Erythromycin in Septic Patients: Immunomodulatory Role and Clinical Impact

Sponsor

Tunis University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04665089

Collaborator

(none)

Enrollment

Location

Arms

15.9

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Sepsis Septic Shock Immunoinflammatory Response	Drug: Erythromycin	N/A

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 Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

single-blind randomized clinical trial comparing 2 arms: erythromycin versus a placebosingle-blind randomized clinical trial comparing 2 arms: erythromycin versus a placebo

Masking:

Single (Participant)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 1, 2022

Anticipated Primary Completion Date :

Jan 30, 2023

Anticipated Study Completion Date :

Apr 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Erythromycin arm The erythromycin arm (n=40) 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=40) 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

Arm

Intervention/Treatment

Active Comparator: Erythromycin arm

The erythromycin arm (n=40) 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=40) 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

Other Names:

specific dosages

Outcome Measures

Primary Outcome Measures

Change of TNF α / IL-10 ratio [Change from Baseline TNF α / IL-10 ratio at 6 days]
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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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