The present meta-analysis focused on the use of 2 antibiotic administration types for treating infected patients. It included 3 studies related to pulmonary infection only and 10 studies that recruited patients with nonpulmonary infection only. Compared with the intermittent group, infected patients in the continuous group had a higher clinical success and a shorter ICU stay, but the results were not significant because of the limited number of enrolled trials. Similarly, a lower incidence of mortality, a shorter total duration of antibiotic prescription, and more efficacy in pulmonary infection population were found in the continuous group, but the results were not significant due to the small sample sizes.
In the current study, the overall OR of clinical success comparing the continuous and intermittent groups was 0.675 (95% CI: 0.523–0.870). No significant differences were found in the primary clinical outcomes (cure rates) between the 2 groups. With regard to clinical success, the continuous group tended to show more favorable results. Zhao et al's results are most comparable to those of Chytra et al who found a nonsignificant difference in cure rates in a trial of 240 critically ill patients randomized to receive meropenem by continuous infusion versus intermittent administration (83% vs. 75%, respectively). Recently, Dulhunty et al conducted an RCT in 25 ICUs to evaluate the efficacy of continuous versus intermittent infusion of β-lactam antibiotics in patients with severe sepsis and found no difference between the treatment groups in clinical cure rates (52.4% vs. 49.5%). By contrast, a retrospective study of meropenem and that of other β-lactam agents found that continuous administration has better results than intermittent administration.[21,20,17]
The overall OR of mortality rate comparing continuous and intermittent groups was 0.834 (95% CI: 0.542–1.282). No significant difference was found in the mortality rate between participants in the continuous and intermittent groups. With regard to mortality rate, the continuous group tended to show more favorable results and more efficacy in pulmonary infection population. A possible explanation for the better effectiveness in the continuous group is the higher tissue concentrations of β-lactam in this patient group than in the intermittent group[8,9]; patients with pneumonia in particular experience persistent maintenance and low penetration of most β-lactams into lung tissue. Other studies had similar outcomes that showed an improved bacteriological efficacy associated with the continuous application of meropenem and β-lactams. In the current study, the overall OR of pulmonary infection comparing continuous group and intermittent group was 0.834 (95% CI: 0.542–1.282), and no significant difference was found in the pulmonary infection between participants in the continuous and intermittent groups. The continuous group tended to show more favorable results in pulmonary infection. We want to focus on continuous application of effective antibiotics for patients with ventilator-associated pneumonia. In addition, our subgroup analysis showed that different study designs or disease types or antibiotic types showed no discrepancies of treatment effectiveness in the continuous group (Table 3). Since only few studies were enrolled in the subgroup, the sample size was too small to assess that heterogeneity of effectiveness.
The overall OR of antibiotic duration comparing continuous and intermittent groups was 1.055 (95% CI: 0.659–1.689). No significant difference was found in the antibiotic duration between participants in the continuous and intermittent groups. The continuous group tended to show more favorable results in antibiotic duration. Our result showed a significantly shorter duration of antibiotic treatment in the continuous group, and this result is the same as that obtained by Zhao et al.
The overall OR of ICU stay comparing continuous and intermittent groups was 0.834 (95% CI: 0.542–1.282). No significant difference was found in the ICU stay between participants in the continuous and intermittent groups. The continuous group tended to show more favorable results in ICU stay. Our result showed a significantly shorter duration of ICU stay in the continuous group, and similar results were observed in the study by Chytra et al. However, Zhao et al reported no differences in ICU mortality rate, length of stay, and values of white blood cell count and procalcitonin. Zhao et al's results are concurrent with those of Dulhunty et al, although previous studies had conflicting results. Meta-analyses by Roberts et al and Shiu et al found no significant differences in cumulative mortality between the 2 groups. By contrast, Falagas et al found a significant mortality difference between continuous and intermittent infusion in their meta-analysis of observational studies and RCTs comparing infusion methods of carbapenems and piperacillin-tazobactam. Such studies have not been conducted in patients with severe sepsis and pneumonia; their mortality rates were much lower than that in our patients.
Majorly, the results of present meta-analysis were not significant due to the limited number of enrolled trials. The present meta-analysis has other limitations. First, the primary outcome was clinical results and microbiological results. The principal reason for this was that only a minority of included trials recorded clinical and microbiological results. Second, we did not serially investigate the detailed confounders of mortality rate, length of stay, and antibiotic duration due to lack of the most commonly documented in the results of the retrieved studies. Third, the outcome of the 2 antibiotic administration types can be modified. Therefore, we also analyzed the OR of the most prevalent clinical major events to examine whether inconsistency exists between all outcomes. Fourth, because ORs are derived from the between-group difference divided by the number, the value of OR may be overestimated. Hence, researchers should consider the influence of measurement precision when reporting treatment effectiveness by using ORs. Finally, due to the above-mentioned limitations, we suggest that future similar studies should record serial changes in continuous infusions of intravenous antibiotics and infection status to warrant clinical effectiveness.
The results of present meta-analysis were insufficient to recommend continuous infusion of intravenous antibiotics better than traditional intermittent infusions of antibiotics at routine clinical care. Hope large-scale RCT to provide more rebuts evidence for making recommendations to warrant continuous infusions of intravenous antibiotics at clinical practice.
The authors thank the staff at the Epidemiology and Biostatistics Center, the Department of Pharmacology, and the Department of Computer at Changhua Christian Hospital for the case findings. This research project would not have been possible without the support of many people. The authors wish to express their gratitude to the staffs of the Department of Neurosurgery, the Department of Critical Care, Epidemiology and Biostatistics Center, the Division of Infectious Diseases, the Department of Pharmacology, the Department of Nursing, and the Department of Healthcare Quality at Changhua Christian Hospital who were extremely helpful and provided invaluable assistance and support.
Conceptualization: Yu-Min Chen, Shu-Hui Wang, Chih-Yen Chang, Hua-Cheng Yen, Chang-Hua Chen.
Data curation: Yu-Min Chen, Chih-Yen Chang, Hua-Cheng Yen, Chang-Hua Chen.
Formal analysis: Changhua Chen, Chih-Yen Chang, Hua-Cheng Yen.
Funding acquisition: Chang-Hua Chen, Hua-Cheng Yen.
Investigation: Hua-Cheng Yen, Chang-Hua Chen.
Methodology: Yu-Jun Chang, Hua-Cheng Yen, Chang-Hua Chen.
Project administration: Hua-Cheng Yen.
Resources: Hua-Cheng Yen.
Software: Yu-Jun Chang, Hua-Cheng Yen.
Supervision: Hua-Cheng Yen.
Validation: Shu-Hui Wang, Hua-Cheng Yen, Chang-Hua Chen.
Visualization: Changhua Chen.
Writing – original draft: Hua-Cheng Yen, Chang-Hua Chen.
Writing – review & editing: Hua-Cheng Yen, Chang-Hua Chen.
Chang-Hua Chen orcid: 0000-0003-4564-8727.
changhua Chen orcid: 0000-0003-4564-8727.
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Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
continuous infusions; intermittent infusions; intravenous antibiotics; meta-analysis