Optimal dosing of antibiotics in critically ill patients by using continuous/extended infusions: a systematic review and meta-analysis

Abstract

Introduction: 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.

Methods: We 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.

Results: Of 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).

Conclusions: Pooled 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.

Figure 1

Flow chart of study selection.

Figure 2

Effects of pharmacodynamic-based antibiotic dosing on ICU[15-17,22,29], hospital[30,34,36,37], 14-day[25], 30-day[35], or unspecified (ICU or hospital)[18-21,27,28,31,33]mortality grouped by RCT versus cohort studies. Individual study RRs with 95% CIs are shown as squares with lines, and pooled RRs with 95% CI, calculated by using random-effects models both overall and separately for each subgroup, are shown as diamonds. The interaction P value, calculated by using a Z test, testing for subgroup differences between the RCT and cohort studies, was not significant (P = 0.61). The pooled results for the RCTs were essentially unchanged if ICU mortality was replaced by the more-prolonged hospital mortality for the studies that also provided these data [22,29] (nine RCTs, 620 patients, RR, 0.86; 95% CI, 0.64 to 1.17; P = 0.34; I² = 0%), or if the results of the partial RCT [16] were excluded (eight RCTs, 602 patients; RR, 0.88; 95% CI, 0.64 to 1.21; P = 0.42, I² = 0%). Weight refers to the weighting of each individual study to the overall pooled RR. CI, confidence interval; IV, inverse variance; RCT, randomized controlled trial; RR, relative risk.

Figure 3

Effects of pharmacodynamic-based antibiotic dosing on clinical failure, defined as lack of clinical cure or improvement, grouped by RCT versus cohort studies. Individual study RR with 95% CIs are shown as squares with lines, and pooled RRs with 95% CI, calculated by using random-effects models both overall and separately for each subgroup, are shown as diamonds. Z tests were used to test for subgroup differences. If clinical failure is defined only as lack of clinical cure, results were identical for the non-RCTs and similar for the RCTs (seven RCTs, 525 patients; RR, 0.83; 95% CI, 0.70 to 0.99; P = 0.04; I² = 11%) and overall (14 studies, 1,509 patients; RR, 0.68; 95% CI, 0.52 to 0.88; P = 0.004; I² = 70%). Weight refers to the weighting of each individual study to the overall pooled RR. CI, confidence interval; IV, inverse variance; RCT, randomized controlled trial; RR, relative risk.

Figure 4

Effects of pharmacodynamic-based antibiotic dosing on ICU length of stay, grouped by RCT versus cohort studies. Individual study RRs with 95% CIs are shown as squares with lines, and pooled RRs with 95% CI, calculated by using random-effects models both overall and separately for each subgroup, are shown as diamonds. Z tests were used to test for subgroup differences. IQR [22,29,35,36] converted to standard deviations by dividing by 1.35, as previously described [11], or standard deviations calculated from reported 95% CIs, assuming equal standard deviations between groups [30]. Weight refers to the weighting of each individual study to the overall pooled RR. CI, confidence interval; IV, inverse variance; RCT, randomized controlled trial; SD, standard deviation; IQR, interquartile range.

Figure 5

Effects of pharmacodynamic-based antibiotic dosing on hospital length of stay, grouped by RCT versus cohort studies. Individual study RRs with 95% CIs are shown as squares with lines, and pooled RRs with 95% CI, calculated by using random-effects models both overall and separately for each subgroup, are shown as diamonds. Z tests were used to test for subgroup differences. Ranges [25] or IQR [22,36,37] converted to standard deviations by using the methods of Hozo [10] or by dividing by 1.35, as previously described [11], respectively, or standard deviations calculated from reported 95% confidence intervals assuming equal standard deviations between groups [30]. Weight refers to the weighting of each individual study to the overall pooled RR. CI, confidence interval; IV, inverse variance; RCT, randomized controlled trial; SD, standard deviation; IQR, interquartile range.

Figure 6

Effects of pharmacodynamic-based antibiotic dosing on mortality separated by class of antibiotic. Individual study RRs with 95% CIs are shown as squares with lines, and pooled RRs with 95% CI, calculated by using random-effects models separately for each class of antibiotic, are shown as diamonds. Weight refers to the weighting of each individual study to the overall pooled RR. CI, confidence interval; IV, inverse variance; RR, relative risk.

Figure 7

Effects of pharmacodynamic-based antibiotic dosing on mortality comparing continuous with extended-infusion subgroups. The continuous-infusion studies included nine RCTs [15-22,29] and two cohort studies [31,34], whereas the extended-infusion studies included only cohort studies. Individual-study RRs with 95% CIs are shown as squares with lines, and pooled RRs with 95% CIs, calculated by using random-effects models both overall and separately for each subgroup, are shown as diamonds. The interaction P value, calculated by using a Z test, testing for subgroup differences between continuous and extended infusion studies, did not achieve statistical significance (P = 0.12). Weight refers to the weighting of each individual study to the overall pooled RR. CI, confidence interval; IV, inverse variance; RCT, randomized controlled trial; RR, relative risk.