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.
Our objectives were:
- to compare beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy in patients with sepsis; and
- to estimate the rate of adverse effects with each treatment regimen, including the development of bacterial resistance to antibiotics.
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.
- Any intravenous beta-lactam antibiotic given as monotherapy, including:
- beta lactam drugs plus beta lactamase inhibitors (e.g. co-amoxiclav);
- cephalosporins (e.g. ceftazidime, cefotaxime);
- carbapenems (e.g. imipenem, meropenem).
- Combination therapy of a beta lactam antibiotic (as specified) with one of the following aminoglycoside antibiotics:
Types of outcome measures
All-cause fatality by the end of the study follow-up.
- 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).
- Length of hospital stay.
- Dropouts: number of patients excluded from the outcome assessment after randomization.
- 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.
- 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.
- Adverse effects:
- life-threatening or associated with permanent disability (severe nephrotoxicity; ototoxicity; anaphylaxis; severe skin reactions);
- serious: requiring discontinuation of therapy (other nephrotoxicity; seizures; pseudomembranous colitis; other allergic reactions);
- any other (other gastrointestinal; other allergic reactions).
Search methods for identification of studies
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):
- 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.
- EMBASE (1980 to March 2003) using the same search terms.
- 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
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).
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.
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:
- date, location, and setting of trial;
- publication status;
- country of origin;
- design (intention-to-treat, method of randomization);
- duration of study follow-up;
- performance of surveillance cultures (routine cultures for the detection of colonization);
- sponsor of trial.
Characteristics of patients:
- number of participants in each group;
- age (mean and standard deviation, or median and range);
- number of patients with renal failure before treatment;
- number of patients with shock.
Characteristics of infection:
- number of patients with infections caused by bacteria resistant to the administered beta lactam antibiotic;
- number of patients with nosocomial infections;
- number of patients with bacteraemia;
- number of patients with bacteriologically documented infection;
- number of patients with infections caused by Gram-negative bacteria;
- number of patients with Gram-negative bacteraemia;
- number of patients with documented Pseudomonas infections (Pseudomonas isolated in the blood or specimen(s) obtained from suspected site(s) of infection);
- number of patients with:
- urinary tract infection;
- intra-abdominal infection;
- skin and soft tissue infection; and
- infection of unknown origin.
Characteristics of interventions:
- antibiotic type and dose;
- duration of therapy (mean).
Characteristics of outcome measures:
- number of deaths at the end of the follow-up period;
- number of patients failing treatment (as defined);
- adverse reactions (as defined) in each group;
- loss of follow-up (dropouts) before the end of the study in each group;
- number of patients developing super-infection;
- number of patients developing colonization (as defined) with resistant bacteria;
- 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.
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 I
- infections caused by Pseudomonas sp. versus all other infections;
- Gram-negative versus all other infections; and
- 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).
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).
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:
- full Intention-to-treat analysis;
- per-protocol analysis, in which the number of dropouts was given per study arm;
- per-protocol analysis, in which the number of dropouts was known, but not given per study arm;
- 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%).
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 (I
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).
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).
(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 (I
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.
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).
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.
|Figure 1. Funnel failure.|
|Figure 2. Funnel mortality.|
All cause mortality
(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.
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.
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.
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
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Appendix 1. Search strategy
Obtaining data on all-cause mortality, 16 June 2013
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 (I
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
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.
Anthony Amadio, BSc. Pharm, ACPR, RPh
Doctor of Pharmacy Student
Faculty of Pharmaceutical Sciences
University of British Columbia
Aaron M Tejani, BSc Pharm, PharmD
Therapeutics Initiative, University of British Columbia
2176 Health Sciences Mall
Vancouver, BC, Canada
Mical Paul, corresponding author
Last assessed as up-to-date: 11 November 2005.
Protocol first published: Issue 4, 2001
Review first published: Issue 1, 2006
Contributions of authors
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
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
- Rabin Medical Center - Beilison Campus, Israel.
- EU 5th Framework - TREAT project (grant number: 1999-11459), Not specified.
- Department for International Development, UK.
Medical Subject Headings (MeSH)
Aminoglycosides [*therapeutic use]; Anti-Bacterial Agents [*therapeutic use]; Bacterial Infections [*drug therapy]; Cause of Death; Drug Therapy, Combination; Gram-Negative Bacterial Infections [drug therapy]; Gram-Positive Bacterial Infections [drug therapy]; Randomized Controlled Trials as Topic; beta-Lactams [*therapeutic use]
MeSH check words
* Indicates the major publication for the study