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Factors associated with the decision to administer β-lactams via prolonged infusion in patients with sepsis: a prospective observational cohort study

Open AccessPublished:September 21, 2022DOI:https://doi.org/10.1016/j.ijid.2022.09.027

      Highlights

      • Prolonged infusion (PI) of β-lactam was associated with a lower mortality in sepsis.
      • PI was not commonly applied and was more often used in severely ill patients.
      • PI had a survival benefit independent of disease severity.

      Abstract

      Objective

      β-lactams are the most widely used antibiotics in sepsis. We aimed to explore the factors that drive physicians to choose prolonged infusion (PI) of β-lactams in septic patients.

      Methods

      This prospective observational national cohort study was conducted in 40 ICUs at the teaching hospitals of 31 provinces in China between August 20, 2021 and September 20, 2021.

      Results

      Of the 441 enrolled patients, 265 (60.09%) received PI therapy. Multivariate analysis showed that multidrug-resistant bacterial infection and septic shock were independent factors associated with PI. However, our data showed that the survival benefit of PI use was evident in subgroups with less severe sepsis, including those with lower Charlson comorbidity index values (<2), those without septic shock, and those with lower acute physiology and chronic health evaluation II scores (<15). Univariate and multivariate Cox regression indicated that PI was an independent protective factor of 28d mortality, even after adjusting the variables associated with disease severity.

      Conclusions

      PI for administering β-lactams was not a commonly applied strategy in sepsis and was more likely to be used in severely ill patients. However, PI had a survival benefit independent of disease severity.

      Keywords

      Introduction

      Sepsis and septic shock are life-threatening organ dysfunctions caused by a dysregulated host response to severe infection, and β-lactams are the most widely used antibiotics in intensive care units (ICU) (
      • Kadri S.S.
      • Rhee C.
      • Strich J.R.
      • et al.
      Estimating Ten-Year Trends in Septic Shock Incidence and Mortality in United States Academic Medical Centers Using Clinical Data.
      ;
      • Drusano G.L.
      Antimicrobial pharmacodynamics: critical interactions of “bug and drug.
      ;
      • Perner A.
      • Rhodes A.
      • Venkatesh B.
      • Angus D.C.
      • et al.
      Sepsis: frontiers in supportive care, organisation and research.
      ;
      • Moriyama B.
      • Henning S.A.
      • Neuhauser M.M.
      • Danner R.L.
      • Walsh T.J.
      Continuous-infusion beta-lactam antibiotics during continuous venovenous hemofiltration for the treatment of resistant gram-negative bacteria.
      ). As a time-dependent antibiotic, the bacterial killing by β-lactams depends on the duration of time that bacteria are exposed to a concentration exceeding the minimum inhibitory concentration (MIC). Additionally, effectiveness increases when the β-lactams plasma concentration at a steady state is more than four times of the pathogen's MIC. To ensure sustained concentrations and effective pharmacodynamics of β-lactams (
      • Craig W.A.
      Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men.
      ), the international guidelines for the management of sepsis and septic shock recommend prolonged infusion (PI) of β-lactams over conventional bolus infusion (CBI), based on a considerable amount of evidence (
      • Abdul-Aziz M.H.
      • Sulaiman H.
      • et al.
      Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis.
      ;
      • Dulhunty J.M.
      • Roberts J.A.
      • Davis J.S.
      • et al.
      Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial.
      ;
      • Evans L.
      • Rhodes A.
      • Alhazzani W.
      • Antonelli M.
      • et al.
      Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.
      ;
      • Kondo Y.
      • Ota K.
      • Imura H.
      • Hara N.
      • Shime N.
      Prolonged versus intermittent beta-lactam antibiotics intravenous infusion strategy in sepsis or septic shock patients: a systematic review with meta-analysis and trial sequential analysis of randomized trials.
      ;
      • Vardakas K.Z.
      • Voulgaris G.L.
      • Maliaros A.
      • Samonis G.
      • Falagas M.E.
      Prolonged versus short-term intravenous infusion of antipseudomonal beta-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials.
      ).
      Although the concept of PI in sepsis is well recognized and accepted by ICU physicians, it is not widely used. This is because the application of the infusion strategy is affected by factors such as the patient's conditions, the severity of illness, and ICU settings. In this study, we aimed to explore the factors that motivated physicians to choose PI of β-lactams in sepsis patients and examined how reasonable their choice was for a given context.

      Methods

      This prospective observational national cohort study was conducted in 40 ICUs at the teaching hospitals of 31 provinces in China between August 20, 2021 and September 20, 2021. Patients who met the diagnostic criteria of sepsis 3.0 and with sepsis onset for <24 h, and patients who were treated with β-lactams for sepsis were included. Refer to the method details in supplementary materials. The following data were collected: the baseline data, admission source, ICU settings, comorbidities and Charlson comorbidity index (CCI), infection source, the levels of infectious biomarkers, multidrug-resistant (MDR) bacterial infections, acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, clinical condition, intensity of care, and the usage of five major β-lactams (penicillins, cephalosporins, monobactams, carbapenems, β-lactam/β-lactamase inhibitor combinations). The outcomes were 28d mortality and length of ICU stay. We used SPSS 22.0 (SPSS Inc., IL, USA) for data analysis.

      Results

      Out of 498 patients with sepsis who were initially enrolled, 57 were excluded (Fig. 1). In this study, PI was used to treat 60.09% of the patients. Compared with CBI, PI was associated with a significantly lower 28d mortality (P = 0.036, Fig. 2). Univariate analysis indicated that the choice of PI was based on the following factors: CCI, presence of a solid tumor, APACHE II score, presence of septic shock, acute respiratory failure, acute kidney injury, the number of syringe pumps per bed, and MDR bacterial infection (Table S1). Multivariate analysis showed that septic shock and MDR were independent factors associated with PI (Table 1). Our data indicated that the benefits of PI in terms of survival were obvious not only in subgroups with severe illness, but also in subgroups with less severe illness, including those with lower CCI values of <2, those without septic shock, those with an APACHE II score <15, and those with lesser organ damage (Fig. 3).
      Figure 1
      Figure 1Flow chart of the study.
      ICU = intensive care unit; CBI = conventional infusion; PI = prolonged infusion.
      Figure 2
      Figure 2Subgroups analyses of the impact of prolonged infusion (PI) on 28d survival rate. Shown are hazard ratios for 28d survival with PI.
      SOFA= sequential organ failure assessment score; APACHE II= acute physiology and chronic health evaluation score; CRRT= continuous renal replacement therapy; PCT= Procalcitonin; Y= Yes; N= No.
      Table 1Multivariate analysis of factors associated with the decision to administer β-lactams via prolonged infusion in patients with sepsis.
      VariablesβWaldP valueOR (95% CI)
      Charlson comorbidity index0.1472.4380.1181.158 (0.963, 1.392)
      Number of syringe pumps per ICU bed-0.1123.3240.0680.894 (0.792, 1.008)
      Solid tumor-0.5421.5280.2160.582 (0.246, 1.374)
      Multidrug-resistant bacterial infections0.5294.8520.0281.698 (1.060, 2.719)
      APACHE II score0.0000.0000.9901.000 (0.971, 1.029)
      Septic shock0.5756.0770.0141.776 (1.125, 2.805)
      Acute heart failure0.3011.4530.2281.351 (0.828, 2.206)
      Acute liver injury0.4441.7930.1811.559 (0.814, 2.988)
      Mechanical ventilation0.4753.7210.0541.608 (0.992, 2.606)
      Renal replacement therapy0.5001.3850.2391.648 (0.717, 3.787)
      APACHE II score = acute physiology and chronic health evaluation II score; ICU = intensive care unit.
      Figure 3
      Figure 3Kaplan-Meier analysis of survival in conventional bolus infusion (CBI) and prolonged infusion (PI) patients, survival of patients was followed for 28d.
      Using univariate and multivariate Cox regression analysis, age, APACHE II score, mechanical ventilation, and PI were proved to be the independent factors of 28d mortality (Table S2 and 2). Propensity score matching (PSM) analysis was performed to reduce the imbalance between the PI and intermittent infusion patients (Table S3). The benefit of PI in the survival still existed after adjusting the potential confounders, including variables associated with disease severity (Table S4, HR 0.283, 95% CI 0.121-0.659; Table 3, HR 0.296, 95% CI 0.127-0.690). Univariate analysis on the whole cohort and PSM cohort further disclosed that PI of carbapenems was associated with the improved outcome and may contribute most to the overall benefit of PI on mortality (Table S2 and S4).
      Table 2Multivariate analysis of factors associated with 28d mortality in patients with sepsis.
      VariablesβWaldP valueHR (95% CI)
      Age0.0299.6620.0021.030 (1.011, 1.049)
      Body weight-0.0080.4630.4960.992 (0.969, 1.015)
      Cerebrovascular disease-0.1350.1660.6840.874 (0.456, 1.673)
      APACHE II score0.06515.800<0.0011.068 (1.034, 1.103)
      Septic shock0.2870.9790.3231.332 (0.755, 2.350)
      Acute heart failure0.2070.5530.4571.230 (0.713, 2.123)
      Mechanical ventilation0.7774.2760.0392.175 (1.041, 4.544)
      Renal replacement therapy0.5171.8450.1741.677 (0.795, 3.535)
      Prolonged infusion-0.7967.9530.0050.451 (0.259, 0.784)
      APACHE II score = acute physiology and chronic health evaluation II score; HR = hazard ratio.
      Table 3Multivariate analysis for 28d mortality in propensity-matched cohort.
      VariablesβWaldP valueHR (95% CI)
      Age0.0243.6560.0561.024 (0.999, 1.049)
      APACHE II score0.0524.0140.0451.053 (1.001, 1.108)
      Mechanical ventilation1.1554.4190.0363.174 (1.081, 9.316)
      Prolonged infusion-1.2187.9450.0050.296 (0.127, 0.690)
      APACHE II score = acute physiology and chronic health evaluation score II score; HR= hazard ratio.

      Discussion

      To the best of our knowledge, this is the first study to reveal the factors that drive physicians to choose PI of β-lactam in sepsis patients. Prolonged infusion of antipseudomonal β-lactams in patients with sepsis was associated with lower mortality than short-term infusion. The overall quality of evidence of PI was high, and this strategy was recommended by the standard guidelines (
      • Abdul-Aziz M.H.
      • Sulaiman H.
      • et al.
      Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis.
      ;
      • Dulhunty J.M.
      • Roberts J.A.
      • Davis J.S.
      • et al.
      Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial.
      ;
      • Abdul-Aziz M.H.
      • Sulaiman H.
      • et al.
      Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis.
      ;
      • Evans L.
      • Rhodes A.
      • Alhazzani W.
      • Antonelli M.
      • et al.
      Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.
      ;
      • Kondo Y.
      • Ota K.
      • Imura H.
      • Hara N.
      • Shime N.
      Prolonged versus intermittent beta-lactam antibiotics intravenous infusion strategy in sepsis or septic shock patients: a systematic review with meta-analysis and trial sequential analysis of randomized trials.
      ;
      • Vardakas K.Z.
      • Voulgaris G.L.
      • Maliaros A.
      • Samonis G.
      • Falagas M.E.
      Prolonged versus short-term intravenous infusion of antipseudomonal beta-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials.
      ). Our results also indicated that PI was associated with significantly lower 28d mortality than CBI.
      However, our study figured out that PI was used to treat 60.09% of the ICU patients. And we found that this strategy was not commonly applied and was more likely to be used in cases of more severe illness. This is probably related to physicians’ understanding that it is reasonable to allocate ICU resources, including PI, to more critically ill patients with sepsis as they are more likely to benefit from this treatment. Our data indicated that the benefits of PI in terms of survival were also obvious in subgroups with less severe illness, including those with lesser comorbidities, organ damage and septic shock. Furthermore, analysis of PSM cohort also indicated that PI could benefit all patients with sepsis regardless of the severity of illness. Based on the above findings, when physicians decide whether to use PI for the administration of β-lactams or not, patients who have less severe illness should not be neglected. Further studies in specific subgroups of patients according to age, sepsis severity, degree of organ dysfunction and immunocompetence are warranted.
      In conclusion, the use of PI for administering β-lactams was not a commonly applied strategy in patients with sepsis and was more likely to be used in more severely ill patients. However, PI had a survival benefit independent of disease severity. To improve the overall survival of sepsis, we suggest that PI should be applied in all patients with sepsis.

      Funding

      This work was supported by National Natural Science Foundation of China [Grant Nos. 81873927 , 82072231 ], Taishan Scholars Program of Shandong Province [Grant No. tsqn202103165], Clinical Research Center of Shandong University [Grant No. 2020SDU-CRCC013], China Postdoctoral Science Foundation [Grant No. 2018M632685], and Project of Science and Technology of Qingdao People's Livelihood (19-6-1-23-nsh).

      Ethics approval and consent to participation

      This study was approved by the hospital ethics committees of Qilu Hospital of Shandong University. Informed consent was waived due to the observational nature of the study.

      Availability of data and materials

      The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

      CRediT authorship contribution statement

      Yang Mao: Funding acquisition, Writing – original draft, Writing – review & editing, Data curation. Nana Xu: Data curation, Formal analysis. Meichen Yan: Data curation. Mingmin Pang: Data curation. Xinyue Zhang: Data curation. Haigang Wang: Formal analysis. Juan Du: Data curation. Dawei Wu: . Hao Wang: Funding acquisition, Writing – original draft, Project administration, Supervision.

      Declaration of Competing Interest

      The authors declare that they have no competing interests.

      Acknowledgments

      We sincerely thank Yuntao Li from Peking University International Hospital, Rui Li from Chongqing Univeristy Cancer Hospital, Xiaobao Lei from Chenzhou First People's Hospital, Qin Wang from Zhenjiang Maternal and child Health Care Hospital, Shaohua Liu from The first affiliated hospital of Zhengzhou University, Huanbo Liu from 425 Hospital of Chinese People's Liberation Army, Xuan Zhou from PLA General Hospital Hainan Hospital, Litao Guo from The First Affiliated Hospital of XI'AN Jiaotong University, Zhongqiang Wang from Shiqian County People's Hospital, Jianning Zhang from The First People's Hospital of Kashga, Lijuan Zhu from Huizhou Central Hospital, Wa Da from Lhasa People's Hospital, Gang Chen from Anqing People's Hospital, Kai Zhang from the Second Affiliated Hospital Zhejiang University School of Medicine, Guowei Tu from Zhongshan Hospital, Shiman Wen from Yunnan First Hospital, Shuming Guo from Gansu provincial hospital of TCM, Shuying Yang from Tianjin First Central Hospital, Qi Li from The First Affiliated Hospital of Nanchang University, Ruiqing Xu from Fujian Provincial Hospital, Xingli Xu from School of Medicine UESTC, Lifang Sun from Renmin hospital of Wuhan university Hubei general hospital, Huifeng Li from Linfeng people's hospital, Fang Liu from the Second Hospital of Hebei Medical University, Guifen Gan from Qinghai university affiliated hospital, Fei Wang from Baoshan Hospital of Chifeng, Feng Wei from Affiliated Hospital of Chifeng University, Jinyuan Zhu from General Hospital of Ningxia Medical University, Feng Ge from the General Hospital of Shenyang Military, Liangyan Jiang from The First Affiliated Hospital of Guanxi medical university, Yunlong Li form The 2nd Affiliated Hospital of Harbin Medical University, Ming xiu from First Hospital of Jilin University, Lu Zhang from The Second Hospital of Shandong University, Haining Lu from Qilu hospital of Shandong university, Fangyu Ning from Binzhou Medical University Hospital, Dongming Cao from Liaocheng People's Hospital, Ming Ma from Huantai County People's Hospital, Caibao Fu from Yantai Mountain Hospital, Qiang Sun and Lekun Wang from The Affiliated Hospital of Jining Medical University for their help with the data collection.

      Appendix. Supplementary materials

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