Prolonged Intravenous Infusion of β-lactam Antibiotics in Early Septic Patients (PROBES)

The prolonged β-lactam Antibiotics intravenous infusion strategy has emerged as the standard treatment for sepsis despite its unknown efficacy. The investigators will conduct a prospective, multi-center, cluster randomized controlled clinical trial. The investigators aimed to compare the clinical efficacy and prognosis of prolonged β-lactam antibiotics intravenous infusion versus short-term intravenous infusion in ICU patients with early sepsis. The investigators expect to recruit 40 branch centers and enroll at least 2600 patients with sepsis.

Study Overview

• Status: Not yet recruiting
• Conditions: Sepsis
• Intervention / Treatment: Behavioral: prolonged intravenous infusion of β-lactams Antibiotics

Detailed Description

Sepsis and septic shock can lead to high morbidity and mortality. The mortality of sepsis is related to inappropriate antibiotic treatment strategy. Due to the pathophysiological characteristics of patients with sepsis, the pharmacokinetics of antibiotics have changed, and antibiotic treatment strategies applied to general mild and severe infections may not be suitable for those patients. The relevant international guidelines recommend that antibiotic treatment for patients with sepsis should base on pharmacokinetic/pharmacodynamic principles, but this recommendation is based on low-level clinical evidence.

β-lactam antibiotics, including penicillins, cephalosporins, carbapenems and so on, are the most widely used antibacterial drugs in clinical practice. The best predictive parameter of those antibiotic bactericidal activity is the time during which the free drug concentration exceeds the target microbial MIC value (fT >MIC). According to Monte Carlo approach and clinical studies, as a PK/PD target value, an effective bactericidal effect can be achieved if fT>MIC reaches more than 40%; fT>MIC reaches more than 60%-70% can achieve the maximum bactericidal effect, which can be used in the treatment of severe cases. For severe infection and prevention of bacterial resistance, fT>MIC needs to reach 90%-100%.

The results of clinical studies have proved that improper or inadequate initial empiric antibiotic treatment is an independent risk factor that affects the therapeutic effectiveness and prognosis of severe infections. Important reasons for the lower-than-expected antibiotic treatment effect in severely ill patients include at least the following two factors: (1) Changes in the pathophysiological state of severely ill patients on drug metabolism, such as capillary leakage leading to increased drug distribution volume. As well as the high excretion and low obstruction hemodynamic characteristics of sepsis, increased renal blood flow leads to high excretion of water-soluble drugs, which often reduces the effective plasma concentration of the drug; (2) ICU infection of pathogenic bacteria has increased drug resistance and increased MIC. The above factors lead to the decrease of drug fT>MIC, which affects the efficacy of antibiotics. In recent years, the optimization of PK/PD-guided time-dependent antimicrobial treatment programs have confirmed that the administration method of prolonging the infusion time or continuous infusion can maintain a good steady-state blood drug concentration, prolong fT> MIC, and improve clinical curative effect, and can reduce the amount of antibiotics.

The main problems with PK/PD-guided antimicrobial therapy are: (1) Lack of convincing large sample clinical research results; (2) It has not been confirmed which subgroup (such as the sepsis severity, drug-resistant patterns of pathogens, immunocompetence) can be benefited from this strategy; (3) It is not clear whether the method of prolonged infusion can be applied in all kinds of β-lactam antibiotics .

This study adopts multi-center, openness, cluster randomization method to group, and eliminates the bias caused by factors such as the treatment environment in a single ward through the multi-center study; through Uniform training realizes the standardization of drug delivery methods to eliminate researchers' human bias in treatment operations and observations. At the same time, the regional randomization method sets the drug delivery method for a certain research center in a certain research phase to be determined, which eliminates the operational error and observation bias when the researcher needs to face multiple drug delivery programs at the same time. It can greatly reduce research costs and human bias, and more reliably obtain the impact of PK/PD-guided antibiotic treatment on the prognosis of patients and the impact of bacterial resistance in the entire ward.

• Study Type: Interventional
• Enrollment (Anticipated): 2600
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients in ICU who need to be treated with β-lactam antibiotics for clinical diagnosis of infection;
2. Meet the diagnostic criteria of sepsis 3.0 in the previous 24h;
3. At assessment of eligibility, treating doctor expects patient to need treatment in ICU beyond the next calendar day.

Exclusion Criteria:

1. The infection is diagnosed clinically, but the acquired pathogens are not sensitive to the study drug;
2. Has a history of allergies to study drugs;
3. Those who have a serious condition and the expected survival time is less than 72 hours.
4. Receipt of potential study medication for > 24 hours before randomization.
5. Pregnancy
6. Death is deemed imminent and inevitable.
7. Receiving palliative or supportive treatment only at the time of assessment for eligibility.
8. Treating doctor not committed to provision of advanced life-support, including any of mechanical ventilation, dialysis and vasopressor administration for at least the next 48 hours.
9. Consent not gained for study participation and entry under a waiver-of-consent not approved by the jurisdictional human research ethics committee.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: prolonged intravenous infusion of β-lactams Antibiotics; Administer according to the PK/PD optimized regimen with the goal of increasing T>MIC. (1) Carbapenems: Calculate the daily dose according to the creatinine clearance rate and divide it into 3 times. Each time, the dose is injected intravenously at 1/2 dose for 15 minutes, and the remaining 1/2 dose is injected at a constant rate for 3 hours. (2) Cephalosporins: calculate the allowable daily dose according to the creatinine clearance rate, inject at a uniform rate within 24 hours. (3) β-lactams and β-lactamase inhibitor compound: the daily dose is calculated according to the creatinine clearance rate and injected at a uniform rate within 24 hours.	Behavioral: prolonged intravenous infusion of β-lactams Antibiotics; (1) Carbapenems: Calculate the daily dose according to the creatinine clearance rate and divide it into 3 times. Each time, the dose is injected intravenously at 1/2 dose for 15 minutes, and the remaining 1/2 dose is injected at a constant rate for 3 hours. (2) Cephalosporins: calculate the allowable daily dose according to the creatinine clearance rate, inject at a uniform rate within 24 hours. (3) β-lactams and β-lactamase inhibitor compound: the daily dose is calculated according to the creatinine clearance rate and injected at a uniform rate within 24 hours.
NO_INTERVENTION: short-term intravenous infusion of β-lactams Antibiotics; The daily allowable dose is calculated according to the creatinine clearance rate. The carbapenems, cephalosporins and β-lactamase inhibitor compound preparations are administered in accordance with the dosage and usage required by the instructions, and the injection is generally 30 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality in ICU	Prolonged β-lactamase Antibiotics Infusion lower the All-cause mortality in ICU compared with normal group	Change of mortality between two arms at 90-day from the day antibiotic therapy begin.
28-day all-cause mortality	Prolonged β-lactamase Antibiotics Infusion lower 28-day all-cause mortality the compared with normal group	Change of mortality between two arms at 28-day from the day antibiotic therapy begin.

Collaborators and Investigators

• Sponsor: Qilu Hospital of Shandong University

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): September 20, 2021
• Primary Completion (ANTICIPATED): December 31, 2022
• Study Completion (ANTICIPATED): September 1, 2023

Study Registration Dates

• First Submitted: August 11, 2021
• First Submitted That Met QC Criteria: August 22, 2021
• First Posted (ACTUAL): August 27, 2021

Study Record Updates

• Last Update Posted (ACTUAL): August 27, 2021
• Last Update Submitted That Met QC Criteria: August 22, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: prolonged intravenous infusion; β-lactam Antibiotics; pharmacokinetics/pharmacodynamics (PK/PD)
• Additional Relevant MeSH Terms: Anti-Infective Agents; Anti-Bacterial Agents; Lactams; beta-Lactams
• Other Study ID Numbers: Wang Hao

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study protocol and ICF will be shared with other researchers when start this trial.
• IPD Sharing Time Frame: Study protocol and ICF will be shared with other researchers when start this trial for five years.
• IPD Sharing Access Criteria: Ever researchers can access our study protocol and ICF from the web of clinical trials.gov.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No