This is not the most recent version of the article. View current version (7 JAN 2014)

Intervention Review

You have free access to this content

Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis

  1. Mical Paul1,*,
  2. Simona Grozinsky-Glasberg2,
  3. Karla Soares-Weiser3,
  4. Leonard Leibovici4

Editorial Group: Cochrane Anaesthesia Group

Published Online: 25 JAN 2006

Assessed as up-to-date: 11 NOV 2005

DOI: 10.1002/14651858.CD003344.pub2

How to Cite

Paul M, Grozinsky-Glasberg S, Soares-Weiser K, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD003344. DOI: 10.1002/14651858.CD003344.pub2.

Author Information

  1. 1

    Rambam Health Care Center. Haifa, Israel and Sackler Faculty of Medicine, Unit of Infectious Diseases, Tel Aviv, Israel

  2. 2

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

  3. 3

    Enhance Reviews Ltd, Wantage, UK

  4. 4

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

*Mical Paul, Unit of Infectious Diseases, Rambam Health Care Center. Haifa, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 49100, 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: 25 JAN 2006

SEARCH

This is not the most recent version of the article. View current version (07 JAN 2014)

 

Background

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

Sepsis is defined as the clinical evidence of infection, accompanied by a systemic inflammatory response such as fever. When associated with organ dysfunction, decreased blood flow in an organ (hypoperfusion), or abnormally low blood pressure (hypotension), sepsis is defined as severe (Bone 1992; Mandell 2004). Sepsis may be a response to direct microbial invasion or may be elicited by microbial signal molecules or toxin production. Infections may be lethal, with fatality rates ranging from less than 10% to more than 40% for those with severe sepsis (Moore 2001; Rangel-Frausto 1995; Russell 2000). Appropriate empirical antibiotic treatment, administered to the patient before identification of the pathogen or its antibiotic susceptibilities, has been shown to halve the fatality associated with sepsis (Bryant 1971; Ibrahim 2000; Leibovici 1998; Whitelaw 1992).

Regimens recommended for the empirical treatment of sepsis include: (1) a single broad-spectrum agent, commonly from the beta lactam class of antibiotics; and (2) a combination of a beta lactam antibiotic with an aminoglycoside antibiotic (Mandell 2004). Combination antibiotic therapy has several theoretical advantages. First, it may have a broader antibiotic spectrum. Second, the combination may possess an enhanced potential (synergism), when compared to the additive effect of each of the antibiotics assessed separately (Giamarellou 1986; Klastersky 1982). Third, combination therapy has been claimed to suppress the emergence of subpopulations of microorganisms resistant to the antibiotics (Allan 1985; Milatovic 1987). The disadvantages of combination therapy may include additional costs, enhanced drug toxicity, the possible induction of resistance caused by the broader antibiotic spectrum (Manian 1996; Weinstein 1985), and possible antagonism between specific drug combinations (Moellering 1986).

Aminoglycoside antibiotics are most active against Gram-negative bacteria (Mandell 2004). In addition, synergism between beta lactam antibiotics and aminoglycoside antibiotics has been repeatedly shown in vitro specifically for Gram-negative bacteria (Giamarellou 1986; Klastersky 1976; Klastersky 1982). Consequently, the benefit of combination therapy, if existent, may be more prominent in patients with Gram-negative infections. Other features related to the infection may affect prognosis. These include the site of infection and the specific causative pathogen. For example, infections caused by Pseudomonas aeruginosa have been shown to portend a poor prognosis (Baine 2001; Geerdes 1991; Leibovici 1997). We expect to deal with factors such as these, expected to underlie heterogeneity, using subgroup analysis where appropriate. Specific guidelines have been instituted for the empirical treatment of cancer patient with neutropenia, basing the suspicion of sepsis on fever alone (Hughes 2002). The authors have therefore considered studies addressing these patients in a separate review (Paul 2013).

Numerous studies have been conducted comparing beta lactam monotherapy to beta lactam-aminoglycoside combination therapy in patients with suspected or proven bacterial infections. Some trials have focused specifically on infections commonly caused by Gram-negative bacteria, such as urinary tract infections and hospital acquired infections, where the benefit of combination therapy may be more prominent. Nevertheless, superiority of either monotherapy or combination therapy has not been shown conclusively in these studies.

 

Objectives

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

Our objectives were:

  1. to compare beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy in patients with sepsis; and
  2. to estimate the rate of adverse effects with each treatment regimen, including the development of bacterial resistance to antibiotics.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  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

We included randomized or quasi-randomized controlled trials.

 

Types of participants

We included hospitalized patients with sepsis acquired either in the community or in the hospital (nosocomial). We defined sepsis as clinical evidence of infection, plus evidence of a systemic response to infection (Bone 1992). We excluded neonates and preterm babies. We also excluded studies including more than 15% neutropenic patients.

 

Types of interventions

We considered studies comparing the antibiotic regimens described below.

  1. Any intravenous beta-lactam antibiotic given as monotherapy, including:
    1. penicillins;
    2. beta lactam drugs plus beta lactamase inhibitors (e.g. co-amoxiclav);
    3. cephalosporins (e.g. ceftazidime, cefotaxime);
    4. carbapenems (e.g. imipenem, meropenem).
  2. Combination therapy of a beta lactam antibiotic (as specified) with one of the following aminoglycoside antibiotics:
    1. gentamicin;
    2. tobramycin;
    3. amikacin;
    4. netilmicin;
    5. streptomycin;
    6. isepamicin;
    7. sisomicin.

 

Types of outcome measures

 

Primary outcomes

All-cause fatality by the end of the study follow-up.

 

Secondary outcomes

  1. Treatment failure defined as death and/or one or more serious morbid events (persistence, recurrence, or worsening of clinical signs or symptoms of presenting infection; any modification of the assigned empirical antibiotic treatment; or any therapeutic invasive intervention required not defined in the protocol).
  2. Length of hospital stay.
  3. Dropouts: number of patients excluded from the outcome assessment after randomization.
  4. Superinfection: recurrent infections defined as new, persistent, or worsening symptoms and/or signs of infection associated with the isolation of a new pathogen (different pathogen, or same pathogen with different susceptibilities) or the development of a new site of infection.
  5. Colonization by resistant bacteria: the isolation of bacteria resistant to the beta lactam antibiotic, during or following antibiotic therapy, with no signs or symptoms of infection.
  6. Adverse effects:
    1. life-threatening or associated with permanent disability (severe nephrotoxicity; ototoxicity; anaphylaxis; severe skin reactions);
    2. serious: requiring discontinuation of therapy (other nephrotoxicity; seizures; pseudomembranous colitis; other allergic reactions);
    3. any other (other gastrointestinal; other allergic reactions).

 

Search methods for identification of studies

 

Electronic searches

We formulated a comprehensive search strategy in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress). The key words used for the search strategy are shown in Appendix 1.

We searched the Cochrane Infectious Diseases Group specialized trials register for relevant trials up to December 2002 using the search terms: ((aminoglycoside* OR netilmicin* OR gentamicin* OR amikacin* OR tobramycin* OR streptomycin* OR isepamicin* OR sisomicin*) AND (pneumonia* OR infection OR infect* OR sepsis OR bacter* OR bacteremia OR septicemia).

We searched the Cochrane Controlled Trials Register, (CENTRAL), (The Cochrane Library, Issue 3, 2004) using the same search terms.

We searched the following electronic databases in combination with the search strategy developed by The Cochrane Collaboration and detailed in the Cochrane Handbook for Systematic Reviews of Interventions to limit the search for randomized or quasi-randomized trials (Higgins 2005):

  1. MEDLINE (1966 to July 2004) using the search: (aminoglycoside* OR netilmicin* OR gentamicin* OR amikacin* OR tobramycin* OR streptomycin* OR isepamicin* OR sisomicin*) AND (combination OR combi*). In a second search, the terms (combination OR combi*) were replaced by endocarditis, Staphylococcus, Streptococcus or pneumonia to enhance the sensitivity and specificity of our search to these infections.
  2. EMBASE (1980 to March 2003) using the same search terms.
  3. LILACS (1982 to July 2004) using the same search terms.

 

Searching other resources

We searched the Interscience Conference of Antimicrobial Agents and Chemotherapy conference proceedings (1995 to 2003) for relevant abstracts.

We contacted the first or corresponding author of each included study, and the researchers active in the field, for information regarding unpublished trials or complementary information on their own trials.

We also checked the citations of major reviews and of all trials identified by the above methods for additional studies.

We did not have a language restriction.

 

Data collection and analysis

 

Study selection

One author (MP) inspected the abstract of each reference identified in the search and applied the inclusion criteria. Where relevant articles were identified, the full article was obtained and inspected independently by two authors (MP, IS or LL).

 

Quality assessment

We assessed the quality of the trials to be included for allocation sequence, allocation concealment, blinding, fatality outcome reporting, intention-to-treat analysis, and number of patients excluded from outcome assessment. Two authors (MP, IS or KSW) independently performed quality assessment. We based methodological quality classification on the evidence of a strong association between poor allocation concealment and over estimation of effect. We defined it as: A (low risk of bias; adequate allocation concealment); B (moderate risk of bias; some doubt about allocation concealment); and C (high risk of bias; inadequate allocation concealment) (Schulz 1995). We performed sensitivity analyses to assess the effect of study quality measures on effect estimates. We intend to assess the effect of number of exclusions on effect estimates (above or below 20%) in future updates of the review.

 

Data collection

Two authors (MP, IS or SG) independently extracted data from included trials. In case of disagreement between the two authors, a third author (KSW, LL) independently extracted the data. A third author (KSW or LL) also extracted the data in 10% of the studies, selected at random. We discussed data extraction, documented decisions, and contacted authors of all studies for clarification. We resolved differences in the data extracted by discussion. We also documented the justification for excluding studies from the review.

We identified the trials by the name of the first author and the year in which the trial was first published, and listed in chronological order. We extracted, checked and recorded the following data.

Characteristics of trials:

  1. date, location, and setting of trial;
  2. publication status;
  3. country of origin;
  4. design (intention-to-treat, method of randomization);
  5. duration of study follow-up;
  6. performance of surveillance cultures (routine cultures for the detection of colonization);
  7. sponsor of trial.

Characteristics of patients:

  1. number of participants in each group;
  2. age (mean and standard deviation, or median and range);
  3. number of patients with renal failure before treatment;
  4. number of patients with shock.

Characteristics of infection:

  1. number of patients with infections caused by bacteria resistant to the administered beta lactam antibiotic;
  2. number of patients with nosocomial infections;
  3. number of patients with bacteraemia;
  4. number of patients with bacteriologically documented infection;
  5. number of patients with infections caused by Gram-negative bacteria;
  6. number of patients with Gram-negative bacteraemia;
  7. number of patients with documented Pseudomonas infections (Pseudomonas isolated in the blood or specimen(s) obtained from suspected site(s) of infection);
  8. number of patients with:
    1. urinary tract infection;
    2. pneumonia;
    3. intra-abdominal infection;
    4. skin and soft tissue infection; and
    5. infection of unknown origin.

Characteristics of interventions:

  1. antibiotic type and dose;
  2. duration of therapy (mean).

Characteristics of outcome measures:

  1. number of deaths at the end of the follow-up period;
  2. number of patients failing treatment (as defined);
  3. adverse reactions (as defined) in each group;
  4. loss of follow-up (dropouts) before the end of the study in each group;
  5. number of patients developing super-infection;
  6. number of patients developing colonization (as defined) with resistant bacteria;
  7. duration of fever and hospital stay.

We collected outcome measures on an intention-to-treat basis whenever possible. Where such data were not presented, we sought information from the authors, and if unavailable, per-protocol results were used. For failure outcome, we performed sensitivity analyses comparing these results with a 'presumed all intention to treat', which we achieved by counting all dropouts as failures. We could not make such an assumption in studies that did not specify the number of dropouts per study arm, and we analysed these studies separately.

 

Data synthesis

We calculated relative risks for dichotomous data. Continuous outcomes were unavailable for this review. We will use weighted mean differences for continuous outcomes in future updates of the review. We initially assessed heterogeneity in the results of the trials using a chi-squared test of heterogeneity (P < 0.1). We used a fixed effect model throughout the review, as the I2 measure of inconsistency was low for all comparisons. We compared results obtained by the fixed effect model to those obtained by a random effect model for the major outcomes. We explored the following factors to explain heterogeneity in relation to the major outcomes:

  1. infections caused by Pseudomonas sp. versus all other infections;
  2. Gram-negative versus all other infections; and
  3. urinary tract infections versus other sites of infection.

We performed subgroup analysis by these factors where data were available. For subgroup analyses we extracted all-cause fatality and treatment failures outcomes. We adjusted the descriptive mean mortality rate in included studies to the inverse of the mortality variance between the trials.

We examined a funnel plot of SE(log(relative risk)) versus relative risk of each study in order to estimate potential selection bias (publication and language).

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  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 search strategy resulted in 5568 references. We filtered double references, and screened 2805 different abstracts for inclusion. We did not evaluate studies in which the comparator antibiotic regimens were clearly incompatible with inclusion criteria in depth. We similarly excluded non-randomized and non-human studies.

We retrieved 145 studies for full-text inspection, of which we excluded 67 publications, representing 63 studies (see table of ' Characteristics of excluded studies'), and categorized two as awaiting assessment (see Additional  Table 1, and 'Table of studies awaiting assessment'). Several studies compared monotherapy versus combination therapy among patients with cystic fibrosis. Patients in these studies typically do not have fever or other signs of sepsis when entering the trial, and thus did not fulfil inclusion criteria for this review. These studies are included in a separate review (Elphick 2005). Seventy-eight studies fulfilled inclusion criteria. Fourteen were double publications, and thus we have included 64 trials in this review. We requested complementary information from nearly all the authors, and included complementary data in 22 studies (see references to studies).

We have detailed study characteristics in the table of ' Characteristics of included studies'. The included studies were performed between the years 1968 to 2001. Twenty-two were multi-centred. Twenty-one were performed in the USA or Canada, 34 in Europe, and 10 in other countries.

The studies included 7586 patients. The median number of included patients per trial was 87.5 (range 20 to 580). Two trials (Cardozo 2001; Naime Libien 1992) included children, while all other trials were restricted to or included mostly adults.

The studies differed by the type of population and infection targeted (see table of ' Characteristics of included studies'). Most trials (designated 'sepsis') included patients with severe sepsis, suspected Gram-negative infections (25 trials), or pneumonia (16 trials). The adjusted mean fatality rate in these studies was 8.6%. Eleven trials included patients with intra-abdominal infections, related mainly to the biliary tract (designated 'abdominal'). The mean fatality in these trials was 1.7%. Seven trials were restricted to patients with urinary tract infections (UTIs), all hospitalized, mainly women (UTI). Five of these studies reported fatality, and no deaths occurred in four. Finally, five of the studies included in the review targeted patients with Gram-positive infections, mainly endocarditis. We will present results for these infections separately, in addition to their inclusion in the overall analysis.

Most studies compared the initial, empirical antibiotic treatment administered to the patients. Four studies assessed the empirical treatment of a specific infection by randomizing patients empirically and evaluating only those subsequently fulfilling criteria for the specific infection. Two such studies randomized patients with suspected endocarditis and evaluated only those with Staphylococcus aureus bacteraemia and proven endocarditis (Abrams 1979; Korzeniowski 1982). The other two randomized patients with suspected biliary tract infections and evaluated only patients with a surgically proven diagnosis (Gerecht 1989; Yellin 1993). Non-evaluated patients in these studies were not counted as dropouts, since the study design defined evaluation only for patients fulfilling definitive criteria. Eight studies, focusing on patients with specific infections or pathogens (e.g., cholecystitis, Staphylococcal infections, etc.), tested the effect of monotherapy versus combination therapy semi-empirically. In these studies (designated 'semi-empirical', see table of ' Characteristics of included studies') randomization occurred after the specific infection was documented, and patients could have received prior antibiotic treatment for this infection. Analysis of empirical and semi-empirical studies was not separated.

The specific antibiotic regimens used are detailed in the table of ' Charcteristics of included studies'. Forty-four studies compared a single beta-lactam drug to a different, narrower spectrum, beta-lactam combined with an aminoglycoside (designated 'different BL'). Sixteen 'different BL' studies reported baseline susceptibility rates of the pathogens isolated on admission to the beta-lactam. The beta-lactam used in the combination arm covered less pathogens than the monotherapy beta-lactam in 13 studies, while the opposite occurred in two studies only. Twenty studies compared the same beta-lactam (designated 'same BL'). Results obtained from studies comparing same and different beta-lactams were kept separated throughout all efficacy analyses. The aminoglycoside was administered once daily in six trials (Cardozo 2001; Jaspers 1998; Rubinstein 1995; Sandberg 1997; Sexton 1998; Speich 1998). Other trials administered the aminoglycosides multiple daily (47 trials), or did not specify the administration schedule (11 trials). Mean antibiotic treatment duration ranged between 4 to 17.5 days in the sepsis studies, 6.8 to 11.9 in the abdominal studies, 4.1 to 7 days in the UTI studies, and 2 to 4 weeks in the endocarditis studies.

 

Risk of bias in included studies

(See Additional  Table 2: Study quality assessment table.)

 

Allocation concealment and generation

Thirty-three percent of the studies (21/64) reported adequate allocation concealment. Two studies were graded as C (Duff 1982; Landau 1990). No information was available for the other studies (34 studies), or envelopes were used but not described as sealed or opaque (7 studies).

Allocation generation was described as adequate in 53% of the studies (34/64). No information was available for 28 studies. Two studies were quasi-randomized, using patient identification numbers (Duff 1982; Landau 1990).
Both allocation generation and concealment were considered adequate in 30% of the studies (19/64).

 

Blinding

Most studies were open. Two studies, including 226 patients, were double blinded (Sanfilippo 1989; Smith 1984). Outcome assessors were blinded in four studies (Brown 1984; Dupont 2000; Rubinstein 1995; Verzasconi 1995). Clinicians were blinded to the treatment in one study (Yellin 1993).

 

Intention-to-treat versus per-protocol analysis

We separated included studies into four different study types with relation to outcome reporting:

  1. full Intention-to-treat analysis;
  2. per-protocol analysis, in which the number of dropouts was given per study arm;
  3. per-protocol analysis, in which the number of dropouts was known, but not given per study arm;
  4. studies which did not distinguish between the number of randomized and number of evaluated patients. These studies did not refer to dropouts, yet did not define the study explicitly as intention-to-treat.

The distribution of included studies by study type was as follows:
All cause fatality (reported in 43 studies):
Type 1: 19 studies (44%);
Type 2 and 3: 18 studies (42%). As authors cannot make assumptions can be made regarding dropouts for mortality, we have joined study groups 2 and 3 are joined for mortality;
Type 4: 6 studies (14%).

Treatment failure: (reported In 63 studies);
Type 1: 13 studies (21%);
Type 2: 23 studies (37%);
Type 3: 16 studies (25%);
Type 4: 11 studies (17%).

 

Follow-up

Forty-three studies (67%) specified follow-up duration, while only 18 studies defined a specific time for outcome collection (28%). Follow-up ranged from 48 hours following treatment cessation to 6 months. Outcomes were extracted preferentially at up to 30 days, with the exception of the Gram-positive infection studies, in which the type of infection mandated a longer follow-up (3 to 6 months).

 

Effects of interventions

 

All cause fatality

(see Analysis 1)

Forty-three trials including 5527 patients were included in this comparison (see  Analysis 1.1). Twelve studies, including 1381 patients, compared the same beta-lactam. These studies showed near equivalence, RR 1.01 (95%CI 0.75-1.35), while studies comparing different beta-lactams tended non-significantly in favour of monotherapy, RR 0.85 (95%CI 0.71-1.01). Analysis was further broken down according to the main study population, excluding Gram-positive infection studies (see  Analysis 1.2). The advantage to the monotherapy among studies comparing different beta-lactams was statistically significant in studies addressing 'sepsis', RR 0.83 (95% CI 0.69 to 0.99). No heterogeneity was present for these comparisons (I2 = 0% for the same beta-lactam comparison, I2 = 19.4 for different beta-lactams).

 

Subgroup analyses

No significant difference between monotherapy and combination therapy was apparent when analysis was restricted to patients with any Gram-negative infection (eight studies) or Gram-negative bacteraemia (four studies, see  Analysis 1.3 to  Analysis 1.4). Only three studies permitted mortality outcome extraction among patients with Pseudomonas aeruginosa infections, and these did not show a differences, either alone or when combined (graph not shown). Five UTI studies reported mortality, and mortality was null in three studies. Excluding patients with urinary tract infection from the analysis ('non-UTI' subgroup, see  Analysis 1.5) strengthened the advantage to monotherapy in studies comparing different beta-lactams (RR 0.70, 95%CI 0.52-0.95).

 

Sensitivity analyses

Adequate allocation concealment and generation were associated with relative risk closer to one, both for studies comparing the same and different beta-lactams. (See  Analysis 7.1 and  Analysis 7.2). Combination therapy was significantly better among studies comparing different beta-lactams classified as B. Blinding was performed in too few studies to assess its effect on mortality. The combined RR for studies comparing the same beta-lactam reporting fatality by intention-to-treat was 0.62 (95% CI 0.27 to 1.43), compared to 1.09 (95% CI 0.80 to 1.51) for studies reporting fatality per-protocol ( Analysis 7.3). Comparing intention to treat to per-protocol studies for different beta-lactams did not reveal a difference. Re-analysis of the mortality comparison by the random effect model was very similar (RR 1.02, 95% CI 0.76-1.38 for same beta-lactam, RR 0.85 95% CI 0.69 to 1.05 for different beta-lactam).

 

Treatment failure

(see Analysis 2)

We included all trials but one (Wiecek 1986) in the clinical failure analysis, comprising 6616 patients (see  Analysis 2.1). We found a significant advantage to monotherapy among studies comparing different beta-lactams, RR 0.77 (95% CI 0.69 to 0.86). We detected no difference between monotherapy and combination therapy among studies comparing the same beta-lactam, RR 1.11 (95% CI 0.95 to 1.29). No heterogeneity was present (I2=0% for both comparisons).

Grouping studies according to study population highlighted an advantage to combination therapy among the 'sepsis' studies that compared the same beta-lactam, RR 1.25 (95%CI 1.01 tp 1.55). This group of studies also accentuated the opposing advantage to monotherapy among studies comparing different beta-lactams (see  Analysis 2.2).

Bacteriological cure occurred more frequently with monotherapy among studies comparing different beta-lactams, RR 0.81 (95% CI 0.69 to 0.94), but did not differ significantly in studies comparing the same beta-lactam (see  Analysis 2.3).

Assessment of efficacy for urinary tract infections included re-infections and relapse as outcomes (see  Analysis 2.4). We noted no significant difference between monotherapy and combination therapy , with six trials and 458 patients included in this comparison.

 

Subgroup analyses

We analysed 28 studies including 1835 patients with Gram-negative infections and 18 studies including 426 patients with Pseudomonas aeruginosa infections were analysed (see  Analysis 2.5 and  Analysis 2.7). We observed no significant differences between the study groups, either for studies comparing the same or different beta-lactams. For studies comparing the same beta-lactam the RR was 1.23 (95% CI 0.90 to 1.68) for Gram-negative infections and 1.02 (95% CI 0.68 to 1.51) for Pseudomonas aeruginosa infections. We observed no difference between study groups among patients with Gram-negative bacteraemia or any bacteraemia (see  Analysis 2.6 and  Analysis 2.8). The latter comparison mainly comprised of patients with Gram-negative bacteremias but was available from a larger number of studies, and showed an advantage to combination therapy among studies comparing different beta-lactams. Both the subgroups of patients with urinary tract infections (see  Analysis 2.8), and patients without urinary tract infections maintained the trends seen previously ( Analysis 2.9).

 

Sensitivity analyses

The quality of allocation concealment and generation did not affect the relative risks for treatment failure, either among studies comparing the same or different beta-lactams. The two studies graded as C compared different beta-lactams, and were non-significantly closer to one than the truly randomized studies (see  Analysis 7.4 to  Analysis 7.5).

Several studies comparing different beta-lactams used some type of blinding. The advantage to monotherapy was non-significantly larger among these studies, compared to non-blinded studies (see  Analysis 7.6).

Among studies comparing the same beta-lactam, we observed an advantage to combination therapy in the presumed intention to treat group (type 2 studies), in which we imputed failure for dropouts. Among studies comparing different beta-lactams, intention to treat, presumed intention to treat, and per-protocol results were similar, favouring monotherapy (see  Analysis 7.7). Analysis by the random effect model did not change results (RR 1.09, 95% CI 0.94-1.27 for same beta lactams, RR 0.76, 95% CI 0.68-0.97, for different beta-lactams).

 

Length of hospital stay

Only four studies contained usable information for the comparison of hospital stay. Significant heterogeneity precluded their combination. Duration of hospitalization was longer with monotherapy in one study (McCormick 1997, 128 patients), shorter in another (Arich 1987, 47 patients), and similar in two (Wing 1998; Yellin 1993, 269 patients).

 

Summary of gain

Among studies comparing the same beta-lactam there was no benefit to the combination arm for all mortality comparisons, including subgroup and sensitivity analyses. Treatment failure tended to favour the combination arm reaching statistical significance only among studies addressing 'sepsis' and when an intention to treat analysis was imposed on studies performed per-protocol, imputing failure for dropouts.

Studies using different beta-lactam usually compared a broad-spectrum beta-lactam to a narrower spectrum beta-lactam combined with an aminoglycoside. The mortality comparisons favoured monotherapy reaching statistical significance in several subgroups. Treatment failure was significantly in favour of monotherapy overall, among the 'sepsis' studies, the non-UTI subgroup and in all the methodology sensitivity analyses. No comparison favoured the combination arm.

 

Resistance development and adverse events

(see 'Analysis' 3 and 4)

We compared studies comparing same and different beta-lactams for the assessment of resistance development and adverse events. These outcomes are intended to assess the antibiotic class effect of aminoglycoside-beta-lactam combinations versus beta-lactams alone, whether same or different.

We detected no significant differences between the rates of bacterial or fungal superinfections (see  Analysis 3.1 to  Analysis 3.4). Bacterial superinfections occurred more frequently with combination therapy, RR 0.76 (95% CI 0.57 to 1.01). This was the largest comparison, including 27 studies and 3085 patients. In outcome 5 we compared bacterial colonization rates only in patients from whom surveillance cultures were taken (7 studies, 751 patients). Colonization was, again, non-significantly more frequent with combination therapy, RR 0.78 (95% CI 0.60-1.01). Few studies monitored development of resistance among pathogens isolated initially ( Analysis 3.6). We observed no difference between monotherapy and combination therapy.

Any adverse event occurred non-significantly more frequently with combination therapy, RR 0.92 (95% CI 0.83 to 1.01; see  Analysis 4.1). We found nephrotoxicity to be more common in the combination arm in nearly all studies, with a highly significant combined relative risk in favour of monotherapy, RR 0.30 (95% CI 0.23 to 0.39,  Analysis 4.3). A significantly increased rate of nephrotoxicity was seen both in studies administering the aminoglycoside once daily and in those with a multiple-day regimen. Vestibular and ototoxicity, other known serious side effects of aminoglycoside treatment, were not reported routinely and could not be analysed. Different definitions and detailing of specific adverse events precluded a meaningful meta-analysis of other adverse events, individually or grouped.

 

Dropouts and selection bias

(see 'Analysis' 5)

The number of patients excluded from each study arm was nearly equal, both for mortality (RR 1.00, 95% CI 0.66 to 1.49,  Analysis 5.1), and failure (RR 1.04, 95% CI 0.88 to 1.23,  Analysis 5.2) outcomes assessment. This comparison included studies in which these outcomes could only be collected per-protocol, and reported the number of dropouts per study arm. It should be noted that counting dropouts as failures did affect the combined failure results (failure sensitivity analysis above). This is because among studies comparing the same beta-lactam, a slightly higher rate of dropouts occurred in the monotherapy arm, while the opposite occurred among studies comparing different beta-lactams.

The funnel plot for treatment failure generated a nearly symmetric 'funnel distribution' (Figure 1). Funnel plot analysis for all-cause fatality showed that small studies favouring combination therapy may be missing (Figure 2). Mortality outcome was unavailable from 33% of the trials.

 FigureFigure 1. Funnel failure.
 FigureFigure 2. Funnel mortality.

All cause mortality

 

Gram positive-infections

(see 'Analysis' 6)

Five studies assessed Gram-positive infections specifically. Four studies addressed patients with endocarditis caused by Staphylococcus aureus (Abrams 1979; Korzeniowski 1982; Ribera 1996), or streptococci (Sexton 1998). One study included any staphylococcal infection (Coppens 1983). All of these compared the same beta-lactam, with or without an aminoglycoside. Although small, we chose to separate this subset of studies and present its meta-analysis, since the rationale and clinical practice of adding an aminoglycoside to the beta-lactam in these infections differ from those underlying combination use in other infections.

The comparison included four outcomes: all cause fatality (three studies, outcome 1), clinical and bacteriological failure (five studies, outcomes 2 to 3), and the need for surgery (four endocarditis studies, outcome 4). None of these comparisons showed an advantage to combination therapy. The combined relative risk consistently favoured monotherapy, although differences were non-significant. The combined relative risk for clinical failure was 0.69 (95% CI 0.40 to 1.19, 5 studies, 305 patients). Clinical failure in these studies could be and indeed was defined more rigorously than in other studies. The time of outcome determination was pre-defined in all the trials and the follow-up was longer (1 to 6 months). Measures of treatment failure included persistence of bacteraemia or signs of endocarditis, relapse, need for valve replacement, and death.

 

Discussion

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

This present review compares beta-lactam-aminoglycoside antibiotic combinations to beta-lactam monotherapy. The primary outcome we assessed was all-cause fatality. Most studies compared one beta-lactam to a different, narrower spectrum beta-lactam, combined with an aminoglycoside. Twenty of the 64 included studies used the same beta-lactam in both study arms.

A special emphasis should be placed on studies comparing the same beta-lactam. These are the studies directly testing the hypothesis that the addition of an aminoglycoside to the beta-lactam is beneficial. Among these studies, all-cause fatality did not differ between study arms (RR 1.02, 95% CI 0.76 to 1.38). Treatment failure occurred more frequently in the monotherapy arm, reaching statistical significance only in subgroup analyses.

In studies comparing different beta-lactams, both failure and mortality were more common in the combination treatment arm. Failure was highly significant, while mortality reached significance only with subgroup analyses. These studies demonstrate an advantage to broad-spectrum beta-lactam monotherapy when compared to a narrower spectrum beta-lactam combined with an aminoglycoside, despite an equal in-vitro coverage of the culprit pathogens in both arms.

Development of resistance was assessed by the occurrence of superinfections and colonization, assuming that bacteria appearing under antibiotic treatment are resistant to the antibiotic administered. No difference between monotherapy and combination therapy was detected. Adverse events occurred more frequently with combination therapy. Specifically, nephrotoxicity occurred significantly more frequently in the combination treatment arm (RR 0.30, 95% CI 0.23 to 0.39).

We defined all-cause fatality as the primary outcome, while most studies assessed and reported treatment failure as a main outcome. Obviously, the most significant outcome for the patient is survival following the infectious episode. Available evidence shows that the addition of an aminoglycoside to a beta-lactam does not reduce mortality. Replacing beta-lactam monotherapy with a narrower spectrum beta-lactam combined with an aminoglycoside may be associated with increased mortality.

Failure was commonly defined as lack of clinical improvement, deterioration, relapse, and/or modifications to the antibiotic treatment. These endpoints are highly subjective and do not necessarily translate to detriments experienced by the patient. Detection bias is a concern in open trials that compared the same beta-lactam, or in trials comparing a 'new' broad spectrum monotherapy to a conventional antibiotic regimen. Thus, the advantage to monotherapy therapy in studies comparing different beta-lactams, and the opposing advantage to combination therapy in studies comparing the same beta-lactams, may be largely biased.

The major adverse event associated with combination therapy was nephrotoxicity. We did not observe a protective effect of the combination with regard to resistance development. During the last decade, once daily administration of aminoglycosides has entered into use, with similar efficacy but lower nephrotoxicity (Barza 1996). Most studies in our review used multiple-day administration schedules for the complete duration of antibiotic therapy or until modification. The RR of 0.30 for any nephrotoxicity we observed may, therefore, be an overestimation. However, the RR among the few studies that did administer the aminglycoside once daily was also highly significant in favour of monotherapy (0.17, 0.06 to 0.53).

The rationale for administering combination therapy arose from in-vitro studies showing synergistic bactericidal activity of specific beta-lactam-aminoglycoside antibiotic combinations. Synergy has been observed for Pseudomonas aeruginosa (Giamarellou 1984), other Gram-negative bacteria (Giamarellou 1986; Klastersky 1976), and Staphylococci (Sande 1975; Sande 1976). Assessment of antibiotic efficacy against specific infections in randomized trials must either be limited to definitive treatment (randomisation performed when infection is microbiologically documented), or be performed as a subgroup analysis to assess empirical treatment (randomizing patients empirically and assessing those with documented infections). Eight studies assessed definitive treatment (semi-empirical studies), while most assessed empirical treatment. We did not find an advantage to combination therapy among patients with any Gram-negative infection, Gram-negative bacteraemia, or Pseudomonas aeruginosa infections. Lack of data precluded the assessment of Pseudomonas aeruginosa bacteraemia.

In a previous non-randomized prospective study of bacteraemic patients, we showed that appropriate beta-lactam monotherapy was as effective as appropriate beta-lactam aminoglycoside combination therapy, both empirically and semi-empirically. Appropriate single aminoglycoside monotherapy was associated with increased mortality (Leibovici 1997). Combination therapy was claimed superior to monotherapy in a prospective observational study of patients with Pseudomonas aeruginosa bacteraemia, but most patients in the monotherapy group received aminoglycosides (Hilf 1989). In a meta-analysis including non-randomized trials (mostly retrospective cohort studies), Safdar and colleagues found a reduction in mortality with combination therapy for patients with Pseudomonas aeruginosa bacteraemia (five studies; OR 0.50, 95%CI 0.32 to 0.79), but not for patients with Gram-negative bacteraemia (17 studies; OR 0.96, 95% CI 0.79 to 1.32). Monotherapy, however, included single aminoglycoside treatment, and analysis was not performed separately for beta-lactam monotherapy (Safdar 2004). Finally, in a previous systematic review and meta-analysis of randomized trials comparing combination therapy to beta-lactam monotherapy for febrile neutropenic patients, no advantage was seen for the combination (Paul 2013). Overall, empirical evidence does not show the synergy effect when adding an aminoglycoside to a beta-lactam in the clinical setting. Why does synergy, observed in-vitro, not translate into clinical benefit? Specific growth conditions in-vitro, unattainable in-vivo, may induce synergism. Pharmacokinetic and pharmacodynamic properties involving specific antibiotics, sites of infection, timing and intervals of administration may prevent synergism in-vivo. Adverse events related directly to the aminoglycoside, or to the combination, may interfere with an in-vivo benefit, amounting altogether to no benefit.

A small subset of studies in our review addressed patients with Gram-positive infections, mainly Staphylococcus aureus endocarditis. No study assessed enterococcal infections specifically. In these, also, no outcome was improved by the addition of an aminoglycoside. Current guidelines for the treatment of Staphylococcus aureus endocarditis advise the addition of an aminoglycoside to the beta-lactam, at least initially (Bayer 1998). These recommendations rely mainly on in-vitro data (Sande 1975; Sande 1976). Animal studies have shown that sterilization of cardiac vegetations may be achieved more rapidly with combination therapy (Sande 1975; Sande 1976). One clinical study included in our review showed that combination therapy shortened the duration of bacteraemia, but this comparison was performed according to the empirical antibiotic regimen, while randomization occurred either empirically or semi-empirically (Korzeniowski 1982). We could not show an advantage to combination therapy combining all trials in humans. On the contrary, all outcomes tended to favour monotherapy, although statistical significance was not reached.

The limitations of our analysis may originate from the quality of data reported in available studies and from our analysis of these data. Of these, we emphasize the lack of data for all-cause fatality from a third of included studies. Survival, with or without the more subjective assessment of infection-related mortality, must be reported comparatively in all trials. Data for subgroups most likely to benefit from combination therapy were also not available from all studies. In our analysis, we did not correct for the appropriateness of antibiotic treatment, which has been shown conclusively to correlate with survival (Ibrahim 2000; Leibovici 1998). Data were not fully available to perform such an analysis. However, among studies comparing the same beta-lactam, combination therapy by definition broadened the spectrum of coverage, without improving outcomes. In studies comparing different beta-lactams, inappropriate beta-lactam was used more frequently in the combination arm, which may partially explain the advantage to monotherapy.

We conclude that the addition of an aminoglycoside to a beta-lactam does not improve the clinical efficacy achieved with the beta-lactam alone. Substituting a narrow-spectrum beta-lactam with an aminoglycoside for a single broad-spectrum beta-lactam, will result in increased failure rates and may be associated with increased mortality. Adverse events occur more frequently with combination treatment. Short-term combination therapy for sepsis does not prevent development of resistant bacteria, as assessed by superinfection or colonization rates following antibiotic treatment. Thus, the use of beta-lactam-aminoglycoside combination therapy for sepsis should be discouraged.

 

Authors' conclusions

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

 

Implications for practice

Clinicians usually face the dilemma of selecting an antibiotic treatment on two occasions during an un-complicated infectious episode. On the initial encounter with a patient the clinician must prescribe empirical antibiotic treatment, since the causative pathogen and its susceptibilities are generally unknown. Most studies addressed this situation, and the results show that there is no difference in overall mortality whether monotherapy or combination therapy is used. Adverse effects, most significantly nephrotoxicity, will occur more frequently with combination therapy. If the choice is between a narrower-spectrum beta-lactam combined with an aminoglycoside versus a broad-spectrum beta-lactam, our results show that treatment will ultimately have to be modified more frequently if the combination is chosen. We have not identified a specific site of infection, or disease severity, where combination treatment has an advantage.

The second decision point occurs when the causative pathogen is identified. Here, the choice of the antibiotic treatment is dictated by known susceptibility results. However, the question remains, whether for specific bacteria beta-lactam-aminoglycoside combination treatment offers an advantage over single beta-lactam treatment. We addressed this question by subgroup analyses of patients with documented infections caused by specific pathogens (Gram-negatives, Pseudomonas aeruginosa, Staphylococcus aureus). In addition, several semi-empirical studies addressed this question specifically. We have not identified a specific pathogen, or pathogen group, where combination therapy is advantageous.

Overall, appropriate beta-lactam monotherapy should be used. Beta-lactam-aminoglycoside combination therapy does not offer an advantage, and is associated with an increased rate of adverse events.

 
Implications for research

We cannot point to a specific patient subgroup that showed a trend for benefit with combination therapy. The design of existing studies did not permit a comparison between monotherapy and combination therapy for specific pathogens when all the antibiotics administered matched the in-vitro susceptibility of the pathogen. However the large body of studies that were performed did not point towards any benefit. Thus we do not see the justification for such future trials.

Exceptions to this are trials addressing patients with endocarditis. Prolonged combination treatment for endocarditis, including an aminoglycoside, is well accepted in clinical practice, but does not seem grounded in clinical evidence. Future trials must examine the justification for this practice.

Further comparisons between monotherapy and combination, if performed, should be limited to comparisons involving the same beta-lactam. This is the only design that explores the benefit of beta-lactam-aminoglycoside combination therapy. Studies comparing broad-spectrum monotherapy, such as new antibiotics, to an older generation beta-lactam with an aminoglycoside should not be performed. Patients may be harmed by combination therapy in such trials.

Appropriate antibiotic treatment has been shown to significantly reduce mortality, and should therefore be reported with results adjusted to it. Outcomes relevant to patients, such as survival and hospitalisation duration should be assessed. Survival, if not assessed as a primary outcome, must at least be reported.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  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 all the authors who responded to our requests for additional data (see 'unpublished data' and 'unpublished data sought but not used', 'References to studies'). Dr Solomkin (Solomkin 1986) and Dr. Sexton (Sexton 1984) supplied supplementary data for their studies, which were not included in the review. Dr. Finer and Dr. Goustas of the GlaxoSmithKline Company supplied detailed data for their study (Finer 1992). Dr Kora Huber sent completed trial results for Kljucar 1990 and supplied requested additional information. Ms Mary Forrest (Managing editor, Journal of Chemotherapy), sent several publications that were not available to us. We would also like to warmly thank Ms Rika Fujiya who translated the Japanese studies (Sukoh 1994; Takamoto 1994).

We thank Dr Vittoria Lutje, Dr Harriet G. MacLehose, and Ms Rieve Robb (Review Group Co-ordinator) of the Cochrane Infectious Diseases Group. We thank Dr Harald Herkner, Prof. Nathan Pace, Kathie Godfrey, Janet Wale and Jane Cracknell (Review Group Co-ordinator) of the Cochrane Anaesthesia Review Group. Both groups supported and provided helpful revisions for this review.

This review was initially developed within the Infectious Diseases Group and supported by a grant from the Department for International Development, UK. The review was transferred to the Anaesthesia Group in May 2005.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  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. Monotherapy versus combination therapy

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

 1 All cause fatality43Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Same BL
121381Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.75, 1.35]

    1.2 Different BL
314146Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.71, 1.01]

 2 All cause fatality by study groups40Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Same sepsis
6789Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.79, 1.67]

    2.2 Same abdominal
2331Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.54, 1.55]

    2.3 Same UTI
173Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.4 Different sepsis
213298Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.69, 0.99]

    2.5 Different abdominal
6550Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.56, 2.15]

    2.6 Different UTI
4298Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.34, 5.21]

 3 All cause fatality (Gram negative infections)8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Same BL
3117Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.08, 4.07]

    3.2 Different BL
5313Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.80, 1.95]

 4 All cause fatality (Gram negative bacteremia)5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Same BL
385Risk Ratio (M-H, Fixed, 95% CI)1.62 [0.30, 8.75]

    4.2 Different BL
2125Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.63, 2.70]

 5 All cause fatality (non urinary tract infections)16Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Same BL
3351Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.53, 1.47]

    5.2 Different BL
131458Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.52, 0.95]

 
Comparison 2. Monotherapy versus combination therapy

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

 1 Clinical failure63Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Same BL
201870Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.95, 1.29]

    1.2 Different BL
434746Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.69, 0.86]

 2 Clinical failure by study groups58Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Same sepsis
121196Risk Ratio (M-H, Fixed, 95% CI)1.25 [1.01, 1.55]

    2.2 Same abdominal
2308Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.80, 1.32]

    2.3 Same UTI
161Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.46, 2.09]

    2.4 Different sepsis
293612Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.66, 0.84]

    2.5 Different abdominal
9675Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.59, 1.13]

    2.6 Different UTI
5459Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.65, 1.91]

 3 Bacteriological failure - all43Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Same BL
14751Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.88, 1.51]

    3.2 Different BL
292760Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.69, 0.94]

 4 UTI relapse or re-infection6458Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.61, 1.67]

 5 Clinical failure (Gram negative infections)28Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Same BL
10432Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.90, 1.68]

    5.2 Different BL
181403Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.66, 1.09]

 6 Clinical failure (Gram negative bacteremia)11Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Same BL
4101Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.45, 2.56]

    6.2 Different BL
7198Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.38, 1.48]

 7 Clinical failure (Pseudomonas aeruginosa infections)18Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Same BL
6124Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.68, 1.51]

    7.2 Different BL
12302Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.80, 1.82]

 8 Clinical failure (bacteremia)22Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Same BL
5141Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.77, 2.66]

    8.2 Different BL
17624Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.46, 0.89]

 9 Clinical failure (urinary tract infections)17Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 Same BL
484Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.59, 2.13]

    9.2 Different BL
13708Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.80, 1.87]

 10 Clinical failure (non urinary tract infections)41Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Same BL
101248Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.99, 1.42]

    10.2 Different BL
312945Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.61, 0.81]

 
Comparison 3. Monotherapy versus combination therapy

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

 1 Bacterial superinfections273085Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.57, 1.01]

 2 Fungal superinfections111119Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.42, 1.48]

 3 Bacterial colonization141635Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.65, 1.10]

 4 Fungal colonization71132Risk Ratio (M-H, Fixed, 95% CI)1.39 [0.93, 2.09]

 5 Bacterial colonization - surveillance cultures6751Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.60, 1.01]

 6 Bacterial resistance development91370Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.54, 1.45]

 
Comparison 4. Monotherapy versus combination therapy

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

 1 Any adverse event394945Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.83, 1.01]

 2 Adverse events requiring treatment discontinuation193042Risk Ratio (M-H, Random, 95% CI)0.89 [0.52, 1.52]

 3 Any nephrotoxicity455213Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.23, 0.39]

    3.1 Once daily aminoglycoside
5865Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.06, 0.53]

    3.2 Twice daily aminoglycoside
71127Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.24, 0.77]

    3.3 Thrice daily aminoglycoside
232082Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.20, 0.39]

    3.4 Non specified aminoglycoside regimen
101139Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.19, 0.58]

 
Comparison 5. Monotherapy versus combination therapy

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

 1 Drop-outs for all cause fatality8910Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.66, 1.49]

    1.1 Same BL
4541Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.55, 2.11]

    1.2 Different BL
4369Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.57, 1.58]

 2 Drop-outs for clinical failure243631Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.88, 1.23]

    2.1 Same BL
101244Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.92, 1.72]

    2.2 Different BL
142387Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.78, 1.17]

 
Comparison 6. Monotherapy versus combination therapy

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

 1 All cause fatality (Gram positive infections)3188Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.12, 1.58]

 2 Clinical failure (Gram positive infections)5305Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.40, 1.19]

 3 Bacteriological failure (Gram positive infections)5300Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.47, 1.69]

 4 Need for operation (endocarditis)4243Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.41, 1.39]

 
Comparison 7. Monotherapy versus combination therapy (sensitivity analyses)

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

 1 All cause fatality by allocation concealment43Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 A same BL
61068Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.71, 1.31]

    1.2 B same BL
6313Risk Ratio (M-H, Fixed, 95% CI)1.56 [0.58, 4.18]

    1.3 A different BL
122154Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.75, 1.19]

    1.4 B different BL
181952Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.53, 0.93]

    1.5 C different BL
140Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.34, 5.21]

 2 All cause fatality by allocation generation43Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 A same BL
61068Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.71, 1.31]

    2.2 B same BL
6313Risk Ratio (M-H, Fixed, 95% CI)1.56 [0.58, 4.18]

    2.3 A different BL
192957Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.72, 1.09]

    2.4 B different BL
111149Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.50, 1.04]

    2.5 C different BL
140Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.34, 5.21]

 3 All cause fatality by ITT vs. per-protocol analysis43Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 ITT - same BL (type 1 studies)
4469Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.27, 1.43]

    3.2 per-protocol - same BL (type 2 and 3 studies)
6761Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.80, 1.51]

    3.3 unknown - same BL (type 4 studies)
2151Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.06, 13.25]

    3.4 ITT - different BL (type 1 studies)
152989Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.71, 1.07]

    3.5 per-protocol - different BL (type 2 and 3 studies)
121037Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.54, 1.07]

    3.6 unknown - different BL (type 4 studies)
4120Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.34, 5.21]

 4 Clinical failure by allocation concealment63Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 A same BL
81138Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.93, 1.32]

    4.2 B same BL
12732Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.79, 1.50]

    4.3 A different BL
132028Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.60, 0.86]

    4.4 B different BL
282604Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.68, 0.92]

    4.5 C different BL
2114Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.63, 1.88]

 5 Clinical failure by allocation generation63Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 A same BL
91319Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.91, 1.29]

    5.2 B same BL
11551Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.83, 1.69]

    5.3 A different BL
253217Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.66, 0.88]

    5.4 B different BL
161415Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.62, 0.92]

    5.5 C different BL
2114Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.63, 1.88]

 6 Clinical failure by blinding63Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Non-blinded - same BL
191666Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.93, 1.35]

    6.2 Any blinding - same BL
1204Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.82, 1.37]

    6.3 Non-blinded - different BL
373809Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.72, 0.94]

    6.4 Any blinding - different BL
6937Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.50, 0.77]

 7 Clinical failure by ITT versus per-protocol analysis63Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 ITT - same BL (type 1)
2110Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.43, 1.40]

    7.2 ITT assuming failure for drop-outs - same BL (type 2)
9902Risk Ratio (M-H, Fixed, 95% CI)1.32 [1.09, 1.60]

    7.3 Per protocol - same BL (type 3 studies)
4580Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.91, 1.33]

    7.4 Type 4 studies - same BL
5278Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.56, 1.61]

    7.5 ITT - different BL (type 1)
111458Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.64, 0.92]

    7.6 ITT assuming failure for drop-outs - different BL (type 2)
142065Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.73, 0.94]

    7.7 Per protocol - different BL (type 3 studies)
121031Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.62, 0.95]

    7.8 Type 4 studies - different BL
6192Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.40, 1.56]

 

Appendices

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

Appendix 1. Search strategy


Type of patientsInterventionsRCT filter

pneumonia* OR(aminoglycoside* ORrandom* OR

infection* OR infect* ORnetilmicin* ORcontrol* OR

sepsis OR septic?emia* ORgentamicin* ORsingle OR double OR blind* OR

bacter* OR bacter?emia*amikacin* ORplacebo OR

tobramycin* ORclinical OR

streptomycin* ORcomparative OR

isepamicin* ORprospectiv*

sisomicin*)



 

Feedback

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

Obtaining data on all-cause mortality, 16 June 2013

 

Summary

Thank you for taking on the large amount of data surrounding topic of aminoglycoside and beta-lactam combination therapy in the treatment of sepsis. With the large volume of studies spanning such a long time period this was no small task. With this is mind we still have some one question regarding the primary outcome analysis of all cause mortality between the two treatment arms.

The primary mortality analysis contained 43 of the total 64 studies included in the review and they were split into two separate subgroups, using wither the same or a different beta-lactam agent as monotherapy as in combination therapy. Our concern is centered on the outstanding 21 studies not included in this analysis. We were wondering what attempts were made to collect mortality data from these remaining trials questioning whether the inclusion of those results would statistically alter the outcomes. We understand that a number of these studies were completed over 40 years ago and the data may be very difficult to obtain.

In the subgroup where a different beta-lactam was used the risk of mortality was non-significantly lowered in the monotherapy arm RR 0.85 (95% CI 0.71, 1.01). With the results being close to statistical significance we were wondering if the addition of data from the outstanding studies would actually make a statistical difference. If this were truly the case then your conclusion of “The addition of an aminoglycoside to beta-lactams for sepsis should be discouraged. All-cause fatality rates are unchanged. Combination treatment carries a significant risk of nephrotoxicity” would change and the call to avoid the use of these antibiotics would be much stronger.

We also pooled all of the data from both subgroups (same and different beta-lactams) and found that it did not change the results of the different beta-lactam group but greatly narrowed the confidence interval of the same beta-lactam group with a RR of 1.13 (0.97, 1.31) - increased risk of mortality in the combination group versus monotherapy. With this analysis we also found very little heterogeneity between same and different beta-lactam studies (I2 = 8%).

We understand the beta-lactam agent selected, specifically in regards the spectrum of activity, greatly impacts the effects of empirical therapy but with this potentially increased risk of mortality that is consistent across this large number of studies leads us to believe that although statistically non-significant it seems plausible that the risk of mortality with combination therapy over beta-lactam monotherapy is real.

We also believe that the possibility of “emotional based medicine” is real in this patient population. As the majority of these studies were open-label despite being randomized, it is not unlikely that “sicker” patients would receive more drugs (i.e. combination therapy). If this were true then it is plausible that patients who were more likely to die received more antibiotics and were in the combination groups but with the effect remaining relatively consistent across this large number of studies, we feel that a true risk may actually exist.

After this long discussion, our question returns to whether or not mortality data is available from the remaining 21 studies and what attempts have been made to retrieve this information. A statistically significant increase in mortality, along with the increase in adverse events see with combination therapy would likely facilitate a rapid change in practice and removal of this therapeutic option. Just as an exercise we inserted the data provided by your review into Review Manager to test how many events it would take to make the difference in mortality. We understand this is not a truly scientific exercise but one based on curiosity.

What we found was that when we added two events (deaths) to the combination group in the most heavily weighted study (Felisart 1985) the outcome of mortality became statistically significantly higher in the combination group. We also combined all of the data between the same different beta-lactam subgroups and found that only 8 more deaths in the combination group made the entire analysis (all 43 studies) statistically significant for an increase in mortality in the combination group. On the flip side, it took 80 events in the monotherapy group to swing the analysis the other way and statistically favour combination therapy in the outcome of mortality.

Thank you for your time

 

Reply

Dear Dr. Amadio,

Thank you for your kind attention to our work and your input for the data analysis.

In response to your question regarding obtaining data on all-cause mortality, we mailed all authors of trials that did not report on this outcome asking for the data, as is routine in Cochrane reviews. We agree with you on the importance of the missing data on mortality and for this reason we made extra efforts to obtain the data. If we did not establish contact with the corresponding author, we tried to contact a second and third author. The data presented in our review are the result of this process and still we miss mortality data from a third of all randomized controlled trials (RCTs) that were conducted.

Selection bias should not occur in adequately conducted RCTs, those using appropriate allocation concealment. Allocation concealment is the procedure ensuring that no one is aware of the treatment assignment when the patient is recruited into the trial and before the patient is allocated to an intervention. We observed in our review that the advantage to combination therapy was larger in trials with unclear methods for allocation concealment (studies not reporting the methods for this procedure) compared to trials that used methods ensuring adequate allocation concealment. Therefore, it is possible that results were affected by selection of sicker patients to the combination therapy group. However the difference between trials with low and unclear risk of bias was not statistically significant and we have no actual data on whether bias could occur in the trials with unclear risk of bias. Most importantly to our view, the trials comparing different beta-lactams usually compared a new, broad-spectrum beta-lactam to an old, classical regimen; we believe that if selection bias crept in to some trials it would have worked in the opposite direction of recruiting the sicker patients to the novel monotherapy arm. The fact that most of the trials were open, might have led to a different type of bias, and dilution of effects, because physicians could add an aminoglycoside to failing patients in the monotherapy arm, while this could not occur in the combination therapy arm.

Methods exist to formally examine the possible effects of missing data in meta-analysis. We will consider adding such an analysis to an update of our review. More importantly, we will highlight the issue of missing data on all-cause mortality. Should your important correspondence result in any authors sending further data from their trials on mortality, these will be added to our review.

 

Contributors

Anthony Amadio, BSc. Pharm, ACPR, RPh

Doctor of Pharmacy Student

Faculty of Pharmaceutical Sciences

University of British Columbia

Vancouver BC

Canada

Aaron M Tejani, BSc Pharm, PharmD
Researcher
Therapeutics Initiative, University of British Columbia
2176 Health Sciences Mall
Vancouver, BC, Canada

Reply

Mical Paul, corresponding author

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  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: 11 November 2005.


DateEventDescription

14 August 2013AmendedAdditional contributor added to feedback section.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  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 4, 2001
Review first published: Issue 1, 2006


DateEventDescription

13 August 2013Feedback has been incorporatedFeedback submitted and responded to.

Two Cochrane references updated and typos corrected.

2 September 2008AmendedConverted to new review format.



 

Contributions of authors

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

Mical Paul (MP): Performed the search and scanned abstracts; retrieved full-text articles and applied inclusion and exclusion criteria; performed quality assessment, data extraction,and analysis. MP communicated with authors; wrote protocol and review.

Ishay Silbiger (IS): Applied inclusion and exclusion criteria, and performed quality assessment, data extraction and analysis.

Simona Grozinsky (SG): Extracted the data

Karla Soares-Weiser (KSW): Assisted with inclusion and exclusion of studies; performed quality assessment, data extraction and analysis; assisted with the writing and reviewed all versions of protocol and review.

Leonard Leibovici (LL): Assisted with inclusion and exclusion of studies; performed quality assessment, data extraction and analysis; assisted with communication with authors; assisted with the writing and reviewed all versions of protocol and review.

 

Declarations of interest

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

We certify that we have no affiliations with or involvement in any organization or entity with a direct financial interest in the subject matter of this review (e.g. employment, consultancy, stock ownership, honoraria, expert testimony).

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  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, Israel.

 

External sources

  • EU 5th Framework - TREAT project (grant number: 1999-11459), Not specified.
  • Department for International Development, UK.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  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. Additional references
  23. References to other published versions of this review
Abrams 1979 {published data only}
  • Abrams B, Sklaver A, Hoffman T, Greenman R. Single or combination therapy of staphylococcal endocarditis in intravenous drug abusers. Annals of Internal Medicine 1979;90(5):789-91.
Aguilar 1992 {published data only}
  • Ramirez de Aguilar R. Clinical trial on efficacy and safety of ceftizoxime compared with penicillin-gentamicin of managing of adult severe infections [Estudio clinico para determinar la eficacia y seguridad de ceftizoxima en comparacion con penicilina-gentamicina en el manejo de las infecciones graves del adulto]. Compend Invest Clin Latinoam 1992;12(3):75-8.
Alvarez-Lerma 2001a {published and unpublished data}
  • Alvarez Lerma F on behalf of the Serious Infection Study Group. Efficacy of meropenem as monotherapy in the treatment of ventilator- associated pneumonia. Journal of Chemotherapy 2001;13(1):70-81.
  • Alvarez-Lerma F. [Efficacy of monotherapy by meropenem in ventilator-associated pneumonia]. Antibiotiki i khimioterapiia 2001;46(12):42-52.
Arich 1987 {published and unpublished data}
  • Arich C, Gouby A, Bengler C, Ardilouze JL, Dubois A, Joubert P, et al. [Comparison of the efficacy of cefotaxime alone and the combination cefazolin-tobramycin in the treatment of enterobacterial septicemia] In French. Pathologie Biologie (Paris) 1987;35(5):613-5.
Bergeron 1988 {published data only}
  • Bergeron MG, Mendelson J, Harding GK, Mandell L, Fong IW, Rachlis A, et al. Cefoperazone compared with ampicillin plus tobramycin for severe biliary tract infections. 13th International Congress of Chemotherapy. 1983.
  • Bergeron MG, Mendelson J, Harding GK, Mandell L, Fong IW, Rachlis A, et al. Cefoperazone compared with ampicillin plus tobramycin for severe biliary tract infections. Antimicrobials Agents and Chemotherapy 1988;32(8):1231-6.
Biglino 1991 {published data only}
  • Biglino A, Bonasso M, Gioannini P. Imipenem/cilastatin as empirical treatment of severe infections in compromised patients. Journal of Chemotherapy 1991;3 Suppl 1:208-12.
Brown 1984 {published data only}
  • Brown RB, Lemeshow S, Teres D. Moxalactam vs carbenicillin plus tobramycin: Treatment of nosocomial gram-negative bacillary pneumonias in non-neutropenic patients. Current therapeutic research, clinical and experimental 1984;36(3):557-64.
Carbon 1987 {published data only}
  • Carbon C, Auboyer C, Becq Giraudon B, Bertrand P, Gallais H, Mouton Y, et al. Cefotaxime (C) vs cefotaxime + amikacin (C + A) in the treatment of septicemia due to enterobacteria: a multicenter study. Chemioterapia 1987;6(2 Suppl):367-8.
Cardozo 2001 {published and unpublished data}
  • Cardozo M, Basualdo W, Martinez R, Matsumura K, Gonzalez-Cabello M, Navarro D, et al. Evolution of the association amoxicillin/sulbactam to a amoxicillin/sulbactam more gentamicins in children with peritonitis of apendicular origin [Evaluacion de la asociacion amoxicilina/sulbactam frente a amoxicilina/sulbactam mas gentamicina en ninos con peritonitis de origen apendicular]. Pediatr. (Asuncion) 2001;28(2):15-19.
Cometta 1994 {published and unpublished data}
  • Cometta A, Baumgartner JD, Lew D, Zimmerli W, Pittet D, Chopart P, et al. Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patients. Antimicrobial Agents and Chemotherapy 1994;38(6):1309-13.
  • Iten A, Cometta A, Eggimann P, Siegrist H, Francioli P. The addition of netilmicin (NET) to imipenem (IMIP) does not prevent the emergence of bacteria resistant (R) to IMIP during treatment (ttt) of severe infections. 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy. 1992; Vol. Abstract no. 522:198.
Cone 1985 {published data only}
  • Cone LA, Woodard DR, Stoltzman DS, Byrd RG. Ceftazidime versus tobramycin-ticarcillin in the treatment of pneumonia and bacteremia. 23rd Interscience Conference Antimicrobial Agents and Chemotherapy. 1983; Vol. Abstract no. 843.
  • Cone LA, Woodard DR, Stoltzman DS, Byrd RG. Ceftazidime versus tobramycin-ticarcillin in the treatment of pneumonia and bacteremia. Antimicrobial Agents and Chemotherapy 1985;28(1):33-6.
Coppens 1983 {published data only}
  • Coppens L, Hanson B, Klastersky J. Therapy of staphylococcal infections with cefamandole or vancomycin alone or with a combination of cefamandole and tobramycin. Antimicrobial Agents and Chemotherapy 1983;23(1):36-41.
D'Antonio 1992 {published and unpublished data}
  • 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.
Duff 1982 {published and unpublished data}
  • Duff P, Keiser JF. A comparative study of two antibiotic regimens for the treatment of operative site infections. American Journal of Obstetrics and Gynecology 1982;142(8):996-1003.
Dupont 2000 {published data only}
  • Dupont H, Carbon C, Carlet J, and the Severe Generalized Peritonitis Study Group. Monotherapy with a broad-spectrum beta-lactam is as effective as its combination with an aminoglycoside in treatment of severe generalized peritonitis: a multicenter randomized controlled trial. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1998; Vol. Abstract MN-48:602.
  • Dupont H, Carbon C, Carlet J, for The Severe Generalized Peritonitis Study Group. Monotherapy with a broad-spectrum beta-lactam is as effective as its combination with an aminoglycoside in treatment of severe generalized peritonitis: a multicenter randomized controlled trial. Antimicrobial Agents and Chemotherapy 2000;44(8):2028-33.
Felisart 1985 {published data only}
Finer 1992 {published and unpublished data}
  • Finer N, Goustas P. Ceftazidime versus aminoglycoside and (ureido)penicillin combination in the empirical treatment of serious infection. Journal of the Royal Society of Medicine 1992;85(9):530-3.
Gerecht 1989 {published data only}
  • Gerecht WB, Henry NK, Hoffman WW, Muller SM, LaRusso NF, Rosenblatt JE, et al. Prospective randomized comparison of mezlocillin therapy alone with combined ampicillin and gentamicin therapy for patients with cholangitis. Archives of Internal Medicine 1989;149(6):1279-84.
Gomez 1990a {published and unpublished data}
  • Gomez J, Moldenauer F, Ruiz G, Canteras M, Redondo C, Molina B, et al. [Monotherapy (ceftazidime) versus combination therapy (cefradine + amikacin) in gram-negative bacteremia. A prospective, randomized study, 1987] In Spanish. Revista Espanola de Quimioterapia 1990;3(1):35-40.
Havig 1973 {published data only}
  • Havig O, Hertzberg J. Effect of ampicillin, chloramphenicol, and penicillin-streptomycin in acute cholecystitis. Scandinavian Journal of Gastroenterology 1973;8(1):55-8.
  • Havig O, Hertzberg J. [Effect of ampicillin, chloramphenicol and penicillin + streptomycin in the treatment of acute cholecystitis]. Tidsskrift for den Norske laegeforening 1975;95(5):298-300.
Hoepelman 1988 {published and unpublished data}
  • 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. 27th Interscience Conference on Antimicrobials Agents and Chemotherapy. 1987; Vol. Abstract no. 89.
  • 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.
Holloway 1985 {published data only (unpublished sought but not used)}
Iakovlev 1998 {published data only}
  • Iakovlev SV, Iakovlev VP, Derevianko, II, Kira EF, and the Meropenem Study Group. [Multicenter open randomized trial of meropenem in comparison to ceftazidime and amikacin used in combination in severe hospital infections]. In Russian. Antibiotiki i Khimioterapiia 1998;43(1):15-23.
Jaspers 1998 {published and unpublished data}
  • Jaspers CA, Kieft H, Speelberg B, Buiting A, van Marwijk Kooij M, Ruys GJ, et al. Meropenem versus cefuroxime plus gentamicin for treatment of serious infections in elderly patients. Antimicrobial Agents and Chemotherapy 1998;42(5):1233-8.
Klastersky 1973 {published data only}
Kljucar 1990 {published and unpublished data}
  • Kljucar S, Heimesaat M, von Pritzbuer E, Bauernfeind A. Comparative clinical trial with ceftazidime (CAZ) versus ceftazidime plus tobramycin (TOB) versus azlocillin (AZL) plus tobramycin in ventilated patients with nosocomial lower respiratory tract infections (LRTI). 30th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1990:Abtract no. 953.
  • Kljucar S, Heimesaat M, von Pritzbuer E, Olms K. [Ceftazidime with and without tobramycin versus azlocillin plus tobramycin in the therapy of bronchopulmonary infections in intensive care patients]. In German. Infection 1987;15(Suppl 4):S185-S191.
Koehler 1990 {published data only}
  • Koehler CO, Arnold H. Controlled clinical study of ceftazidime (3 x 1 g daily) versus piperacillin + tobramycin in patients with nosocomial pneumonia. International Journal of Experimental and Clinical Chemotherapy 1990;3(4):211-8.
Korzeniowski 1982 {published data only}
  • Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: A prospective study. Annals of Internal Medicine 1982;97(4):496-503.
Landau 1990 {published data only}
  • Landau Z, Feld S, Krupsky M. [Ceftriaxone or combined cefazolin-gentamicin for complicated urinary tract infections]. In Hebrew. Harefuah 1990;118(3):152-3.
Limson 1988 {published data only (unpublished sought but not used)}
  • Limson BM, Navarro Almario E, Litam P, Que E, Kua LT. Ceftazidime monotherapy compared with amikacin/ticarcillin combination therapy in severe infections. Journal of the Philippines Medical Association 1988;64(1):33-5.
  • Limson BM, Navarro Almario E, Litam P, Que E, Kua LT. Ceftazidime versus a combination of amikacin and ticarcillin in the treatment of severe infections. Clinical Therapeutics 1988;10(5):589-93.
Mandell 1987 {published data only (unpublished sought but not used)}
  • Mandell LA, Nicolle LE, Ronald AR, Duperval R, Robson HG, Feld R, et al. A multicentre prospective randomized trial comparing ceftazidime with cefazolin/tobramycin in the treatment of hospitalized patients with non- pneumococcal pneumonia. Journal of Antimicrobial Chemotherapy 1983;12(Suppl A):9-20.
  • Mandell LA, Nicolle LE, Ronald AR, Landis SJ, Duperval R, Harding GK, et al. A prospective randomized trial of ceftazidime versus cefazolin/tobramycin in the treatment of hospitalized patients with pneumonia. Journal of Antimicrobial Chemotherapy 1987;20(1):95-107.
Martin 1991 {published data only}
  • Martin PY, Unger PF, Auckenthaler R, Waldvogel FA. Efficacy and costs of treatment with ceftriaxone compared to ampicillin-gentamycin in acute pyelonephritis. In French [Efficacite et cout d'un traitement de ceftriaxone compare a l'ampicilline-gentamicine dans les pyelonehrites aigues]. Reveu Medicale Suisse Romande 1991;111(7):609-17.
McCormick 1997 {published and unpublished data}
  • McCormick PA, Greenslade L, Kibbler CC, Chin JK, Burroughs AK, McIntyre N. A prospective randomized trial of ceftazidime versus netilmicin plus mezlocillin in the empirical therapy of presumed sepsis in cirrhotic patients. Hepatology 1997;25(4):833-6.
Mergoni 1987 {published and unpublished data}
  • Mergoni M, Stocchetti N, De Cristofaro A, Antonioni M, Zuccoli P. Azlocillin versus azlocillin plus amikacin in the treatment of severe infections in intensive care unit patients. Chemioterapia 1987;6(4):286-9.
Moreno 1997 {published data only}
  • Moreno A, Vilardell J, Ricart MJ, Claramonte X, Campistol JM, Oppenheimer F. Efficacy of several empirical antibacterial treatment regimens in renal transplant patients with fever [Eficacia de varias pautas de tratamiento empirico antibacteriano en pacientes receptores de trasplante renal con fiebre]. Revista Espanola De Quimioterapia 1997;10(2):138-45.
Mouton 1990 {published data only}
  • Mouton Y, Deboscker Y, Bazin C, Fourrier F, Moulront S, Philippon A, et al. [Prospective, randomized, controlled study of imipenem-cilastatin versus cefotaxime-amikacin in the treatment of lower respiratory tract infection and septicemia at intensive care units], in French. Presse Medicale 1990;19(13):607-12.
Mouton 1995 {published data only}
  • Mouton YJ, Beuscart C, and the Meropenem Study Group. Empirical monotherapy with meropenem in serious bacterial infections. Journal of Antimicrobial Chemotherapy 1995;36(Suppl A):145-56.
Muller 1987 {published data only}
  • Muller EL, Pitt HA, Thompson JE Jr, Doty JE, Mann LL, Manchester B. Antibiotics in infections of the biliary tract. Surgery, gynecology & obstetrics 1987;165(4):285-92.
Naime Libien 1992 {published data only}
  • Naime Libien J, Vigueras Rendon A, Sanchez Diaz G, Abraham Jalil A. Clinical study to evaluate efficacy and safety of ceftizoxime compared vs penicillin-gentamicin fixed combination in the treatment of severe respiratory infections [Estudio clinico para determinar la eficacia y seguridad de ceftizoxima en comparacion con la asociacion penicilina gentamicina en el tratamiento de las infecciones respiratorias graves]. Compend Invest Clin Latinoam 1992;12(2):42-8.
Piccart 1984 {published data only (unpublished sought but not used)}
  • 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.
Rapp 1984 {published data only}
  • Rapp RP, Young B, Foster TS, Tibbs PA, O'Neal W. Ceftazidime versus tobramycin/ticarcillin in treating hospital acquired pneumonia and bacteremia. International Conference on Antimicrobial Agents and Chemotherapy. 1983.
  • Rapp RP, Young B, Foster TS, Tibbs PA, O'Neal W. Ceftazidime versus tobramycin/ticarcillin in treating hospital acquired pneumonia and bacteremia. Pharmacotherapy 1984;4(4):211-5.
Rasmussen 1986 {published and unpublished data}
  • Rasmussen D, Bremmelgaard A, Rasmussen F, Thorup J. Treatment of serious urological infections with cefotaxime compared to ampicillin plus netilmicin. Danish Medical Bulletin 1986;33(1):49-51.
Ribera 1996 {published and unpublished data}
  • Ribera E, Gomez-Jimenez J, Cortes E, del Valle O, Planes A, Gonzalez-Alujas T, et al. Effectiveness of cloxacillin with and without gentamicin in short-term therapy for right-sided Staphylococcus aureus endocarditis. A randomized, controlled trial. Annals of Internal Medicine 1996;125(12):969-74.
Rubinstein 1995 {published and unpublished data}
  • Rubinstein E, Lode H, Grassi C, Castelo A, Ward K, Alanko K et al (Antibiotic Study Group). Ceftazidime monotherapy vs. Ceftriaxone/tobramycin for serious hospital- acquired gram-negative infections.. Clinical Infectious Diseases 1995;20(5):1217-28.
Sage 1987 {published data only}
  • Sage R, Nazareth B, Noone P. A prospective randomised comparison of cefotaxime vs. netilmicin vs. cefotaxime plus netilmicin in the treatment of hospitalised patients with serious sepsis. Scandinavian Journal of Infectious Diseases 1987;19(3):331-7.
Sandberg 1997 {published and unpublished data}
  • Sandberg T, Alestig K, Eilard T, Ek E, Hebelka M, Johansson E, et al. Aminoglycosides do not improve the efficacy of cephalosporins for treatment of acute pyelonephritis in women. Scandinavian Journal of Infectious Diseases 1997;29(2):175-9.
Sanfilippo 1989 {published data only}
  • Sanfilippo JS, Schikler KN. Mezlocillin versus penicillin and tobramycin in adolescent pelvic inflammatory disease: A prospective study. International Pediatrics 1989;4(1):53-6.
Sculier 1982 {published data only (unpublished sought but not used)}
  • Sculier JP, Coppens L, Klastersky J. Effectiveness of mezlocillin and endotracheally administered sisomicin with or without parenteral sisomicin in the treatment of Gram-negative bronchopneumonia. Journal of Antimicrobial Chemotherapy 1982;9(1):63-8.
Sexton 1998 {published data only}
  • Sexton DJ, Tenenbaum MJ, Wilson WR, Steckelberg JM, Tice AD, Gilbert D, et al. Ceftriaxone once daily for four weeks compared with ceftriaxone plus gentamicin once daily for two weeks for treatment of endocarditis due to penicillin-susceptible streptococci. Endocarditis Treatment Consortium Group. Clinical Infectious Diseases 1998;27(6):1470-4.
Sieger 1997 {published data only}
  • Sieger B, Berman SJ, Geckler RW, Farkas SA, for the Meropenem Lower Respiratory Infection Group. Empiric treatment of hospital-acquired lower respiratory tract infections with meropenem or ceftazidime with tobramycin: a randomized study. Critical Care Medicine 1997;25(10):1663-70.
  • Sieger B, Geckler RW. A comparison of meropenem and ceftazidime plus tobramycin in the treatment of hospital-acquired lower respiratory tract infections. 33rd Interscience Conference on Antimicrobials Agents and Chemotherapy. 1993; Vol. Abstract no. 640:236.
Smith 1984 {published data only (unpublished sought but not used)}
  • Moore RD, Smith CR, Holloway JJ, Lietman PS. Cefotaxime vs nafcillin and tobramycin for the treatment of serious infection. Comparative cost-effectiveness. Archives of Internal Medicine 1986;146(6):1153-7.
  • Moore RD, Smith CR, Lietman PS. Increased risk of renal dysfunction due to interaction of liver disease and aminoglycosides. American Journal of Medicine 1986;80(6):1093-7.
  • Smith CR, Ambinder R, Lipsky JJ, Petty BG, Israel E, Levitt R, et al. Cefotaxime compared with nafcillin plus tobramycin for serious bacterial infections. A randomized, double-blind trial. Annals of Internal Medicine 1984;101(4):469-77.
Speich 1998 {published and unpublished data}
  • Speich R, Imhof E, Vogt M, Grossenbacher M, Zimmerli W. Efficacy, safety, and tolerance of piperacillin/tazobactam compared to co-amoxiclav plus an aminoglycoside in the treatment of severe pneumonia. European Journal of Clinical Microbiology and Infectious Diseases 1998;17(5):313-17.
Stille 1992 {published data only}
  • Stille W, Shah PM, Ullmann U, Hoffstedt B, Kreisl C, Bommersbach B et al. For the German and Austrian Imipenem/Cilastatin Study Group. Randomized multicenter clinical trial with imipenem/cilastatin versus cefotaxime/gentamicin in the treatment of patients with non-life-threatening infections. European Journal of Clinical Microbiology and Infectious Diseases 1992;11(8):683-92.
Sukoh 1994 {published and unpublished data}
  • Sukoh M, Inoue T, Morita Y, Ito K, Togano Y, Yamanaka K, et al. [Clinical evaluation of combination therapy of sulbactam/cefoperazone and aminoglycoside in respiratory tract infections]. In Japanese. Japanese Journal of Antibiotics 1994;47(2):170-80.
Takamoto 1994 {published data only}
  • Takamoto M, Ishibashi T, Toyoshima H, Tanaka H, Tamaru N, Watanabe K, et al. [Imipenem/cilastatin sodium alone or combined with amikacin sulfate in respiratory infections]. In Japanese. Japanese Journal of Antibiotics 1994;47(9):1131-44.
Thompson 1990 {published data only}
  • Thompson JE Jr, Pitt HA, Doty JE, Coleman J, Irving C. Broad spectrum penicillin as an adequate therapy for acute cholangitis. Surgery, gynecology & obstetrics 1990;171(4):275-82.
Thompson 1993 {published data only}
  • Thompson JE Jr, Bennion RS, Roettger R, Lally KP, Hopkins JA, Wilson SE. Cefepime for infections of the biliary tract. Surgery, gynecology & obstetrics 1993;177(Suppl):30-4.
Trujillo 1992 {published data only}
  • Zavala Trujillo I. Research on efficacy and safety of ceftizoxime in treating lower respiratory tract and skin and soft tissues infections [Busqueda de la eficacia y seguridad de ceftizoxima en el tratamiento de infecciones del tracto respiratorio inferior y de la piel y de los tejidos blandos]. Compend Invest Clin Latinoam 1992;12(2):31-41.
Vergnon 1985 {published data only}
  • Vergnon JM, Vincent M, Ros A, Brun Y, Brune J. [Comparative clinical trial of cefoperazone versus ampicillin + tobramycin in severe bronchopulmonary and pleural infectious pathology]. In French. Revue de pneumologie clinique 1985;41(3):205-11.
Verzasconi 1995 {published data only}
  • Verzasconi R, Rodoni P, Monotti R, Marone C, Mombelli G. [Amoxicillin and clavulanic acid versus amoxicillin plus gentamicin in the empirical initial treatment of urinary tract infections in hospitalized patients] [In German]. Schweizerische medizinische Wochenschrift 1995;125(33):1533-9.
Warren 1983 {published data only}
  • Warren JW, Miller EH Jr, Fitzpatrick B, DiFranco DE, Caplan ES, Tenney JH, et al. A randomized, controlled trial of cefoperazone vs. cefamandole- tobramycin in the treatment of putative, severe infections with gram- negative bacilli. Reviews in Infectious Diseases 1983;5(Suppl 1):S173-S180.
Wiecek 1986 {published data only}
  • Wiecek A, Kokot F, Andrzejowska H, Grzeszczak W. [Clinical evaluation of ceftazidime and the combined administration of cefotaxime and tobramycin in the treatment of urinary tract infections. Prospective and randomized studies] In Polish. Polski tygodnik lekarski 1986;41(39):1242-46.
Wing 1998 {published and unpublished data}
Yellin 1993 {published and unpublished data}
  • Yellin AE, Berne TV, Appleman MD, Heseltine PN, Gill MA, Okamoto MP, et al. A randomized study of cefepime versus the combination of gentamicin and mezlocillin as an adjunct to surgical treatment in patients with acute cholecystitis. Surgery, gynecology & obstetrics 1993;177(Suppl):23-9.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  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. Additional references
  23. References to other published versions of this review
Alvarez-Lerma 2001b {published data only}
  • Alvarez-Lerma F, Insausti-Ordenana J, Jorda-Marcos R, Maravi-Poma E, Torres-Marti A, Nava J, et al. Efficacy and tolerability of piperacillin/tazobactam versus ceftazidime in association with amikacin for treating nosocomial pneumonia in intensive care patients: a prospective randomized multicenter trial. Intensive Care Medicine 2001;27(3):493-502.
Badaro 2002 {published data only}
  • Badaro R, Molinar F, Seas C, Stamboulian D, Mendonca J, Massud J, et al. A multicenter comparative study of cefepime versus broad-spectrum antibacterial therapy in moderate and severe bacterial infections. Brazilian Journal of Infectious Diseases 2002;6(5):206-18.
Benlloch 1995 {published data only}
  • Benlloch C, Costa E, Segarra V, Velazquez JA, Ruiz CS. Systemic antibiotherapy in acute appendicitis. Comparison of three antibiotic regimes [Antibioterapia sistemica en apendicitis aguda. Comparacion entre tres pautas antibioticas]. Acta Pediatrica Espanola 1995;53(6):367-9.
Blumer 2003 {published data only}
  • Blumer JL, Minkwitz M, Saiman L, San Gabriel P, Iaconis J, Melnick D. Meropenem (MEM) compared with ceftazidime (CAZ) in combination with tobramycin (TOB) for treatment of actue pulmonary exacerbations (APE) in patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa (PA) or burkholderia cepacia (BC). Pediatric Pulmonology. 2003; Vol. Suppl 25:294.
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(2):155-60.
Ciftci 1997 {published data only}
  • Ciftci AO, Tanyel FC, Buyukpamukcu N, Hicsonmez A. Comparative trial of four antibiotic combinations for perforated appendicitis in children. European Journal of Surgery 1997;163(8):591-6.
Crenshaw 1983 {published data only}
  • Crenshaw C, Glanges E, Webber C, McReynolds DB. A prospective random study of a single agent versus combination antibiotics as therapy in penetrating injuries of the abdomen. Surgery Gynecology & Obstetrics 1983;156(3):289-94.
Croce 1993 {published data only}
  • Croce M, Fabian TC, Stewart RM, Pritchard FE, Minard G, Trenthem L, et al. Empiric monotherapy versus combination therapy of nosocomial pneumonia in trauma patients. The Journal of Trauma 1993;35(2):303-9.
De Louvois 1992 {published data only}
  • De Louvois J, Dagan R, Tessin I. A comparison of ceftazidime and aminoglycoside based regimens as empirical treatment in 1316 cases of suspected sepsis in the newborn. European Society for Paediatric Infectious Diseases--Neonatal Sepsis Study Group. European Journal of Pediatrics 1992;151(12):876-84.
Extermann 1995 {published data only}
  • Extermann M, Regamey C, Humair L, Murisier F, Rhyner K, Vonwiller HM. Initial Treatment of Sepsis in Non-Neutropenic Patients - Ceftazidime Alone Versus Best Guess Combined Antibiotic-Therapy. Chemotherapy 1995;41:306-15.
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.
Fernandez 1991 {published data only}
  • Fernandez GM, Gudiol F, Rodriguez TA, Arnau C, Valdes L, Vallve C. Nosocomial pneumonia: comparative multicentre trial between monotherapy with cefotaxime and treatment with antibiotic combinations. Infection 1991;19(Suppl 6):S320-S325.
Foord 1985 {published data only}
Gentry 1980 {published data only}
  • Gentry LO, Wood BA, Martin MD, Smythe J. Cefamandole alone and combined with gentamicin or tobramycin in the treatment of acute pyelonephritis. Scandinavian Journal of Infectious Diseases 1980;suppl(25):96-100.
Gentry 1984 {published data only}
Gentry 1985 {published data only}
Gerber 1989 {published data only}
  • Gerber B, Retzke F, Wilken H. [Effectiveness of perioperative preventive use of antibiotics with ampicillin/gentamycin or cefotiam in abdominal cesarean section]. Zentralbl Gynakol 1989;111(10):658-63.
Gilbert 1998 {published data only}
  • Gilbert DN, Lee BL, Dworkin RJ, Leggett JL, Chambers HF, Modin G, et al. A randomized comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin-clavulanate. American Journal of Medicine 1998;105(3):182-191.
Giraud 1989 {published data only}
  • Giraud JR, Chartier M, Ciraru Vigneron N, Becue J, Landes P, Leng JJ, et al. [A comparison of the efficacy of and tolerance to Augmentin used alone and as one of three drugs used to treat acute upper genital tract infections. Results of a multicentre trial 152 cases] [Comparaison de l'efficacite et de la tolerance de l'Augmentine en monotherapie versus triple association dans le traitment des infections genitales hautes aigues. Resultats d'une etude multicentrique portant sur 152 cas]. Contracept Fertil Sex 1989;17(10):941-8.
Gold 1985 {published data only}
  • Gold R, Overmeyer A, Knie B, Fleming PC, Levison H. Controlled trial of ceftazidime vs. ticarcillin and tobramycin in the treatment of acute respiratory exacerbations in patients with cystic fibrosis. Pediatric Infectious Disease 1985;4(2):172-7.
Gomez 1990b {published data only}
  • Gomez J, Moldenhauer F, Ruiz Gomez J, Ros CM, Martinez Hernandez J, Canteras M, et al. Monotherapy versus antibiotic combinations in bacteremias in an internal medicine department. A prospective study in 1987 [Monoterapia frente a combinaciones antibioticas en las bacteriemias de un departamento de medicina interna. estudio prospectivo durante 1987]. Revista Espanola de Microbiologia Clinica 1990;5(2):89-93.
Greco 1989 {published data only}
  • Greco T. Treatment of nosocomial pneumonia: monotherapy versus combination therapy. Geriatrics 1989;44 Suppl A:28-31.
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.
  • 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. 21st Interscience Conference on Antimicrobial Agents and Chemotherapy. 1981.
Haffejee 1984 {published data only}
  • Haffejee IE. A therapeutic trial of cefotaxime versus penicillin-gentamicin for severe infections in children. Journal of Antimicrobial Chemotherapy 1984;14 Suppl B:147-52.
Hall 1988 {published data only}
  • Hall MA, Ducker DA, Lowes JA, McMichael J, Clarke P, Rowe D, et al. A randomised prospective comparison of cefotaxime versus netilmicin/penicillin for treatment of suspected neonatal sepsis. Drugs 1988;35(Suppl 2):169-77.
Hammerberg 1989 {published data only}
  • Hammerberg O, Kurnitzki C, Watts J, Rosenbloom D. Randomized trial using piperacillin versus ampicillin and amikacin for treatment of premature neonates with risk factors for sepsis. European Journal of Clinical Microbiology and Infectious Diseases 1989;8(3):241-4.
Hanson 1982 {published data only}
  • Hanson B, Coppens L, Klastersky J. Comparative studies of ticarcillin and mezlocillin plus sisomicin in Gram-negative bacillary bacteraemia and bronchopneumonia. Journal of Antimicrobial Chemotherapy 1982;10(4):335-41.
Hoogkamp 1983 {published data only}
  • Hoogkamp-Korstanje JA, van der Laag J. Piperacillin and tobramycin in the treatment of Pseudomonas lung infections in cystic fibrosis. Journal of Antimicrobial Chemotherapy 1983;12(2):175-83.
Iakovlev 1997 {published data only}
  • Iakovlev SV, Shakhova TV, Dvoretskii LI, Romanovskii I, Eremina LV, Koroleva TA, et al. [Use of piperacillin/tazobactam as empirical monotherapy in the treatment of bacterial infections in a resuscitation department]. Antibiotiki i Khimioterapia 1997;42(2):33-7.
Iakovlev 2000 {published data only}
  • Iakovlev SV, Dvoretskii LI, Shakhova TV. [The clinical efficacy of ticarcillin/clavulanate in severe pneumonia]. Antibiotiki i Khimioterapia 2000;45(3):30-4.
Ker 1989 {published data only}
  • Ker CG, Hou MF, Chen JS, Lee KT, Sheen PC, Akbary MA. A comparative study of cefotaxime sodium versus a combination of cefapirin and gentamicin in the prophylactic treatment of patients undergoing cholecystectomy. Methods and Findings in Experimental and Clinical Pharmacology 1989;11(11):711-5.
Krumpe 1999 {published data only}
  • Krumpe PE, Cohn S, Garreltes J, Ramirez J, Coulter H, Haverstock D, et al. Intravenous and oral mono- or combination-therapy in the treatment of severe infections: ciprofloxacin versus standard antibiotic therapy. Ciprofloxacin Study Group. Journal of Antimicrobial Chemotherapy 1999;43(Suppl A):117-28.
Ludwig 1980 {published data only}
  • Ludwig G, Knebel L. Cefotaxime in urinary tract infections--comparative clinical studies with gentamicin and with cefoxitin. Journal of Antimicrobial Chemotherapy 1980;6 Suppl A:207-11.
Maller 1991 {published data only}
  • Maller R, Ahrne H, Eilard T, Eriksson I, Lausen I. Efficacy and safety of amikacin in systemic infections when given as a single daily dose or in two divided doses. Scandinavian Amikacin Once Daily Study Group. Journal of Antimicrobial Chemotherapy 1991;27(Suppl C):121-8.
Mangi 1988 {published data only}
McArdle 1987 {published data only}
  • McArdle C, Morran C, Greig J, Mason B, Haddock G, Sleigh J, et al. Comparison of cefotetan and gentamicin/ampicillin in high-risk biliary tract surgery. Chemioterapia 1987;6(2 Suppl):593-4.
McCarty 1988 {published data only}
  • McCarty JM, Tilden SJ, Black P, Craft JC, Blumer J, Waring W, et al. Comparison of piperacillin alone versus piperacillin plus tobramycin for treatment of respiratory infections in children with cystic fibrosis. Pediatric Pulmonology 1988;4(4):201-4.
McLaughlin 1983 {published data only}
  • McLaughlin FJ, Matthews WJ Jr, Strieder DJ, Sullivan B, Taneja A, Murphy P, Goldmann DA. Clinical and bacteriological responses to three antibiotic regimens for acute exacerbations of cystic fibrosis: ticarcillin-tobramycin, azlocillin-tobramycin, and azlocillin-placebo. Journal of Infectious Diseases 1983;147(3):559-567.
  • McLaughlin FJ, Matthews WJ, Jr, Strieder DJ, Sullivan B, Goldmann DA. Randomized, double-blind evaluation of azlocillin for the treatment of pulmonary exacerbations of cystic fibrosis. Journal of Antimicrobial Chemotherapy 1983;11(Suppl B):195-203.
Mondorf 1987 {published data only}
  • Mondorf A, Mondorf W, Banzer S. A multiple-center comparative study of the kidney tolerance of ceftazidime versus cefotaxime and tobramycin. Chemioterapia 1987;6(2 Suppl):331-2.
Mondorf 1989 {published data only}
  • Mondorf AW, Bonsiepe C, Mondorf W. Randomized multi center study comparing nephrotoxicity of ceftazidime versus the combination of piperacillin and netilmicin with and without furosemide. Advances in Experimental Medicine and Biology 1989;252:307-12.
Moreno-Martinez 1998 {published data only}
  • Moreno Martinez A, Mensa J, Martinez JA, Marco F, Vila J, Almela M, et al. Cefixime versus amoxicillin plus netilmicin in the treatment of community-acquired non-complicated acute pyelonephritis. Medicina Clinica 1998;111(14):521-4.
Mouton 1985 {published data only}
  • Mouton Y, Deboscker Y, Beuscart C, Beaucaire G, Fourrier A. Third generation cephalosporins in combination with aminoglycosides or in monotherapy for life-threatening infections in an intensive care unit. 25th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1985:Abstract no. 958.
Oblinger 1982 {published data only}
  • Oblinger MJ, Bowers JT, Sande MA, Mandell GL. Moxalactam therapy vs. standard antimicrobial therapy for selected serious infections. Reviews of Infectious Diseases 1982;4(Suppl):S639-S649.
Odio 1987 {published data only}
  • Odio CM, Umana MA, Saenz A, Salas JL, McCracken GH. Comparative efficacy of ceftazidime vs. carbenicillin and amikacin for treatment of neonatal septicemia. Pediatric Infectious Diseases Journal 1987;6(4):371-7.
Padoan 1987 {published data only}
  • Padoan R, Cambisano W, Costantini D, Crossignani RM, Danza ML, Trezzi G, et al. Ceftazidime monotherapy vs. combined therapy in Pseudomonas pulmonary infections in cystic fibrosis. Pediatric Infectious Diseases Journal 1987;6(7):648-53.
Paoletti 1989 {published data only}
  • Paoletti V, Mammarella A, Mariani A, Filippello CP, Franchino L, Barlattani M. Netilmicin in the treatment of infections of the lower urinary tract [La netilimicina nel trattamento delle infeziono delle basse vie urinarie]. Clinical Therapeutics 1989;128(6):405-9.
Rodloff 1998 {published data only}
  • Rodloff Ac, Kujath P, Lunstedt B, Gaus W. Comparative study of the cost-effectiveness of initial therapy with imipenem/cilastatin in secondary peritonitis. Chirurgia 1998;69(10):1093-1100.
Romanelli 2002 {published data only}
  • Romanelli G, Cravarezza P, Pozzi A, Franchino L, Ravizzola G, Zulli R, et al. Carbapenems in the treatment of severe community-acquired pneumonia in hospitalized elderly patients: a comparative study against standard therapy. Journal of Chemotherapy 2002;14(6):609-17.
Schoengut 1983 {published data only}
  • Schoengut H, Jelinek R. Comparative study of the effects of ceftazidime compared with tobramycin plus cefamandole in the treatment of gall bladder empyema. Journal of Antimicrobial Chemotherapy 1983;12 Suppl A:219-22.
Schuler 1995 {published data only}
  • Schuler D, and the Meropenem Paediatric Study Group. Safety and efficacy of meropenem in hospitalised children: randomised comparison with cefotaxime, alone and combined with metronidazole or amikacin. Journal of Antimicrobial Chemotherapy 1995;36(Suppl A):99-108.
Scott 1987 {published data only}
  • Scott SD, Saddler B, Lowes JA, Karran SJ. Comparison of cefotetan versus combination therapy in peritonitis and serious intra-abdominal sepsis. Chemioterapia 1987;6(2 Suppl):475-6.
Sexton 1984 {published data only}
  • Sexton DJ, Wlodaver CG, Tobey LE, Finn LA, Chubb JM. Ceftazidime therapy for Gram-negative bone and joint infections. 24th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1984; Vol. Abstract no. 1213:305.
Sheftel 1986 {published data only}
  • Sheftel TG, Mader JT. Randomized evaluation of ceftazidime or ticarcillin and tobramycin for the treatment of osteomyelitis caused by gram-negative bacilli. Antimicrobial Agents and Chemotherapy 1986;29(1):112-5.
Smith 1999 {published data only}
  • Smith AL, Doershuk C, Goldmann D, Gore E, Hilman B, Marks M, et al. Comparison of a beta-lactam alone versus beta-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis. Journal of Pediatrica 1999;134(4):413-21.
Solberg 1995 {published data only}
  • Solberg CO, Sjursen H. Safety and efficacy of meropenem in patients with septicaemia: a randomised comparison with ceftazidime, alone or combined with amikacin. Journal of Antimicrobial Chemotherapy 1995;36(Suppl A):157-66.
Solomkin 1986 {published data only}
  • Solomkin JS, Cocchetto DM. Ceftazidime versus tobramycin plus ticarcillin in the treatment of soft-tissue infections. Clinical Therapeutics 1986;9(1):123-34.
Stack 1985 {published data only}
  • Stack BHR, Geddes DM, Williams KJ, Dinwiddie R, Selkon JB, Godfrey RC, for the British Thoracic Society Research Committee. Ceftazidime compared with gentamicin and carbenicillin in patients with cystic fibrosis, pulmonary pseudomonas infection, and an exacerbation of respiratory symptoms. Thorax 1985;40(5):358-63.
Tally 1986 {published data only}
  • Tally FP, Kellum JM, Ho JL, O'Donnell TF, Barza M, Gorbach SL. Randomized prospective study comparing moxalactam and cefoxitin with or without tobramycin for the treatment of serious surgical infections. Antimicrobial Agents and Chemotherapy 1986;29(2):244-9.
Thompson 1980 {published data only}
  • Thompson SE, Hager WD, Wong KH, Lopez B, Ramsey C, Allen SD, et al. The microbiology and therapy of acute pelvic inflammatory disease in hospitalized patients. American Journal of Obstetrics & Gynecology 1980;136(2):179-86.
Vazquez 1994 {published data only}
  • Vazquez Vela Sanchez G, De Leon Zavala J, Ochoa Cozares M. Comparative study of two preventive antibiotic programs for treatment of open fractures [Estudio comparativo de dos esquemas de antibioticos para la prevencion de la infeccion en las fracturas expuestas]. Rev mex ortoptraumatol 1994;8(5):263-4.
Vetter 1987 {published data only}
  • Vetter N, Feist H, Armbruster C, Drlicek M. Comparison of the effectiveness of ceftazidime and cefazolin/tobramycin in patients with inflammatory diseases of the lower respiratory tract. In German [Efficacy of ceftazidime and cefazolin/tobramycin in lower respiratory tract infections]. Infection 1987;15(Suppl 4):S192-4.
  • Vetter N, Feist H, Muhar F, Williams KJ. A comparative study of the efficacy of ceftazidime versus cefazolin and tobramycin in patients with acute exacerbations of chronic bronchitis. Journal of Antimicrobial Chemotherapy 1983;12(Suppl A):35-9.
Vetter 1992 {published data only}
  • Vetter N. Efficacy of meropenem in the treatment of respiratory tract infection: a comparative evaluation. Journal of Chemotherapy. 1993; Vol. 5 Suppl 1.
  • Vetter N. Efficacy of meropenem in the treatment of respiratory tract infection:a comparative evaluation. Proceedings of the Eighth Mediterranean Congress of Chemotherapy. 1992:175.
Watanakunakorn 1997 {published data only}
  • Watanakunakorn C, Baird IM. Prognostic factors in Staphylococcus aureus endocarditis and results of therapy with a penicillin and gentamicin. The American journal of Medical Sciences 1977;273(2):133-9.

References to studies awaiting assessment

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  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. Additional references
  23. References to other published versions of this review
Figueroa-Damian 1996 {published data only}
  • Figueroa-Damian R, Villagrana-Zesati R, San Martin-Herrasti JM, Arredondo-Garcia JL. Comparison of the therapeutic efficacy of the piperacillin/tazobactame combination vs. ampicillin and gentamycin in the management of post-cesarean endometritis [Comparación de la eficacia terapéutica de piperacilina\tazobactam vs ampicilina más gentamicina en el tratamiento de endometritis poscesárea]. Ginecologia y Obstetricia de Mexico 1996;64(5):214-8.
Luis-Alberto 1999 {published data only}
  • Luis Alberto GR, Enrique RJ, Manuel de Jesus UV, Ana Patricia MB, Jose Javier LN, Jaime MM. Ceftazidime vs crystalline sodium penicillin and amikacin in the treatment of nosocomial pneumonia [Ceftazidima vs penicilina sodica cristalina y amikacina en el manejo de la neumonia nosocomial]. Medicina interna Mexico 1999;15(4):135-7.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  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. Additional references
  23. References to other published versions of this review
Allan 1985
  • Allan JD, Moellering RC. Management of infections caused by gram-negative bacilli: the role of antimicrobial combinations. Reviews of Infectious Diseases 1985;7 Suppl 4:559-71.
Baine 2001
  • Baine WB, Yu W, Summe JP. The epidemiology of hospitalization of elderly Americans for septicemia or bacteremia in 1991-1998. Application of Medicare claims data. Annals of Epidemiology 2001;11(2):118-26.
Barza 1996
  • Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996;312(7027):338-45.
Bayer 1998
  • Bayer AS, Bolger AF, Taubert KA, Wilson W, Steckelberg J, Karchmer AW, et al. Diagnosis and management of infective endocarditis and its complications. Circulation 1998;98(25):2936-48.
Bone 1992
Bryant 1971
  • Bryant RE, Hood AF, Hood CE, Koenig MG. Factors affecting mortality of gram-negative rod bacteremia. Archives of Internal Medicine 1971;127(1):120-8.
Elphick 2005
Geerdes 1991
  • Geerdes HF, Ziegler D, Lode H, Hund M, Loehr A, Fangmann W, et al. Septicemia in 980 patients at a university hospital in Berlin: prospective studies during 4 selected years between 1979 and 1989. Clinical Infectious Diseases 1992;15(6):991-1002.
Giamarellou 1984
  • Giamarellou H, Zissis NP, Tagari G, Bouzos J. In vitro synergistic activities of aminoglycosides and new beta-lactams against multiresistant Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 1984;25(4):534-6.
Giamarellou 1986
Higgins 2005
  • Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005]. Appendix 5c.: In: The Cochrane Library, Issue 3, 2005. Chichester, UK: John Wiley & Sons, Ltd.
Hilf 1989
  • Hilf M, Yu VL, Sharp J, Zuravleff JJ, Korvick JA, Muder RR. Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients. American Journal of Medicine 1989;87(5):540-6.
Hughes 2002
  • Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clinical Infectious Diseases 2002;34(6):730-51.
Ibrahim 2000
  • Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000;118(1):146-55.
Klastersky 1976
  • Klastersky J, Meunier-Carpentier F, Prevost JM, Staquet M. Synergism between amikacin and cefazolin against Klebsiella: in vitro studies and effect on the bactericidal activity of serum. Journal of Infectious Diseases 1976;134(3):271-6.
Klastersky 1982
  • Klastersky J, Zinner SH. Synergistic combinations of antibiotics in gram-negative bacillary infections. Reviews of Infectious Diseases 1982;4(2):294-301.
Leibovici 1997
  • Leibovici L, Paul M, Poznanski O, Drucker M, Samra Z, Konigsberger H, et al. Monotherapy versus beta-lactam-aminoglycoside combination treatment for gram-negative bacteremia: a prospective, observational study. Antimicrobial Agents and Chemotherapy 1997;41(5):1127-33.
Leibovici 1998
  • Leibovici L, Shraga I, Drucker M, Konigsberger H, Samra Z, Pitlik SD. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection. Journal of Internal Medicine 1998;244(5):379-86.
Mandell 2004
  • Mandell GL, Bennet JE, Dolin R, editors. Principles and practice of infectious diseases. 6th Edition. Philadelphia: Churchill Livingstone, 2004.
Manian 1996
  • Manian FA, Meyer L, Jenne J, Owen A, Taff T. Loss of antimicrobial susceptibility in aerobic gram-negative bacilli repeatedly isolated from patients in intensive-care units. Infection Control and Hospital Epidemiology 1996;17(4):222-6.
Milatovic 1987
Moellering 1986
  • Moellering RC, Jr, Eliopoulos GM, Allan JD. Beta-lactam/aminoglycoside combinations: interactions and their mechanisms. American Journal of Medicine 1986;80(5C):30-4.
Moore 2001
  • Moore RB, Shapiro NI, Wolfe RE, Smith ES, Bermudez S, Bates D. The value of sirs criteria in ed patients with presumed infection in predicting mortality. Academic Emergency Medicine 2001;8(5):477.
Paul 2013
  • 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. [DOI: 10.1002/14651858.CD003038.pub2]
Rangel-Frausto 1995
  • Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. Journal of the American Medical Association 1995;273(2):117-23.
Russell 2000
  • Russell JA, Singer J, Bernard GR, Wheeler A, Fulkerson W, Hudson L, et al. Changing pattern of organ dysfunction in early human sepsis is related to mortality. Critical Care Medicine 2000;28(10):3405-11.
Safdar 2004
Sande 1975
  • Sande MA, Johnson ML. Antimicrobial therapy of experimental endocarditis caused by Staphylococcus aureus. Journal of Infectious Diseases 1975;131(4):367-75.
Sande 1976
Schulz 1995
  • Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Journal of the American Medical Association 1995;273(5):408-12.
Weinstein 1985
  • Weinstein L. Gram-negative bacterial infections: a look at the past, a view of the present, and a glance at the future. Reviews of Infectious Diseases 1985;7 Suppl 4:538-44.
Whitelaw 1992
  • Whitelaw DA, Rayner BL, Willcox PA. Community-acquired bacteremia in the elderly: a prospective study of 121 cases. Journal of the American Geriatrics Society 1992;40(10):996-1000.