Erythromycin in Septic Patients: Immunomodulatory Role and Clinical Impact

Immunomodulatory Role and Clinical Impact of Erythromycin in Critically Septic Patients: a Randomized Clinical Trial

In sepsis and septic shock, the host response is characterized by a complex of immune-inflammatory reactions; triggered and activated by microbial components. These reactions are controlled by a balance of pro-inflammatory cytokines and anti-inflammatory cytokines. The imbalance of this immune response is a source of organ dysfunction; major prognostic factor during septic condition. This pretext has created the need for therapies aimed to modulate the overstated of host response. During the past 2 decades, macrolide molecules proved interest to be immunomodulatory agents; due beyond their antibacterial activity. Their regulatory role in the production of cytokines was demonstrated in the management of severe acute community pneumonia.

The investigators hypothesize that the adjunction of macrolides to standard therapy in patients with sepsis or septic shock is associated to a favorable immunomodulatory and clinical effects.

Study Overview

• Status: Completed
• Conditions: Sepsis; Septic Shock; Immunoinflammatory Response
• Intervention / Treatment: Drug: Erythromycin

Detailed Description

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It is considered as the main cause of death in critically ill patients ranging from 20 to 50%. These alarming death rates have prompted several intense research efforts to better understand the mechanisms underlying the pathogenesis of sepsis. Currently, sepsis is recognized as a complex entity created by an immuno-inflammatory reaction of the infected host; triggered and activated by microbial components. This reaction brings together the cellular and humoral immunity defense systems. Activation of the cellular system involves macrophages, polymorphonuclear cells, lymphocytes and endothelial cells.

Therefore, pro-inflammatory cytokines are secreted in order to control the infection (IL-1, IL-6, IL-8, and TNF-alpha). Simultaneously, anti-inflammatory cytokines (IL-4, IL-10) are also released, allowing a local and systemic regulation of the inflammatory cascade. The imbalance of this immune response is a source of organ dysfunction aggravated by the lack of tissue oxygenation.

Understanding that sepsis results from a disproportionate immune-inflammatory response have created the need for therapies aimed to modulate the overstated host response. The agents tested were: anti-endotoxin antibodies, tumor necrosis factor (TNF), anti-TNF-alpha, recombinant human activated protein C (rhAPC), stress-dose hydrocortisone and statins. Most of these clinical trials showed no obvious clinical impact or a limited clinical efficacy.

During the past 2 decades, macrolides molecules were revealed to be immune-modulator agents; beyond their antibacterial activity. Their immune-modulator properties result from their ability to induce the activity of various immune cells and their regulatory role in the production of cytokines. Several cellular targets and mechanisms have been described to explain the immune-modulator effects of macrolides: Respiratory epithelial cells and innate immunity cells. Overall, macrolides decrease the production of pro-inflammatory cytokines by innate and adaptive immunity cells.

In this clinical trial, the investigators are focusing on the effects of macrolides on the pro-inflammatory / anti-inflammatory balance by assaying cytokines and other immune-inflammatory markers during sepsis and septic shock. The main hypothesis is that the use of macrolides in addition to standard therapy in critically septic patients has a favorable immune-modulator and clinical effects compared to critically septic patients not receiving macrolide.

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Tunisia
  • Tunis, Tunisia, 1007
    • intensive care unit of the University Hospital Center La Rabta

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• a patient in whom the diagnosis of sepsis or septic shock is diagnosed (According to the definitions updated by the sepsis 3 consensus in 2016)

Exclusion Criteria:

• Macrolide use for another indication.
• Known allergy to macrolides.
• A corrected QT prolonged (> 440 ms for man and 460 ms for woman) or taking drugs with an increased risk of QT prolongation.
• QT prolongation attributed to erythromycin
• Underlying dysimmunity (unbalanced diabetes, autoimmune disease, etc.)
• Pregnant or breastfeeding woman.
• Death or discharge while participating in the protocol (day 0 to day 6)
• Non-compliance with the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Erythromycin arm; The erythromycin arm (n=55) receives, in addition to the standard antimicrobial therapy, erythromycin 1 g three times per day intravenously: each gram is diluted in 250 ml of 5% glucose serum to be administered over 1 hour for 5 days.	Drug: Erythromycin; Before each intervention (either at inclusion: day 0) and after the end of 5 days of erythromycin or placebo (day 6), the following dosages will be performed: Pro-inflammatory cytokine (TNF alpha); Anti-inflammatory cytokine (IL-10); Procalcitonin (PCT) Then, analysis of the variations in the TNF/ IL-10 ratio, the blood count, CRP and PCT parameters (between Day 0 and Day 6); Other Names: specific dosages
Placebo Comparator: Placebo arm; The placebo arm (n=55) receives, in addition to the standard antimicrobial therapy, isotonic saline, intravenously, 20 ml diluted in 250 ml of 5% glucose serum to be administered over 1 hour for 5 days.	Drug: Erythromycin; Before each intervention (either at inclusion: day 0) and after the end of 5 days of erythromycin or placebo (day 6), the following dosages will be performed: Pro-inflammatory cytokine (TNF alpha); Anti-inflammatory cytokine (IL-10); Procalcitonin (PCT) Then, analysis of the variations in the TNF/ IL-10 ratio, the blood count, CRP and PCT parameters (between Day 0 and Day 6); Other Names: specific dosages

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of TNF α / IL-10 ratio	The pro-inflammatory / anti-inflammatory balance will be estimated by measuring the TNF α / IL-10 ratio at baseline and that at day 6. The difference (Δ) of TNF α / IL-10 ratio between day 0 (or baseline) and day 6 will be calculated in each arm then compared between the 2 arms.	Change from Baseline TNF α / IL-10 ratio at 6 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mortality	28-day mortality	28 days
Procalcitonine	bilogical parameter with measurement of the difference (Δ) in procalcitonine between day 6 and day 0	At day 0 and day 6 of inclusion
vasopressors requirement in mg/H	maximum dose of vasopressors use	during follow-up, an average of 28 days
vasopressors requirement in days	time needed of vasopressors use	during follow-up, an average of 28 days

Collaborators and Investigators

• Sponsor: Tunis University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Actual): January 30, 2023
• Study Completion (Actual): April 30, 2023

Study Registration Dates

• First Submitted: November 20, 2020
• First Submitted That Met QC Criteria: December 10, 2020
• First Posted (Actual): December 11, 2020

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: May 10, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: inflammation; sepsis; mortality; immunity; erythromycin
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Shock, Septic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Erythromycin; Erythromycin Estolate; Erythromycin Ethylsuccinate; Erythromycin stearate
• Other Study ID Numbers: Rabta

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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