. Comparison of meropenem with amikacin plus ceftazidime in the empirical treatment of febrile neutropenia: a prospective randomised multicentre trial in patients without previous prophylactic antibiotics. Meropenem Study Group of Turkey. International Journal of Antimicrobial Agents 1999;13(1):15-9.
Alanis 1983 {published data only}
  • Alanis A, Rehm S, Weinstein AJ. Comparative efficacy and toxicity of moxalactam and the combination of nafcillin and tobramycin in febrile granulocytopenic patients. Cleveland Clinic Quarterly 1983;50(4):385-95.
Antmen 2001 {published data only}
  • Antmen B, Sasmaz I, Tanyeli A, Yaman A, Kocabas E, Bayram I, et al. Initial empiric antibiotic treatments in childhood febrile neutropenia: meropenem versus ceftazidime plus amikacin combination. Proceedings of the 11th European Congress of Clinical Microbiology and Infectious Diseases Apr 1-4; Istanbul, Turkey. 2001:Poster 1087. [MEDLINE: http://www.akm.ch/eccmid2001]
Au 1994 {published data only}
  • Au E, Tow A, Allen DM, Ang PT. Randomised study comparing imipenem/cilastatin to ceftriaxone plus gentamicin in cancer chemotherapy-induced neutropenic fever. Annals of the Academy of Medicine Singapore 1994;23(6):819-22.
Behre 1998 {published and unpublished data}
  • Behre G, Link H, Maschmeyer G, Meyer P, Paaz U, Wilhelm M, et al. Meropenem monotherapy versus combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients. Annals of Hematology 1998;76(2):73-80.
Bezwoda 1985 {published data only}
  • Bezwoda WR, Derman DP, Perkins S, Cassel R. Treatment of neutropenic infection: a randomized trial comparing latamoxef (moxalactam) with cephradine plus tobramycin. Journal of Antimicrobial Chemotherapy 1985;15(2):239-45.
Borbolla 2001 {published data only}
  • Borbolla JR, Lopez-Hernandez MA, Gonzalez-Avante M, DeDiego J, Trueba E, Alvarado ML, et al. Comparison of cefepime versus ceftriaxone-amikacin as empirical regimens for the treatment of febrile neutropenia in acute leukemia patients. Chemotherapy 2001;47(5):381-4.
Cometta 1996 {published data only}
  • Cometta A, Calandra T, Gaya H, Zinner SH, De Bock R, Del Favero A, et al (EORTC). Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. Antimicrobial Agents and Chemotherapy 1996;40(5):1108-15.
Conte 1996 {published data only}
  • Conte G, Flores C, Alfaro J, Araos D, Thompson L, Barahona O, et al. Single agent sulperazone vs. two agent ceftazidime-amikacin in high risk febrile neutropenic patients. Blood 1996;88(10):30b.
Corapcioglu 2005 {published data only}
  • Corapcioglu F, Sarper N. Cefepime versus ceftazidime + amikacin as empirical therapy for febrile neutropenia in children with cancer: a prospective randomized trial of the treatment efficacy and cost. Pediatric Hematologic Oncology 2005;22(1):59-70.
Cornelissen 1992 {published data only}
  • Cornelissen JJ, de Graeff A, Verdonck LF, Branger T, Rozenberg-Arska M, Verhoef J, et al. Imipenem versus gentamicin combined with either cefuroxime or cephalothin as initial therapy for febrile neutropenic patients. Antimicrobial Agents and Chemotherapy 1992;36(4):801-7.
Cornely 2001 {unpublished data only}
  • Cornely OA, Reichert D, Buchheidt D, Maschmeyer G, Wilhelm M, Chiel X (for the Paul-Erlich-Gesellschaft). Three-armed multicenter randomized study on the empiric treatment of neutropenic fever in a high risk patient population (PEG study III). Proceedings of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy;Abstract L-775. 2001.
  • Maschmeyer G. Cefepime in the empirical initial treatment of febrile neutropenic cancer patients [Cefepim in der empirischen Initial therapie bei febrilen neutropenischen Patienten mit mignen erkankungen]. Chemotherapie Journal 2004;13:174-180.
De la Camara 1997 {published and unpublished data}
  • De la Camara R, Figuera A, Sureda A, Hermida G, Verge G, Olalla I, et al. Meropenem versus ceftazidime plus amikacin in the treatment of febrile episodes in neutropenic patients: a randomized study. Haematologica 1997;82(6):668-75.
Del Favero 2001 {published data only}
  • 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. Clinical Infectious Diseases 2001;33(8):1295-301.
  • Del Favero A, Micozzi A, Bucaneve G, Martino P. Double-blind, randomised, clinical trial comparing monotherapy with piperacillin-tazobactam vs piperacillin-tazobactam plus amikacin as empiric therapy for febrile neutropenic cancer patients. Proceedings of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; Abstract No. 1092. 1999.
  • Micozzi A, Bucaneve G, Menichetti F, Martino P, Del Favero A, G.I.M.E.M.A.Infection Program. 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, Abstract 63.
De Pauw 1983 {published data only}
  • De Witte T. Antibiotic treatment in patients with haematological malignancies and bone marrow transplantation. Perspectives on Therapeutics in Northern Europe. Vol. 46, London: Glaxo, 26 September 1986:6-7.
  • de Pauw BE, Kauw F, Muytjens H, Williams KJ, Bothof T. Randomized study of ceftazidime versus gentamicin plus cefotaxime for infections in severe granulocytopenic patients. Journal of Antimicrobial Chemotherapy 1983;12 Suppl A:93-9.
De Pauw 1994 {published and unpublished data}
  • De Pauw BE, Deresinski SC, Feld R, Lane Allman EF, Donnelly JP. Ceftazidime compared with piperacillin and tobramycin for the empiric treatment of fever in neutropenic patients with cancer: a multicenter randomized trial. The Intercontinental Antimicrobial Study Group. Annals of Internal Medicine 1994;120(10):834-44.
  • De Pauw BE, Feld R, Deresinski S, Donnelly JP, Lane-Allman E. Multicentre, randomised, comparative study of ceftazidime vs piperacillin as empirical therapy for febrile granulocytic patients. Proceedings of the Sixth International Symposium of Infections in the Immunocompromised Host. Abstract No 116. 1990.
  • Dompeling EC, Donnelly JP, Deresinski SC, Feld R, Lane Allman EF, De Pauw BE. Early identification of neutropenic patients at risk of gram positive bacteraemia and the impact of empirical administration of vancomycin. European Journal of Cancer 1996;32a(8):1332-9.
Dincol 1998 {published and unpublished data}
  • Dincol D, Arican A, Aydin F, Samur M, Willke A, Akbulut H, et al. A comparison of imipenem monotherapy versus cefoperazone/sulbactam plus amikacin combination treatment in febrile neutropenic cancer patients. Cancer Journal 1998;11(2):89-93.
Doyen 1983 {published and unpublished data}
  • Doyen C, Tepantondele JM, Wauters G, Michaux JL. A randomized therapeutic trial for ceftazidime versus ceftazidime and amikacin in febrile granulopenic patients. Proceedings of the 13th International Congress of Chemotherapy. Vienna: Spitzy KH, 1983:26-29.
Duzova 2001 {published and unpublished data}
  • Duzova A, Kutluk T, Kanra G, Buyukpamukcu M, Akyuz C, Secmeer G, Ceyhan, M. Monotherapy with meropenem versus combination therapy with piperacillin plus amikacin as empiric therapy for neutropenic fever in children with lymphoma and solid tumors. The Turkish Journal of Pediatrics 2001;43(2):105-9.
El Haddad 1995 {published data only}
  • El Haddad AMA. Comparison of cefoperazone-sulbactam versus piperacillin plus amikacin as empiric therapy in pediatric febrile neutropenic cancer patients. Current Therapeutic Research Clinical and Experimental 1995;56(10):1094-9.
Erjavec 1994 {published data only}
  • Erjavec Z, de Vries Hospers HG, van Kamp H, van der Waaij D, Halie MR, Daenen SM. Comparison of imipenem versus cefuroxime plus tobramycin as empirical therapy for febrile granulocytopenic patients and efficacy of vancomycin and aztreonam in case of failure. Scandinavian Journal of Infectious Diseases 1994;26(5):585-95.
Esteve 1997 {published data only}
  • 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;10(Suppl 1 (Pt 2)):229b. Abstract 3767.
Gaytan-Martinez 2002 {published data only}
  • Gaytan-Martinez JE, Mateos-Garcia E, Casanova LJ, Fuentes-Allen JL, Sanchez-Cortes E, Manjarrez-Tellez B, et al. Efficacy of empirical therapy with cefepime compared with ceftazidime plus amikacin in febrile neutropenic patients. Proceedings of the Annual Meeting of the American Society of Hematology. 2002:Abstract No. 3655.
Gibson 1989 {published data only}
  • Gibson J, Date L, Joshua DE, Young GA, Wilson A, Benn R, et al. A randomised trial of empirical antibiotic therapy in febrile neutropenic patients with hematological disorders: ceftazidime versus azlocillin plus amikacin. Australian and New Zealand Journal of Medicine 1989;19(5):417-25.
Gorschluter 2003 {published data only}
  • Glasmacher A, Hahn C, Molitor E, Fixson A, Mey U, Sauerbruch T, et al. A randomized comparison of piperacillin-tazobactam vs. ceftriaxone and gentamicin in 172 severely neutropenic patients with hematologic malignancies. Proceedings of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1999:Abstract 1090.
  • Gorschluter M, Hahn C, Fixson A, Mey U, Ziske C, Molitor E, et al. Piperacillin-tazobactam is more effective than ceftriaxone plus gentamicin in febrile neutropenic patients with hematological malignancies: a randomized comparison. Supportive Care in Cancer 2003;11(6):362-70.
Gribble 1983 {published data only}
  • Gribble MJ, Chow AW, Naiman SC, Smith JA, Bowie WR, Sacks SL, et al. Prospective randomized trial of piperacillin monotherapy versus carboxypenicillin-aminoglycoside combination regimens in the empirical treatment of serious bacterial infections. Antimicrobial Agents and Chemotherapy 1983;24(3):388-93.
Hansen 1986 {published data only}
  • Hansen SW, Friis H, Ernst P, Vejlsgaard R, Hansen HH. Latamoxef versus carbenicillin plus gentamicin or carbenicillin plus mecillinam in leukopenic, febrile patients with solid tumors. Acta Med Scand 1986;220(3):249-54.
Hense 2000 {published and unpublished data}
  • Hense J, Bertz H, Leifert J, Meusers P, Mertelsmann R, Brittinger G. Final results of a prospective randomized trial of bolus meropenem versus infusion meropenem versus ceftazidime/amikacin as empiric initial therapy for infections and fever of unknown origin in neutropenic patients with hematologic malignancies. Supportive Care in Cancer 2000;8:Suppl:160. Abstract 64.
  • Hense J, Uppenkamp M, Meusers P, Hofeler H, Brittinger G. Prospective randomized trial of bolus meropenem versus infusion meropenem versus ceftazidime/amikacin as empiric initial therapy for infections and fever of unknown origin in neutropenic patients with hematologic malignancies. Annals of Hematology 1998;77:Suppl 2:S199.
Hess 1998 {published data only}
  • Hess UBC, Rey K, Senn HJ. Monotherapy with piperacillin/tazobactam versus combination therapy with ceftazidime plus amikacin as an empiric therapy for fever in neutropenic cancer patients. Supportive Care in Cancer 1998;6:402-9.
Hung 2003 {published data only}
  • Hung KC, Chiu HH, Tseng YC, Wang JH, Lin HC, Tsai FJ, et al. Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empirical therapy for neutropenic fever in children with malignancy. Journal of Microbiology, Immunology, and Infection 2003;36(4):254-9.
Jacobs 1993 {published data only}
  • Jacobs RF, Vats TS, Pappa KA, Chaudhary S, Kletzel M, Becton DL. Ceftazidime versus ceftazidime plus tobramycin in febrile neutropenic children. Infection 1993;21(4):223-8.
Jimeno 2006 {published and unpublished data}
  • Jimeno A, Arcediano A, Bazares S, Amador ML, Gonzalez-Cortijo L, Ciruelos E, et al. Randomized study of cefepime versus ceftazidime plus amikacin in patients with solid tumors treated with high dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) with febrile neutropenia. Clinical Transplantation and Oncology 2006;8(12):889-95.
  • Jimeno A, Arcediano A, Gomez C, Bezares S, Castellano D, Paz-Ares L, et al. Randomized study of cefepime versus ceftazidime plus amikacin in febrile neutropenic patients with solid tumors treated with high dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS). Proceedings of the Annual Meeting of the American Society of Clinical Oncology; Abstract 3387. 2003.
Kiehl 2001 {published data only}
  • Kiehl MG, Bischoff M, Basara N, Guenzelmann S, Fauser AA. A prospective randomized trial comparing the efficacy and safety of piperacillin/tazobactam versus piperacillin/tazobactam plus netilmicin in the treatment of tebrile neutropenia in allogeneic stem cell recipients. Proceedings of the Interscience Conference on Antimicrobial Agents and Chemotherapy. 2001.
Kinsey 1990 {published data only}
  • Kinsey SE, Machin SJ, Goldstone AH. Ceftazidime monotherapy is as effective as ceftazidime combined with gentamicin in the treatment of febrile neutropenic patients. Journal of Hospital Infection 1990;15:49-53.
Kliasova 2001 {published data only}
  • Kliasova G, Savchenko V, Lubimova L, Mendeleeva L, Parovichnikova E, Tolkacheva T, et al. Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for febrile neutropenic bone marrow transplant patients. Proceedings of the 11th European Congress of Clinical Microbiology and Infectious Diseases. 2001. [MEDLINE: http://www.akm.ch/eccmid2001/]
Koehler 1990 {published data only}
  • Koehler M, Bubala H, Sonta-Jakimczyk D, Wieczorek M, Janik-Moszant A, Kuder K. [Assessment of the efficacy of treating infections in hematopoietic proliferative diseases: monotherapy with ceftazidime and tobramycin combined with amoxycillin/ampicillin]. Pol Tyg Lek 1990;45(21-22):417-20.
Kojima 1994 {published and unpublished data}
  • 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. American Journal of Clinicial Oncology 1994;17(5):400-4.
Leyland 1992 {published data only}
  • Leyland MJ, Bayst K, Cohen J, Warren R, Newland AC, Bint AJ, et al. A comparative study of imipenem versus piperacillin plus gentamicin in the initial management of febrile neutropenic patients with haematological malignancies. Journal of Antimicrobial Chemotherapy 1992;30(6):843-54.
Lieschke 1990 {published and unpublished data}
  • Lieschke GJ, Bell D, Rawlinson W, Green M, Sheridan W, Morstyn G, et al. Imipenem/cilastatin versus tobramycin and piperacillin as initial empiric therapy for febrile episodes in neutropenic patients: interim analysis of a prospective randomized comparison. Australian and New Zealand Journal of Medicine 1990;3:Suppl 1:424.
Liu 1989 {published data only}
  • Liu CY, Wang FD. A comparative study of ceftriaxone plus amikacin, ceftazidime plus amikacin and imipenem/cilastatin in the empiric therapy of febrile granulocytopenic cancer patients. Chemotherapy 1989;35:Suppl 2:16-22.
Marie 1991 {published data only}
  • 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 [Traitement empirique des episodes febriles survenant chez les patients cancereux presentant une neutropenie prolongee: essai comparatif ceftazidime seule, ceftazidime+amikacine et ceftazidime+vancomycine]. Medicine et Maladies Infectieuses 1991;21:386-8.
  • Marie JP, Pico JL, Chiche D, Fitoussi F, Delmer A, Baume D, et al. [Antibiotic therapy protocol using ceftazidime 3g/day alone or in combination with vancomycin or amikacin. In febrile episodes in neutropenic patients]. [French] [Protocole d'antibiotherie utilisant la ceftazidime a la dose de 3g/jour seule ou en association avec la vancomycin ou l'amikacin]. Presse Medicale 1988;17(37):1968-70.
  • 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. Journal of Antimicrobial Chemotherapy 1998;41(Suppl D):57-64.
  • Pico JL, Marie JP, Chiche D, Guiguet M, Andremont A, Lapierre V, et al. Should vancomycin be used empirically in febrile patients with prolonged and profound neutropenia? Results of a randomized trial. Eur J Med 1993;2(5):275-80.
Matsui 1991 {published and unpublished data}
  • Matsui K, Masuda N, Takada M, Kusunoki Y, Fukuoka M. A randomized trial comparing imipenem/cilastatine alone with latamoxef plus tobramycin in febrile neutropenic patients with lung cancer. Jpn J Clin Oncol 1991;21(6):428-34.
Miller 1993 {published data only}
  • Miller JA, Butler T, Beveridge RA, Kales AN, Binder RA, Smith LJ, et al. Efficacy and tolerability of imipenem-cilastatin versus ceftazidime plus tobramycin as empiric therapy of presumed bacterial infection in neutropenic cancer patients. Clinical Therapeutics 1993;15(3):486-99.
Morgan 1983 {published data only}
  • Morgan G, Duerden BI, Lilleyman JS. Ceftazidime as a single agent in the management of children with fever and neutropenia. Journal of Antimicrobial Chemotherapy 1983;12:Suppl A:347-51.
Norrby 1987 {published and unpublished data}
  • Norrby SR, Vandercam B, Louie T, Runde V, Norberg B, Anniko M, et al. Imipenem/cilastatin versus amikacin plus piperacillin in the treatment of infections in neutropenic patients: a prospective, randomized multiclinic study. Scandinavian Journal of Infectious Diseases Supplement 1987;52:65-78.
  • Vandercam B, Ezzeddine H, Agaliotis D, Gala JL, Gigi J, Wauters G, et al. Imipenem/cilastatin versus piperacillin plus amikacin as empiric therapy in the treatment of febrile episodes in neutropenic patients with haematologic malignancies. Acta Clinica Belgica 1989;44(2):99-109.
Novakova 1990 {published data only}
  • Novakova I, Donnelly P, De Pauw B. Amikacin plus piperacillin versus ceftazidime as initial therapy in granulocytopenic patients with presumed bacteremia. Scandinavian Journal of Infectious Diseases 1990;22(6):705-11.
Novakova 1991 {published data only}
  • Novakova IR, Donnelly JP, de Pauw BE. Ceftazidime with or without amikacin for the empiric treatment of localized infections in febrile, granulocytopenic patients. Annals of Hematology 1991;63(4):195-200.
Ozyilkan 1999 {published and unpublished data}
  • Ozyilkan O, Yalcintas U, Baskan S. Imipenem-cilastatin versus sulbactam-cefoperazone plus amikacin in the initial treatment of febrile neutropenic cancer patients. The Korean Journal of Internal Medicine 1999;14(2):15-9.
Papachristodoulou 96 {published data only}
  • Papachristodoulou A, Vaslamatzis M, Xynogalos S, Papacharalambous A, Alexopoulos CG. Ceftazidime (CFZ) monotherapy as empirical initial treatment of febrile neutropenia cancer patients (Pts). Annals of Oncology 1996;7:Suppl 5:140. Abstract 676.
Pegram 1984 {published data only}
  • 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.
  • 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}
  • Pellegrin JL, Marit G, Fourche J, Broustet A, Texier MJ, Leng B, et al. Response to infection in patients with acute leukemia during remission induction treatment: ceftazidime versus cefotaxime + tobramycin [Etude prospective randomisee de la ceftazidime versus l'association cefotaxime-tobramycine, dans les leucemies aigues en aplasie therapeutique]. Presse Med 1988;17(37):1960-3.
Pereira 2009 {published data only (unpublished sought but not used)}
  • Pereira CAP, Petrilli AS, Carlesse FA, Luisi FAV, da 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.
Perez 1995 {published data only}
  • 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.
Petrilli 2003 {published and unpublished data}
  • 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.
Piccart 1984 {published data only}
  • 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. Antimicrobial Agents and Chemotherapy 1984;26(6):870-5.
Pickard 1983 {published and unpublished data}
  • 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.
  • Pickard W, Durack D, Gallis H. A randomized trial of moxalactam versus tobramycin plus ticarcillin in 50 febrile neutropenic patients. Proceedings of the 22nd Interscience Conference on Antimicrobial Agents and Chemotherapy; Abstract No. 66. 1982.
  • 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}
  • 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.
Rodjer 1987 {published data only}
  • 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.
Rodriguez 1995 {published data only}
  • 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}
  • 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.
Schuchter 1988 {published data only}
  • Schuchter L, Kaelin W, Petty B, Wingard J, Altomonte V, Dick J, et al. Ceftazidime vs ticalcillin and gentamicin in febrile neutropenic bone marrow transplant patients: a prospective, randomized, double-blind trial. Blood 1988;Abstract 1534(Suppl 1):1:406a.
Smith 1990 {published and unpublished data}
Tamura 2002 {published and unpublished data}
  • 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;71:248-55.
Tamura 2004 {published and unpublished data}
  • 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.
Wade 1987 {published data only}
  • Bustamante CI. Initial empiric therapy for fever in neutropenia. Recent Results in Cancer Research 1993;132:45-56.
  • Wade JC. Antibiotic therapy for the febrile granulocytopenic cancer patient: combination therapy versus monotherapy. Reviews of Infectious Diseases 1989;11:Suppl 7:S1572-81.
  • 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}
  • 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}
  • 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.
  • 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.
Yildirim 2008 {published data only (unpublished sought but not used)}
  • Yildirim I, Aytac S, Ceyhan M, Cetin M, Tuncer M, Cengiz AB, et al. Piperacillin/tazobactam plus amikacin versus carbapenem monotherapy as empirical treatment of febrile neutropenia in childhood hematological malignancies. Pediatric Hematology and Oncology 2008;25:291-9.
Zengin 2011 {published and unpublished data}
  • Zengin E, Sarper N, Kiliç S. Piperacillin/tazobactam monotherapy versus piperacillin/tazobactam plus amikacin as initial empirical therapy for febrile neutropenia in children with acute leukemia. Pediatric Hematology and Oncology 2011;28:311-20.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Berezin 2003 {published data only}
  • 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: http://www.akm.ch/eccmid2003/]
Bodey 1976 {published data only}
  • 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.
Bru 1986 {published data only}
  • 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.
Cetto 1983 {published data only}
  • Cetto GL, Todeschini G, Caramaschi G, Vinante F, Benini F, Perona G. Empiric therapy of infections in hematologic malignancies: a prospective, randomized trial. Tumori 1983;69:155-60.
D'Antonio 1992 {published data only}
  • D'Antonio D, Fioritoni G, Iacone A, Dell'Isola M, Natale D, D'Arcangelo L, et al. Randomized comparison of ceftriaxone versus ceftriaxone plus amikacin for the empirical treatment of infections in patients with altered host defense: microbiological and clinical evaluation. Chemotherapy 1992;38(6):420-7.
Drusano 1985 {published data only}
  • Drusano GL, Joshi J, Forrest A, Ruxer R, Standiford H, Leslie J, et al. Pharmacokinetics of ceftazidime, alone or in combination with piperacillin or tobramycin, in the sera of cancer patients. Antimicrobial Agents and Chemotherapy 1985;27(4):605-7.
EORTC 1987 {published data only}
  • The EORTC International Antimicrobial Therapy Cooperative Group. Ceftazidime combined with a short or long course of amikacin for empirical therapy of gram-negative bacteremia in cancer patients with granulocytopenia. New England Journal of Medicine 1987;317(27):1692-8.
Fainstein 1983 {published data only}
  • Fainstein V, Bodey GP, Elting L, Bolivar R, Keating MJ, McCredie KB, et al. A randomized study of ceftazidime compared to ceftazidime and tobramycin for the treatment of infections in cancer patients. Journal of Antimicrobial Chemotherapy 1983;12:Suppl A:101-10.
Hauer 1990 {published data only}
Hazel 1998 {published data only}
  • Hazel DL, Phelan L, Kinsey SE, Picton S, Todd N, Hawkey PM, et al. Piperacillin-tazobactam plus tobramycin is safe and effective therapy in children with febrile neutropenic episodes who are colonised with Enterobacteriaceae expressing extended spectrum β-lactamases. Blood 1998;10:Suppl 1 (Pt 1):612a. Abstract 2526.
Hoepelman 1988 {published data only}
  • 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.
  • 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.
Karthaus 1998 {published data only}
  • 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}
  • 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}
  • 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}
  • 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.
Petrilli 1991 {published data only}
  • 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.
Pizzo 1986 {published data only}
  • 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.
Reilly 1983 {published data only}
  • 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.
Sampi 1987 {published data only}
  • 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.
Sanz 2005 {published data only}
  • 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.
Sawae 1996 {published data only}
  • 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.
Wrzesien-Kus 2000 {published data only}
  • 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 ongoing studies

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Bilgir 2005 {published data only}
  • Bilgir O, Kadikoylu V, Bilgir F. The comparison of imipenem with piperacillin/tazobactam and amikacin combination in patients with hematological malignancies in the treatment of febrile neutropenia. Proceedings of the 10th Congress of the European Hematology Association. 2005:Abstract No. 1021.

Additional references

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
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