JAC Advance Access originally published online on June 11, 2007
Journal of Antimicrobial Chemotherapy 2007 60(2):247-257; doi:10.1093/jac/dkm193
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Systematic reviews |
Efficacy and safety of aminoglycoside monotherapy: systematic review and meta-analysis of randomized controlled trials
1 Department of Internal Medicine E, Rabin Medical Center, Beilinson Campus, Petah-Tikva 49100, Israel 2 Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel 3 Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK
* Corresponding author. Tel: +972-3-9376501; Fax: +972-3-9376512; E-mail: vidallit{at}yahoo.com
Received 1 February 2007; returned 17 April 2007; accepted 3 May 2007
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Abstract |
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Objectives: This study sought to compare the efficacy and adverse effects of any aminoglycoside as a single antibiotic with other antibiotics for the treatment of patients with infection.
Methods: Systematic review of the literature and meta-analysis. We searched for randomized controlled trials comparing the efficacy of single aminoglycoside antibiotic treatment with one or more non-aminoglycoside antibiotic for patients with infection in the Cochrane Library, MEDLINE, EMBASE, LILACS, databases of ongoing trials and conference proceedings. Two reviewers assessed trial eligibility, quality and extracted data. Pooled relative risks (RR) with 95% confidence intervals (CI) were calculated for dichotomous data.
Results: The search yielded 37 trials of which 26 included patients with urinary tract infection. Aminoglycosides were equally effective as comparators in the analysis of the primary outcomes, all-cause mortality (RR 1.11, 95% CI 0.68, 1.81, 9 trials, 503 patients) and treatment failure (RR 1.10, 95% CI 0.96, 1.27, 32 trials, 1890 patients). Aminoglycosides were associated with a significantly higher rate of bacteriological failure at end of therapy (RR 1.44, 95% CI 1.21, 1.72, 27 trials, 1668 patients). Subgroup analyses according to quality of trial, type of antibiotics, source of infection and rate of clinical sepsis did not alter the outcomes. Less adverse effects in total but more nephrotoxic effects were observed in patients treated with aminoglycosides.
Conclusions: The present data support the use of aminoglycosides for urinary tract infections. The paucity of trials including patients with sepsis or reporting on mortality precludes firm recommendations for patients with infections other than of the urinary tract.
Keywords: antibiotics , infections , sepsis , meta-analysis
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Introduction |
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The use of aminoglycosides has decreased during the last decade.1 Their major drawback is adverse effects that are more common and severe than those of other antibiotics.2–4 Observational studies have raised doubts as to their efficacy as single drugs for the treatment of severe infections.5–7 Finally, there is evidence that their synergism with ß-lactam drugs is of no clinical importance.8,9 On the other hand, the prevalence of microbial resistance to aminoglycosides has remained low over the years and emergence of bacterial resistance during therapy is rare.10,11
Emergence of resistance is inevitably linked with the use of antibiotics.12 Bacterial resistance increases the chances of administering inappropriate antibiotic treatment, and is therefore associated with increased mortality.13–16 Appropriate use of antibiotics can decelerate this process but cannot prevent it.17 However, the development of new antimicrobial drugs lags behind the rapid development of resistant strains.18 Use of previous generation antibacterial drugs to treat infections caused by new resistant bacteria has been suggested as means to confront this problem.19
With increasing resistance to other antibiotics, we might reach a point where aminoglycosides will be considered as single treatment for sepsis. The aim of the present systematic review is to evaluate the efficacy and adverse effects of aminoglycoside antibiotics as single treatment of patients with infection.
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Materials and methods |
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Inclusion criteria
We included randomized trials, irrespective of language and publication status, comparing systemically administered aminoglycosides as a single drug with a systemically administered single antibiotic or an antibiotic combination without aminoglycosides in patients with a clinically documented infection.
The primary outcomes were (i) all-cause mortality at 30 days and (ii) treatment failure. For the purpose of this review, treatment failure was defined as a composite end-point comprising of one or more of the following: death, non-resolving primary infection, any modification to allocated antibiotics, or any therapeutic invasive intervention not defined by protocol, or as defined by individual trials. Secondary outcomes were: bacteriological failure, defined as persistence of the primary pathogen; bacterial and fungal superinfections: 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 aminoglycoside or comparator antibiotic, during or following antibiotic therapy, with no signs or symptoms of infection; and resistance development: development of resistance to study drugs. We also collected data on adverse events: life threatening or associated with permanent disability; requiring discontinuation of therapy; nephrotoxicity and ototoxicity.
We compared the efficacy of these treatment modalities in the following predefined subgroups: Pseudomonas aeruginosa infections; specific sources of infection (pneumonia, urinary tract, abdominal, soft tissue infection); type of comparator antibiotic; and type of aminoglycoside antibiotic.
Search strategy for identification of studies
Relevant trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library (Issue 2, 2006); MEDLINE (1966 to September 2006); EMBASE (1974 to September 2006); and LILACS (1982 to September 2006) with the terms:
((aminoglycoside* or gentam* or amikacin or netil* or kanam* or tobra* or sisom* or streptom*) and (bacteremia or bacteraemia or sepsis or septic?emia or pneumonia or pyelonephritis or infection)) not (prophylaxis or combi*). For MEDLINE, the highly sensitive search strategy for identifying reports of randomized controlled trials was used.20,21
References of all identified studies as well as major reviews were inspected to track down further studies. We searched conference proceedings and trial databases for ongoing and unpublished trials (http://www.controlled-trials.com/, http://clinicaltrials.gov/, http://www.nci.nih.gov/clinicaltrials).
One reviewer inspected the abstract of each reference identified by the search and applied inclusion criteria. Two reviewers independently assessed the full article of possibly relevant trials and evaluated for the methodological quality and extracted data from included trials. Methodological quality assessment was conducted using the criteria described in the Cochrane handbook, which are based on the evidence of a strong association between poor allocation concealment and overestimation of effect.20,22 In case of disagreement between the two reviewers, a third reviewer extracted the data. All data were collected on an intention-to-treat basis whenever possible.
Pooled relative risks (RR) with 95% confidence intervals (CI) were calculated for dichotomous data. RR below 1 favours aminoglycoside treatment for all comparisons. Heterogeneity (degree of difference between the results of different trials) in the results of the trials was graphically inspected and assessed by calculating tests of heterogeneity (
2 and I2). A fixed effect model (Mantel–Haenszel method) was used unless significant heterogeneity (P < 0.10 or I2 > 50%) was detected, in which case a random effects model (DerSimonian and Laird method) was used. Meta-regression was performed in order to find an association between percentage of septic patients and the RR for treatment failure.
A funnel plot estimating the treatment effect against the precision of trials (plots of the log of the relative risk for efficacy against the standard error) was examined in order to estimate potential asymmetry that may indicate selection bias, e.g. selective publication of trials with positive findings or methodological flaw in the small studies.
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Results |
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The process used to identify eligible trials is described in Figure 1.
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Thirty-seven trials fulfilled inclusion criteria (Table 1).71–107 The studies were performed during the years 1967–2005, and randomized 2495 patients. Most of the trials included adult patients (16–91 years old); three trials included children.86,89,104 Most trials excluded pregnant women, neutropenic patients and patients with renal impairment. Patients in the aminoglycoside group were treated with amikacin,77,84,91,95,106 gentamicin,72,76,79,80,82,83,85–88,90,92,94,99,101,105 netilmicin,73–75,100 or tobramycin.71,78,81,96,102,103 Aminoglycosides were given once daily in three trials.77,95,100 Patients in the comparator groups were treated with penicillins in three trials,82,87,88 monobactams in six,72,85,95,99,101,105 first-generation cephalosporins in one trial,96 third-generation cephalosporins in 19 trials,73,75,76,78,79,81,84,89–93,95,98,100,102,103,106,107 of them ceftazidime in five,78,81,93,95,103 fluoroquinolones in five74,80,83,86,104 and macrolides in one trial.97 All antibiotics were given by injection (intramuscular or intravenous), besides three trials in which pefloxacin, a single dose of amoxicillin and a single dose of fosfomycin were given orally.83,88,104
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Most of the trials included patients with urinary tract infection, two trials included patients with respiratory infections,87,98 two trials included patients with soft tissue infections87,106 and two trials included patients with abdominal infections.77,86 The proportion of patients with clinical sepsis, defined as SIRS plus a proven or clinically suspected infection,17 ranged from 0% to 100% (median 18%).
No significant statistical heterogeneity was shown in all the analyses presented below. Inspection of the funnel plot did not indicate a selection bias.
Mortality data were available in only nine of the included trials (503 patients) and are presented in Figure 2. There was no significant difference in the RR for mortality with aminoglycoside versus other antibiotics (RR 1.11, 95% CI 0.68, 1.81). Six trials assessed urinary tract infections (RR 1.96, 95% CI 0.61, 6.29, unadjusted control event rate 1.5%) and three assessed other types of infections (RR 0.93, 95% CI 0.54, 1.59, unadjusted control event rate 31%).
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Treatment failure
An intention to treat analysis of treatment failure (1890 patients) comparing aminoglycosides with other antibiotics demonstrated no significant difference (RR 1.10, 95% CI 0.96, 1.27) (Figure 3). An efficacy analysis of treatment failure (1926 patients) demonstrated a borderline advantage of other antibiotics over aminoglycosides (RR 1.17, 95% CI 1.01, 1.36).
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Secondary outcomes
Bacteriological failure was assessed at three different time points: at the end of therapy, 5–9 days post-therapy and 30 days post-therapy. The use of aminoglycosides resulted in significantly increased bacteriological failure at the end of therapy (RR 1.44, 95% CI 1.21, 1.72, 1688 patients) (Figure 4) and 5–9 days after end of therapy (RR 1.40, 95% CI 1.16, 1.69, 1244 patients). Aminoglycosides were inferior both to ß-lactams (RR 1.41, 95% CI 1.16, 1.71, 1361 patients) and to quinolones at end of therapy (RR 1.94, 95% 1.15, 3.27, 183 patients). At 30 days post-treatment no difference was shown (RR 0.98, 95% CI 0.83, 1.16, 1042 patients). Accordingly, urinary tract infection persistence rates were higher with aminoglycosides compared with other antibiotics (RR 2.03, 95% CI 1.46, 2.82), but the rates of relapse and reinfection were not significantly different (Table 2). No significant difference was observed with regard to relapse and reinfection rates.
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Sensitivity analysis (treatment failure)
Analysis according to the type of the aminoglycoside did not affect outcomes. Gentamicin was comparable to comparator antibiotics (RR 1.08, 95% CI 0.9, 1.31). The effect estimates for treatment failure were similar for the different types of the comparator antibiotics. The main comparisons were with ß-lactams (RR 1.14, 95% CI 0.98, 1.34, 23 trials, 1400 patients) and quinolones (RR 1.03, 95% 0.68, 1.55, 4 trials, 262 patients). Analysis according to the source of infection did not affect the outcomes (Figure 3). In patients with abdominal infections, aminoglycoside monotherapy was inferior to treatment with other antibiotics. It must be emphasized, however, that outcomes are based on a very small number of patients with infections other than urinary tract infection (i.e. respiratory, skin, abdominal infections).
Since most studies recruited patients with urinary tract infection without sepsis, we conducted post hoc analyses to assess whether effect estimates are affected by the presence of clinical sepsis. A meta-regression did not support an association between the rate of patients with clinical sepsis and the RR for treatment failure.
We examined the effect of aminoglycosides versus comparator antibiotics in patients with documented P. aeruginosa infections, as observational studies demonstrated a disadvantage with aminoglycoside monotherapy in these patients. Aminoglycosides were as efficacious as comparator antibiotics in patients with P. aeruginosa infections (RR 1.00, 95% CI 0.63, 1.60, 183 patients).
Effect of quality of trials (Figure 5)
Adequate allocation concealment was reported in seven trials.72–75,77,83,101 Comparator antibiotics were superior to aminoglycosides with regard to treatment failure in trials with unclear allocation concealment but not in trials with adequate allocation concealment (Table 2). There was no difference in the effect of assigned therapy in clinical failure in trials where randomization was adequate, and in those in which randomization generation was not reported. There was no significant difference in drop outs (lost to follow-up) after randomization (RR 0.83, 95% CI 0.61, 1.12).
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Resistance
Only five trials (286 patients) out of 37 reported data on the susceptibility of isolates post-treatment.80,87,99,102,103 The RR for developing an isolate resistant to aminoglycosides in the aminoglycoside arm compared with the development of an isolate resistant to ß-lactams in the ß-lactam arm was 0.44, 95% CI 0.23, 0.83, in favour of aminoglycosides (I2 = 50%).
Significantly less adverse effects overall were observed in patients treated with aminoglycosides compared with patients treated with ß-lactams (RR 0.46, 95% CI 0.33, 0.63) (Figure 6). Rash, phlebitis, gastrointestinal and hepatic adverse effects were more common with ß-lactam therapy and probably account for the high adverse effect rate observed with ß-lactams. Although nephrotoxicity was significantly more common in patients who received aminoglycoside therapy than with other antibiotics (RR 3.61, 95% CI 1.67, 7.80), discontinuation rates were similar.
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Discussion |
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Aminoglycoside treatment for urinary tract infection
This review demonstrates that aminoglycoside antibiotics are equally effective as comparator antibiotics: ß-lactams or quinolones in achieving a clinical improvement in patients with urinary tract infection (UTI). The rate of bacteriological failure and persistence was higher with aminoglycosides at the end of therapy, but not at 30 days. The rate of patients with sepsis did not affect results.
Adverse effects were more common with ß-lactam antibiotics due to higher rates of skin, gastrointestinal and hepatic adverse events. Despite a higher nephrotoxicity rate with aminoglycoside therapy, the discontinuation rate was similar. Based on a 14% control event rate with ß-lactams, the number of patients needed to treat with aminoglycosides to prevent one adverse event is 12 (95% CI 10–16). Based on a 2% event rate with comparator antibiotics, the number needed to harm with aminoglycosides to cause one event of renal impairment is 18 patients (95% CI 7–71). Most trials did not define the severity of nephrotoxic events and therefore the clinical significance of the renal impairment is unclear. Despite a trend towards higher rate of resistance induction with ß-lactams compared with aminoglycosides, the data from our analysis of post-treatment development of resistant organisms are too scarce to allow definitive conclusions.
Although aminoglycosides are an acceptable option for the treatment of pyelonephritis, they are less often prescribed than other available antibiotics. The concern regarding the reduced efficacy of aminoglycosides in documented P. aeruginosa infections is not supported by the results of the current analysis. The present data support the use of aminoglycosides in patients with urinary tract infection who are not immunosuppressed, without renal dysfunction and who are not pregnant.
Aminoglycosides for infections other than UTI
Despite no effect of infection site on outcomes, the small number of patients with respiratory, skin or abdominal infection precludes firm conclusions on aminoglycoside monotherapy for these patients. Comparative non-randomized studies show inferiority of single aminoglycoside treatment compared with ß-lactams for infections other than UTI. Bacteraemic patients treated with an appropriate aminoglycoside had a significantly higher mortality rate than those given an appropriate ß-lactam.6,8,108–110 The higher rate of microbiological failure with aminoglycosides observed in our study might indicate their lower efficacy. However, in the few randomized trials that reported on mortality there was no significant difference between aminoglycosides and comparators.
Given the paucity of evidence from randomized controlled trials and the data available from non-randomized studies, aminoglycosides should not be administered as single treatment to patients with infections other than of the urinary tract, when established alternatives are possible. However, when antibiotic resistance precludes the use of ß-lactams and quinolones, single aminoglycoside treatment should be offered to patients.
Since the conduct of the trials included in our review resistance patterns have changed, and results should be judged in the perspective of local, present susceptibility patterns. The efficacy of aminoglycosides as compared with last resort antibiotics available for the treatment of multidrug-resistant Gram-negative bacteria, such as colistin, tetracyclines and tigecycline is unknown. Future trials are needed to address this issue.
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None to declare.
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Acknowledgements |
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We would like to thank Drs Bonadio, Chen, Frimodt-Moller, Hoepelman and Lynn for their cooperation and for additional information. We would also like to thank The Cochrane Anaesthesia Review Group for their advice and help. This study was presented at the Seventeenth European Congress of Clinical Microbiology and Infectious Diseases, Munich, Germany, 2007. The protocol of this systematic review is published in The Cochrane Library.
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References |
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