Abstract
IntroductionThe aim of this study was to determine whether using pharmacodynamic-based dosing of antimicrobials, such as extended/continuous infusions, in critically ill patients is associated with improved outcomes as compared with traditional dosing methods.MethodsWe searched Medline, HealthStar, EMBASE, Cochrane Clinical Trial Registry, and CINAHL from inception to September 2013 without language restrictions for studies comparing the use of extended/continuous infusions with traditional dosing. Two authors independently selected studies, extracted data on methodology and outcomes, and performed quality assessment. Meta-analyses were performed by using random-effects models.ResultsOf 1,319 citations, 13 randomized controlled trials (RCTs) (n = 782 patients) and 13 cohort studies (n = 2,117 patients) met the inclusion criteria. Compared with traditional non-pharmacodynamic-based dosing, RCTs of continuous/extended infusions significantly reduced clinical failure rates (relative risk (RR) 0.68; 95% confidence interval (CI) 0.49 to 0.94, P = 0.02) and intensive care unit length of stay (mean difference, −1.5; 95% CI, −2.8 to −0.2 days, P = 0.02), but not mortality (RR, 0.87; 95% CI, 0.64 to 1.19; P = 0.38). No significant between-trial heterogeneity was found for these analyses (I2 = 0). Reduced mortality rates almost achieved statistical significance when the results of all included studies (RCTs and cohort studies) were pooled (RR, 0.83; 95% CI, 0.69 to 1.00; P = 0.054).ConclusionsPooled results from small RCTs suggest reduced clinical failure rates and intensive care unit length-of-stay when using continuous/extended infusions of antibiotics in critically ill patients. Reduced mortality rates almost achieved statistical significance when the results of RCTs were combined with cohort studies. These results support the conduct of adequately powered RCTs to define better the utility of continuous/extended infusions in the era of antibiotic resistance.
Highlights
The aim of this study was to determine whether using pharmacodynamic-based dosing of antimicrobials, such as extended/continuous infusions, in critically ill patients is associated with improved outcomes as compared with traditional dosing methods
Study selection Inclusion criteria for this meta-analysis were as follows: (a) adult critically ill patients, (b) intervention that compared pharmacodynamics-based dosing (PDD) to aid in the determination of antibiotic dosage with a control group that did not use such dosing strategies by using either a randomized or nonrandomized study design; (c) reporting of any patient outcomes; and (d) any antibacterial whose PD associated with optimal killing is the proportion of time during dosing interval that is above the minimum inhibitory concentration (MIC) of the pathogenic organism
Reduced mortality rates almost achieved statistical significance when the results of Randomized controlled trial (RCT) were combined with cohort studies
Summary
The aim of this study was to determine whether using pharmacodynamic-based dosing of antimicrobials, such as extended/continuous infusions, in critically ill patients is associated with improved outcomes as compared with traditional dosing methods. Unless clinical benefits are compelling, widespread clinical application of pharmacodynamics-based dosing (PDD) is unlikely, given the multitude of barriers to their implementation These barriers include (a) identification of the types of patients that would benefit the most, with the critically ill patient population being the most obvious choice, given their heightened risk of infectiousrelated morbidity and mortality and increasing resistance; (b) requirement of significant practice changes in microbiology, such as routine MIC determination by using more accurate nonautomated techniques; (c) better-defined pharmacokinetics of antimicrobials in patients in the intensive care unit (ICU) with varying degrees of renal and hepatic dysfunction, as well as the extent of medication removal by a variety of renalreplacement therapies; and (d) methods to manage the need of a dedicated intravenous line for administration via continuous/extended infusions. Previous systematic reviews that included both critically ill and non-critically ill patient populations have provided inconsistent results [5,6,7]
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