JAC Advance Access originally published online on February 24, 2006
Journal of Antimicrobial Chemotherapy 2006 57(4):639-647; doi:10.1093/jac/dkl044
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Systematic review |
The role of aminoglycosides in combination with a ß-lactam for the treatment of bacterial endocarditis: a meta-analysis of comparative trials
1 Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece; 2 Department of Medicine, Tufts University School of Medicine, Boston, MA, USA
* Correspondence author. Tel: +30-694-611-0000; Fax: +30-210-683-9605; E-mail: m.falagas{at}aibs.gr
Received 2 November 2005; returned 15 December 2005; revised 27 January 2006; accepted 30 January 2006
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Abstract |
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Background: The addition of an aminoglycoside to a ß-lactam for the treatment of patients with infective endocarditis has been supported by data from laboratory and animal studies.
Purpose: We sought to review the evidence from the available comparative clinical trials regarding the role of aminoglycosides in combination with a ß-lactam for the treatment of bacterial endocarditis caused by Gram-positive cocci.
Data sources: The studies for our meta-analysis were retrieved from searches of the PubMed and Cochrane Central Register of Controlled Trials databases, as well as from the references cited in relevant articles. No limits were set regarding the language and date of publication of the studies.
Study selection: Included studies were prospective studies that provided comparative data regarding the effectiveness of the treatment and/or mortality in patients receiving monotherapy with a ß-lactam or ß-lactam/aminoglycoside combination therapy.
Data extraction: Two independent reviewers performed the literature search, study selection and extraction of data from relevant studies.
Data synthesis: No clinical trial comparing ß-lactam monotherapy with ß-lactam/aminoglycoside combination therapy for the treatment of enterococcal endocarditis was found. We performed a meta-analysis of five available comparative trials [four randomized controlled trials (RCTs) and one comparative prospective trial], which included 261 patients with bacterial endocarditis in native valves due to Staphylococcus aureus (four studies) or streptococci of the viridans group (one study). There was no statistically significant difference between ß-lactam monotherapy and ß-lactam/aminoglycoside combination therapy regarding mortality [odds ratio (OR) = 0.59, 95% confidence interval (95% CI) = 0.21–1.66], treatment success (OR = 1.25, 95% CI = 0.49–3.05), treatment success without surgery (OR = 1.66, 95% CI = 0.64–4.30) or relapse of endocarditis (OR = 0.79, 95% CI = 0.15–4.29). Nephrotoxicity was less common in the ß-lactam monotherapy arm than in the ß-lactam/aminoglycoside combination therapy arm (OR = 0.38, 95% CI = 0.16–0.88, P = 0.024). No difference between the two treatment arms was found in subanalyses of the four studies that included only patients with staphylococcal infections in terms of mortality (OR = 0.69, 95% CI = 0.26–1.86, fixed effects model), treatment success (OR = 1.27, 95% CI = 0.47–3.43, fixed effects model) or relapse (OR = 0.76, 95% CI = 0.12–4.92, fixed effects model).
Limitations: The relatively small number of available comparative trials was the major limitation of this meta-analysis.
Conclusions: The limited evidence from the available prospective comparative studies does not offer support for the addition of an aminoglycoside to ß-lactam treatment of patients with endocarditis caused by Gram-positive cocci. A large multicentre RCT is necessary to reach a definitive conclusion on this issue.
Keywords: gentamicin , oxacillin , nafcillin , Staphylococcus , Streptococcus
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Introduction |
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ß-Lactams are considered an important part of the medical treatment of patients with bacterial endocarditis since Gram-positive cocci are the aetiological agents in the vast majority of cases with this infection. Combination therapy of ß-lactam with an aminoglycoside has been tested both in vitro and in clinical studies, but results, especially from clinical studies, are often contradictory. The combination of an aminoglycoside with a ß-lactam has been shown to exhibit partial or full synergy against a variety of isolates in some laboratory studies.1–4 However, the potential increase in the effectiveness of an antimicrobial regimen after the addition of an aminoglycoside should be weighed against the increased toxicity that may be conferred by the aminoglycoside. Consequently, the need for the addition of an aminoglycoside in the treatment of patients with certain types of bacterial endocarditis has been questioned.5,6 In addition, the continuous changes of the susceptibilities of pathogens to antibiotics make the decision regarding the appropriate medical therapy for bacterial endocarditis more complex.7–9
We sought to further examine the role of aminoglycosides as combination therapy with a ß-lactam in the treatment of patients with bacterial endocarditis. Although there have been few reviews in the literature about this issue, they are mostly narrative.10–12 Thus, we systematically reviewed the available clinical data from studies that compared ß-lactam monotherapy with the ß-lactam/aminoglycoside combination therapy in terms of effectiveness and toxicity.
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Methods |
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Data sources
Two independent reviewers performed the literature search, study selection and extraction of data (D. K. M. and I. A. B.). Any disagreement between the two reviewers was resolved by consensus in meetings that involved all authors. The studies for our meta-analysis were retrieved from searches of the PubMed and Cochrane Central Register of Controlled Trials databases and from references cited in relevant articles. Search terms included ‘endocarditis’, ‘randomized control trial’, ‘clinical trial’, ‘lactam’, ‘aminoglycoside’, ‘monotherapy’ and ‘combination therapy’.
Study selection
The relevant studies identified were further evaluated. A study was considered eligible if (i) it was a randomized controlled trial (RCT) or a prospective comparative trial; (ii) it compared ß-lactam monotherapy with the ß-lactam/aminoglycoside combination therapy for the treatment of bacterial endocarditis caused by Gram-positive cocci; and (iii) it examined the effectiveness of the treatment and/or mortality. Studies examining different ß-lactams in each treatment arm were not excluded from the analysis. No limits were set regarding the language and date of publication of the studies. Endocarditis was defined by at least two positive blood cultures not attributable to other sources of infection, together with other clinical, imaging or laboratory findings considered by the authors of the trials as being consistent with endocarditis. In addition, Duke criteria were considered sufficient to define endocarditis.13,14
Data extraction
Various characteristics and outcomes of interest were extracted from each of the studies included. A quality review of each RCT included in our analysis was performed using the Jadad score, which examines whether there is randomization, blinding and information on withdrawals in the study and evaluates the appropriateness of randomization and blinding, if present.15,16 One point was awarded for the presence of each of the first three criteria, whereas the last two criteria could take the values of –1 (inappropriate), 0 (no data) and +1 (appropriate). Thus, the maximum score for a study was 5, and a score of more than 2 points denoted a good quality RCT. The scoring system was the same for both independent reviewers and it was calculated independently by each of them.
Outcomes
The primary outcome of the analysis was the effectiveness of each administered regimen. Treatment was considered successful when the clinical findings of endocarditis had resolved and there was no further evidence (any laboratory or imaging finding) of active endocarditis after the completion of therapy and during the follow-up of the patients. Secondary outcomes were treatment success without the need for surgical repair of the affected valve(s), mortality, nephrotoxicity (defined as a twofold rise in the serum creatinine level compared with the baseline value of creatinine during the start of treatment) and occurrence of relapse (defined as the isolation of the same pathogen from blood specimens during the follow-up).
Statistical analyses
Statistical analyses were performed using the Meta-analyst software (Joseph Lau, Tufts University School of Medicine, Boston, MA). We presented results from the fixed effects models when there was no heterogeneity between the studies analysed (P value > 0.1). Otherwise, we presented results from the random effects models. Pooled odds ratios (OR) and confidence intervals (CI) for all the outcomes were calculated using the Mantel–Haenszel fixed effects and the DerSimonian–Laird random effects models. A finding was considered statistically significant if there was a P value < 0.05 in the analysis of the outcomes. Secondary analyses were performed for different subsets of studies based on the study design, the patient population and the isolated pathogen.
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Results |
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Selected studies
In Figure 1 we present a flow diagram showing the consecutive steps that were followed in order to identify the appropriate studies. A total of 29 studies were identified as most relevant,17–50 19 of which were excluded because, although they were prospective, they were non-comparative studies, and 10 were excluded because, although they were comparative prospective studies, they compared other treatment regimens (e.g. ß-lactam monotherapy against glycopeptide monotherapy or short against long duration ß-lactam/aminoglycoside combination therapy). Thus, we included in our meta-analysis four evaluable RCTs and one prospective comparative clinical study that were performed in patients with bacterial endocarditis comparing ß-lactam monotherapy with ß-lactam/aminoglycoside combination therapy.46–50
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The main characteristics of these studies are presented in Table 1. In four studies (three RCTs and the one prospective study), the pathogen causing endocarditis was Staphylococcus aureus,46–49 and the pathogens were streptococci of the viridans group in the remaining RCT (2 of the 51 patients of this study had endocarditis due to Streptococcus bovis).50 As shown in Table 1, the studies included patients with both left-sided and right-sided native valve infective endocarditis. Quality analysis of the four RCTs showed that the mean Jadad score of the studies was 2.5, but two of them scored only 2 points. The prospective comparative study was not assessed in terms of quality, since this specific score system is not appropriate for non-RCT studies.
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Administration of drugs
A variety of ß-lactam agents was used in the monotherapy and consequently in the comparator combination therapy arm of the studies included in our analysis (Table 1). In each of the studies included, the same ß-lactam was administered in both treatment arms, although this was not mandated by our inclusion criteria. Owing to the fact that four of five studies presented data for S. aureus infections, oxacillin, cloxacillin and nafcillin were the ß-lactams tested in three of these studies, whereas various penicillinase-resistant ß-lactams were used in the fourth study. Ceftriaxone was the ß-lactam used for the treatment of patients in the RCT that examined streptococcal infections. The aminoglycoside used in all studies was gentamicin, mainly at a daily dosage of 3 mg/kg body weight. Other aminoglycosides (although not specifically reported) were also used in some patients in the comparative study by Rajashekaraiah et al.48 Both the intramuscular and the intravenous route of administration of aminoglycosides were used in the selected trials. In one study the aminoglycoside was administered once daily,50 and in three studies multiple times daily,46,47,49 whereas in one study the dosage scheme was not clearly stated.48
Treatment success
Data regarding treatment success are summarized in Table 2. Overall treatment success was reported in each treatment arm in all RCTs included in our paper, whereas no clear definition for treatment success was provided in the prospective comparative study; thus, this study was excluded from the analysis of treatment success. There was no statistically significant difference between the two arms (OR = 1.25, 95% CI = 0.49–3.05, fixed effects model) (Figure 2). Also, no difference regarding this outcome was found between the monotherapy and combination therapy in a sensitivity analysis of three RCTs that examined staphylococcal infections (OR = 1.27, 95% CI = 0.47–3.43, fixed effects model) or in a subset of patients who were intravenous drug addicts (OR = 1.07, 95% CI = 0.29–3.94, fixed effects model).
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Treatment success without surgery
Treatment success without the need for surgical repair of the affected valves was reported in three RCTs (Table 2). No statistically significant difference was found between the two treatment arms (OR = 1.66, 95% CI = 0.64–4.30, fixed effects model).
Mortality
Mortality was reported in all studies included in our meta-analysis. The data regarding mortality are also summarized in Table 2. There was no statistically significant difference regarding mortality between the monotherapy and combination therapy groups (OR = 0.59, 95% CI = 0.21–1.66, fixed effects model) (Figure 3). Also, no difference in mortality between the treatment arms compared was found in sensitivity analyses of mortality of patients in the four RCTs, excluding the prospective comparative study (OR = 0.40, 95% CI = 0.10–1.59, fixed effects model), and in intravenous drug addicts (OR = 0.45, 95% CI = 0.12–1.64, fixed effects model). Finally, no statistically significant difference was found in mortality between the compared treatment arms when the four studies that examined patients with S. aureus infections were analysed separately (OR = 0.69, 95% CI = 0.26–1.86, fixed effects model).
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Nephrotoxicity
Nephrotoxicity was reported for each treatment arm in three RCTs (Table 2). Nephrotoxicity occurred less often in the ß-lactam monotherapy arm, compared with the ß-lactam/aminoglycoside combination therapy, a result with statistical significance (OR = 0.38, 95% CI = 0.16–0.88, P = 0.024, fixed effects model).
Relapse
Four RCTs reported data regarding relapse of bacterial endocarditis after therapy (Table 2). Most of the episodes of relapse reported in the included studies occurred a few days after the completion of therapy. There was no statistically significant difference regarding relapse between the ß-lactam monotherapy and the ß-lactam/aminoglycoside combination therapy arms (OR = 0.79, 95% CI = 0.15–4.29, fixed effects model). No difference in relapse was found in two sensitivity analyses, in the subset of patients with staphylococcal infections (OR = 0.76, 95% CI = 0.12–4.92, fixed effects model) and in the subset of addicts (OR = 0.43, 95% CI = 0.06–3.11, fixed effects model).
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Discussion |
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The purpose of our study was to compare the effectiveness and several secondary outcomes between ß-lactam monotherapy and ß-lactam/aminoglycoside combination therapy of patients with bacterial endocarditis. The main finding of our study is that the evidence available from the trials analysed does not show any special benefit for the addition of an aminoglycoside to a ß-lactam treatment of patients with bacterial endocarditis. On the contrary, such an addition can lead to increased nephrotoxicity.
It is interesting that our literature search retrieved only five published comparative trials examining this clinically important question in patients with staphylococcal or streptococcal endocarditis. In addition, we could not find any trial that compared the effectiveness and toxicity of the ß-lactam monotherapy and the ß-lactam/aminoglycoside combination therapy for enterococcal endocarditis. It should be noted that the addition of an aminoglycoside to a ß-lactam for the treatment of bacterial endocarditis was originally supported by in vitro, animal and some non-comparative clinical studies.5,18,51–53 However, this practice does not seem to be supported by the available prospective comparative studies and RCTs, which represent the definitive way to answer questions regarding the effectiveness and toxicity of various therapeutic regimens.
The latest recommendations for the treatment of patients with bacterial endocarditis, published by the American Heart Association (AHA) in 2005, suggest that in the case of S. aureus infections of native valves an optional addition of gentamicin to oxacillin or nafcillin could be made for the first 3–5 days and comment that benefits from such an addition have not been established.54 On the other hand, in the case of S. bovis or streptococcal infections of the viridans group, the addition of gentamicin to penicillin G or ceftriaxone is highly recommended by the AHA for the first 2 weeks of treatment. Our findings are in accordance with the suggestions of the AHA regarding S. aureus bacterial endocarditis, but they cannot provide support for the recommendations regarding the streptococcal infections because of the lack of available evidence from clinical trials. The only RCT reporting on streptococcal endocarditis included in our analysis does not show any important benefit from the addition of gentamicin. However, it should be noted that combination therapy was found to be as effective as ß-lactam monotherapy, despite the fact that the drugs in the combination arm were administered for a significantly shorter period.
There are several limitations of our study that should be taken into consideration. First of all, one can claim that the number of the studies and the number of patients that we included in our analysis is relatively small to allow a safe conclusion to be drawn regarding the effect of the therapies compared on the examined outcomes. Second, the definitions for bacterial endocarditis used in each study varied to some degree. This fact, in combination with the overall scarcity of comparative prospective studies examining the available treatment options for bacterial endocarditis, made us adopt an inclusive definition for bacterial endocarditis. Third, it should be mentioned that aminoglycoside serum concentrations were measured systematically in only two of the five studies included,47,50 a fact that may have influenced both the recorded effectiveness and nephrotoxicity in the combination therapy treatment arm. Fourth, we did not examine other secondary outcomes such as time to defervescence and overall toxicity of the compared regimen because not all studies reported sufficient data to perform meaningful analyses.
Also, we included in our meta-analysis comparative trials that were performed in different time periods and examined different populations and ß-lactams. However, we performed several sensitivity analyses focusing on more homogeneous subsets of patients, such as intravenous drug addicts and patients with bacterial endocarditis caused by S. aureus, in order to further evaluate our main research question. In addition, it should be noted that the inclusion of comparative trials with some differences in various characteristics such as study design, patient population and setting is considered to be one of the strengths of systematic reviews and meta-analyses, because it examines the generalizability of a main clinical question.
Bacterial endocarditis is an infection that still causes considerable morbidity and mortality worldwide. The choice of medical treatment of patients with bacterial endocarditis, both regarding the type of antibiotic used and its duration, is a difficult task because several factors should be taken into account.54 These include the heart valve affected, whether the valve is prosthetic or native and the type of infecting organism, as well as the immune status and the general health condition of the patient. We believe that despite the limitations of the study, our meta-analysis offers potentially useful information regarding the management of bacterial endocarditis.
In conclusion, the meta-analysis of the available clinical trials that compared ß-lactam monotherapy with ß-lactam/aminoglycoside combination therapy for the treatment of bacterial endocarditis caused by Gram-positive cocci suggested that there was no benefit in the effectiveness for the combination therapy. On the contrary, there was a statistically significant increase in renal toxicity when the ß-lactam/aminoglycoside combination therapy is used. It should be emphasized that the findings of our study should be interpreted with caution owing to the relatively small number of available prospective comparative studies examining this issue. We believe that the results of our meta-analysis underline the great need for a large, well-designed RCT examining various aspects in the treatment of patients with bacterial endocarditis.
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None to declare.
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Acknowledgements |
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We thank George J. Sermaides, MSc, for his help in the statistical analysis of the data. Funding: none. Authors' contributions: M. E. F. had the idea for the study and designed it. I. A. B. and D. K. M. performed the literature search, study selection, extraction of data from relevant studies and statistical analysis. M. E. F. wrote the first draft. I. A. B. and D. K. M. made substantial revisions of the manuscript. All authors approved the final version of the manuscript.
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References |
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D. Yung, D. Kottachchi, B. Neupane, S. Haider, and M. Loeb Antimicrobials for right-sided endocarditis in intravenous drug users: a systematic review J. Antimicrob. Chemother., November 1, 2007; 60(5): 921 - 928. [Abstract] [Full Text] [PDF]
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P. Baudoux, N. Bles, S. Lemaire, M.-P. Mingeot-Leclercq, P. M. Tulkens, and F. Van Bambeke Combined effect of pH and concentration on the activities of gentamicin and oxacillin against Staphylococcus aureus in pharmacodynamic models of extracellular and intracellular infections J. Antimicrob. Chemother., February 1, 2007; 59(2): 246 - 253. [Abstract] [Full Text] [PDF]
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L. M. Baddour, J. M. Steckelberg, and W. R. Wilson Comment on: The role of aminoglycosides in combination with a {beta}-lactam for the treatment of bacterial endocarditis: a meta-analysis of comparative trials J. Antimicrob. Chemother., June 1, 2006; 57(6): 1255 - 1255. [Full Text] [PDF]
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M. E. Falagas, D. K. Matthaiou, and I. A. Bliziotis Aminoglycosides in combination with a {beta}-lactam for the treatment of bacterial endocarditis: authors' response J. Antimicrob. Chemother., June 1, 2006; 57(6): 1255 - 1256. [Full Text] [PDF]
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