lactam monotherapy versus lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-anal
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《英国医生杂志》
1 Department of Medicine E and Infectious Diseases Unit, Rabin Medical Centre, Beilinson Campus, Petah-Tikva 49100, Israel, 2 Department of Medicine E, Rabin Medical Centre, Beilinson Campus, Petah-Tikva
Correspondence to: M Paul mica@zahav.net.il
Abstract
Treatment with a combination of lactam and an aminoglycoside is purported to be superior to lactam monotherapy for sepsis on the basis of potential advantages such as in vitro synergism and prevention of development of resistance.1-7 Textbooks and guidelines advise the combination for specific pathogens, such as Pseudomonas aeruginosa and other Gram negative bacteria, and for infections commonly caused by these pathogens.8 9 In aiming for optimal antibiotic treatment of severe infections, hospital clinicians tend to use combination therapy despite the lack of direct evidence for its effectiveness. Observational studies show that 25-30% of patients with bacteraemia,10 11 surgical infections,12 or pneumonia,13 14 50% of those with klebsiella bacteraemia,15 and 56% of patients with septic shock in the intensive care unit16 are given lactam-aminoglycoside combination therapy.
We performed a systematic review and meta-analysis of randomised trials comparing lactam-aminoglycoside combination therapy with lactam monotherapy for severe infections in patients without neutropenia.
Methods
We evaluated 144 eligible randomised trials and included 64 in the review (fig 1). The trials included 7586 patients, nearly all adults, and were performed between the years 1968-2001. The median number of patients per trial was 87 (range 20-580). Trials differed by the population targeted, type of infection, and antibiotics compared (table 1). The major conditions were severe sepsis, pneumonia, or Gram negative infections (41 trials), abdominal infections (11 trials), urinary tract infections (7 trials), and Gram positive infections (5 trials). Allocation to antibiotics was empirical in 56 trials. The same lactam was compared in 20 trials, while all other trials compared one lactam to a different, narrower spectrum lactam combined with an aminoglycoside.
Fig 1 Detail of trial selection. The list of excluded references (w1-w80) can be found on bmj.com>
Table 1 Characteristics of included studies: patients and intervention
All cause fatality—Forty three trials including 5527 patients reported all cause fatality. There was no significant difference between monotherapy and combination therapy when we combined these studies (relative risk 0.90, 95% confidence interval 0.77 to 1.06, fig 2). There was no difference among the 12 studies with 1381 patients that compared the same lactam (1.02, 0.76 to 1.38) or among studies that compared different lactams (0.85, 0.69 to 1.05). The heterogeneity for this comparison was low (I2 = 7.7%).
Fig 2 All cause fatality in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight
Treatment failure—We compared clinical and bacteriological failures in 63 and 43 trials, respectively (figs 3 and 4). For both comparisons, monotherapy was not significantly different from combination therapy among studies that compared the same lactam. Monotherapy was significantly superior to combination therapy among studies that compared different lactams. The overall comparison favoured monotherapy for clinical failure (0.87, 0.78 to 0.97; 6616 patients; number needed to treat 34, 20 to 147) and for bacteriological failure (0.86, 0.72 to 1.02; 3511 patients).
Fig 3 Clinical failure in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight
Fig 4 Bacteriological failure in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight
Subgroup analysis—Major effectiveness outcomes were compared within the defined patient subgroups expected to benefit most from combination therapy (tables 2 and 3). We did not detect an advantage to combination therapy with any subgroup tested. Mortality was higher among patients with P aeruginosa (21%), Gram negative infections (13%), and bacteraemia (15%), and outcomes were similar with combination versus monotherapy. Patients with infections outside the urinary tract (mainly pneumonia) had significantly fewer failures with monotherapy. Five trials specifically assessed Gram positive infections, endocarditis in four (table 1). 21 32 48 63 69 Combined relative risks for fatality and failure favoured monotherapy, although differences were non-significant.
Table 2 All cause fatality in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis: subgroup analyses
Table 3 Clinical failure in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis: subgroup analyses
Development of resistance—Combination therapy did not lower bacterial superinfection or colonisation rates, which we would have expected if combination therapy prevented the development of resistance (fig 5). Relative risks tended in favour of monotherapy for bacterial superinfections (0.79, 0.59 to 1.06). Rates of fungal superinfection were similar. Six studies performed routine surveillance cultures, and nine assessed the development of resistance among pretreatment isolates. In these also we found no advantage with combination therapy. Twenty six studies reported coverage rates of the allocated treatment, although outcomes were not related to coverage. Among studies with different lactams, the monotherapy lactam provided broader coverage than the combination lactam in 13 studies, the opposite occurring in two studies. Combined coverage of the lactam and the aminoglycoside equalled monotherapy in these studies.
Fig 5 Summary relative risks for outcome relating to resistance development in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight
Drop outs and adverse events—The dropout rate was 12.6% and similar in both study groups (1.01, 0.85 to 1.20, 24 studies, 3631 patients). Few patients (2%) discontinued treatment because of adverse events with no difference between study groups (0.89, 0.52 to 1.52, 15 studies, 3042 patient). Nephrotoxicity was more common with combination therapy in nearly all studies, and the combined relative risk was 0.36 (0.28 to 0.47, fig 6), corresponding to a number needed to harm of 15 (14 to 17) for combination therapy.
Fig 6 Adverse events: nephrotoxicity in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight
Sensitivity analysis—Figure 7 shows sensitivity analyses for measures of study quality. Two studies were quasi-randomised as they used patient identifications numbers for allocation (table 4).34 49 Concealment of allocation was adequate in 33% (21/64) of studies, and generation of allocation was adequate in 53% (34/64). Seven studies used some type of blinding, most commonly of outcome assessors only. Extraction of data by intention to treat was possible in 46% (20/43) of studies for fatality and in 21% (13/63) for failure (table 4).4 All sensitivity comparisons were non-significant. Adequate concealment and generation of allocation were associated with relative risks closer to 1 for fatality. The advantage of monotherapy was more significant in trials that used some type of blinding. Smaller trials showed larger effect estimates regarding failure. Analysis per protocol and by the fixed effect model did not affect results. The funnel plot for treatment failure generated a nearly symmetrical "funnel distribution."
Fig 7 Sensitivity analyses Randomisation methods were classified as A=adequate; B=unknown; C=inadequate.85 Central randomisation, inaccessible computer randomisation, and sealed opaque envelopes were considered adequate for allocation concealment. Table of random numbers, computer generated lists, and consecutive selection were considered adequate for allocation generation. *Fatality comparison includes studies that reported results for all randomised patients (ITT=intention to treat) v studies reporting results for evaluable patients only (PP=per protocol). Studies that did not state method of analysis and did not refer to drop outs are not included. Failure comparison includes studies that reported results or drop outs for all randomised patients (drop outs counted as failures, ITT) v studies performed per protocol that did not state number of drop outs per study arm (PP). Results with all studies combined in this graph differ from those attained in main comparison because drop outs are counted as failures (relative risk 0.92, 0.82 to 1.03). Comparison for studies comparing same lactam was not performed as only one study used blinding
Table 4 Characteristics of included studies: methods
Discussion
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Correspondence to: M Paul mica@zahav.net.il
Abstract
Treatment with a combination of lactam and an aminoglycoside is purported to be superior to lactam monotherapy for sepsis on the basis of potential advantages such as in vitro synergism and prevention of development of resistance.1-7 Textbooks and guidelines advise the combination for specific pathogens, such as Pseudomonas aeruginosa and other Gram negative bacteria, and for infections commonly caused by these pathogens.8 9 In aiming for optimal antibiotic treatment of severe infections, hospital clinicians tend to use combination therapy despite the lack of direct evidence for its effectiveness. Observational studies show that 25-30% of patients with bacteraemia,10 11 surgical infections,12 or pneumonia,13 14 50% of those with klebsiella bacteraemia,15 and 56% of patients with septic shock in the intensive care unit16 are given lactam-aminoglycoside combination therapy.
We performed a systematic review and meta-analysis of randomised trials comparing lactam-aminoglycoside combination therapy with lactam monotherapy for severe infections in patients without neutropenia.
Methods
We evaluated 144 eligible randomised trials and included 64 in the review (fig 1). The trials included 7586 patients, nearly all adults, and were performed between the years 1968-2001. The median number of patients per trial was 87 (range 20-580). Trials differed by the population targeted, type of infection, and antibiotics compared (table 1). The major conditions were severe sepsis, pneumonia, or Gram negative infections (41 trials), abdominal infections (11 trials), urinary tract infections (7 trials), and Gram positive infections (5 trials). Allocation to antibiotics was empirical in 56 trials. The same lactam was compared in 20 trials, while all other trials compared one lactam to a different, narrower spectrum lactam combined with an aminoglycoside.
Fig 1 Detail of trial selection. The list of excluded references (w1-w80) can be found on bmj.com>
Table 1 Characteristics of included studies: patients and intervention
All cause fatality—Forty three trials including 5527 patients reported all cause fatality. There was no significant difference between monotherapy and combination therapy when we combined these studies (relative risk 0.90, 95% confidence interval 0.77 to 1.06, fig 2). There was no difference among the 12 studies with 1381 patients that compared the same lactam (1.02, 0.76 to 1.38) or among studies that compared different lactams (0.85, 0.69 to 1.05). The heterogeneity for this comparison was low (I2 = 7.7%).
Fig 2 All cause fatality in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight
Treatment failure—We compared clinical and bacteriological failures in 63 and 43 trials, respectively (figs 3 and 4). For both comparisons, monotherapy was not significantly different from combination therapy among studies that compared the same lactam. Monotherapy was significantly superior to combination therapy among studies that compared different lactams. The overall comparison favoured monotherapy for clinical failure (0.87, 0.78 to 0.97; 6616 patients; number needed to treat 34, 20 to 147) and for bacteriological failure (0.86, 0.72 to 1.02; 3511 patients).
Fig 3 Clinical failure in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight
Fig 4 Bacteriological failure in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight
Subgroup analysis—Major effectiveness outcomes were compared within the defined patient subgroups expected to benefit most from combination therapy (tables 2 and 3). We did not detect an advantage to combination therapy with any subgroup tested. Mortality was higher among patients with P aeruginosa (21%), Gram negative infections (13%), and bacteraemia (15%), and outcomes were similar with combination versus monotherapy. Patients with infections outside the urinary tract (mainly pneumonia) had significantly fewer failures with monotherapy. Five trials specifically assessed Gram positive infections, endocarditis in four (table 1). 21 32 48 63 69 Combined relative risks for fatality and failure favoured monotherapy, although differences were non-significant.
Table 2 All cause fatality in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis: subgroup analyses
Table 3 Clinical failure in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis: subgroup analyses
Development of resistance—Combination therapy did not lower bacterial superinfection or colonisation rates, which we would have expected if combination therapy prevented the development of resistance (fig 5). Relative risks tended in favour of monotherapy for bacterial superinfections (0.79, 0.59 to 1.06). Rates of fungal superinfection were similar. Six studies performed routine surveillance cultures, and nine assessed the development of resistance among pretreatment isolates. In these also we found no advantage with combination therapy. Twenty six studies reported coverage rates of the allocated treatment, although outcomes were not related to coverage. Among studies with different lactams, the monotherapy lactam provided broader coverage than the combination lactam in 13 studies, the opposite occurring in two studies. Combined coverage of the lactam and the aminoglycoside equalled monotherapy in these studies.
Fig 5 Summary relative risks for outcome relating to resistance development in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight
Drop outs and adverse events—The dropout rate was 12.6% and similar in both study groups (1.01, 0.85 to 1.20, 24 studies, 3631 patients). Few patients (2%) discontinued treatment because of adverse events with no difference between study groups (0.89, 0.52 to 1.52, 15 studies, 3042 patient). Nephrotoxicity was more common with combination therapy in nearly all studies, and the combined relative risk was 0.36 (0.28 to 0.47, fig 6), corresponding to a number needed to harm of 15 (14 to 17) for combination therapy.
Fig 6 Adverse events: nephrotoxicity in comparison of lactam monotherapy v lactam-aminoglycoside combination therapy for treatment of sepsis. Log scale of relative risks (95% confidence intervals), random effect model. Studies ordered by weight
Sensitivity analysis—Figure 7 shows sensitivity analyses for measures of study quality. Two studies were quasi-randomised as they used patient identifications numbers for allocation (table 4).34 49 Concealment of allocation was adequate in 33% (21/64) of studies, and generation of allocation was adequate in 53% (34/64). Seven studies used some type of blinding, most commonly of outcome assessors only. Extraction of data by intention to treat was possible in 46% (20/43) of studies for fatality and in 21% (13/63) for failure (table 4).4 All sensitivity comparisons were non-significant. Adequate concealment and generation of allocation were associated with relative risks closer to 1 for fatality. The advantage of monotherapy was more significant in trials that used some type of blinding. Smaller trials showed larger effect estimates regarding failure. Analysis per protocol and by the fixed effect model did not affect results. The funnel plot for treatment failure generated a nearly symmetrical "funnel distribution."
Fig 7 Sensitivity analyses Randomisation methods were classified as A=adequate; B=unknown; C=inadequate.85 Central randomisation, inaccessible computer randomisation, and sealed opaque envelopes were considered adequate for allocation concealment. Table of random numbers, computer generated lists, and consecutive selection were considered adequate for allocation generation. *Fatality comparison includes studies that reported results for all randomised patients (ITT=intention to treat) v studies reporting results for evaluable patients only (PP=per protocol). Studies that did not state method of analysis and did not refer to drop outs are not included. Failure comparison includes studies that reported results or drop outs for all randomised patients (drop outs counted as failures, ITT) v studies performed per protocol that did not state number of drop outs per study arm (PP). Results with all studies combined in this graph differ from those attained in main comparison because drop outs are counted as failures (relative risk 0.92, 0.82 to 1.03). Comparison for studies comparing same lactam was not performed as only one study used blinding
Table 4 Characteristics of included studies: methods
Discussion
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