The Effect of Adjunctive Melatonin With Colistin in Patients With Multidrug-Resistant Gram-Negative Bacterial Infections

This study evaluates whether adding melatonin to standard colistin therapy improves outcomes in patients with multidrug-resistant (MDR) Gram-negative bacterial infections. These infections are difficult to treat and are associated with high morbidity and mortality, particularly in critically ill patients.

Colistin is often used as a last-line antibiotic for these infections; however, its effectiveness may be limited, and it is associated with side effects such as kidney injury. Melatonin, a naturally occurring hormone, has antioxidant, anti-inflammatory, and immune-modulating properties that may enhance the effectiveness of antibiotics and reduce treatment-related complications.

In this randomized, double-blind, placebo-controlled study, adult patients receiving colistin will be assigned to receive either melatonin or a placebo in addition to standard care. The study will assess whether melatonin improves oxidative stress, infection control, and clinical outcomes while maintaining safety.

Study Overview

• Status: Not yet recruiting
• Conditions: Antimicrobial Resistance; Multidrug-Resistant Gram-Negative Bacterial Infections
• Intervention / Treatment: Drug: Melatonin; Other: Placebo

Detailed Description

Antimicrobial resistance is a major global health challenge, particularly among Gram-negative bacteria, which have developed resistance to multiple antibiotic classes, including last-line agents such as colistin. These infections are especially prevalent in intensive care units and are associated with poor clinical outcomes.

Given the limited development of new antibiotics, alternative strategies such as the use of adjunctive therapies are being explored. Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous hormone known for its role in circadian rhythm regulation, but it also exhibits antioxidant, anti-inflammatory, and immunomodulatory effects. Emerging experimental evidence suggests that melatonin may enhance antibiotic activity and help overcome resistance mechanisms, including those affecting colistin.

This study is a prospective, randomized, double-blind, placebo-controlled clinical trial conducted in adult patients with confirmed MDR Gram-negative bacterial infections requiring intravenous colistin therapy in the intensive care setting.

Participants will be randomly assigned in a 1:1 ratio to receive either oral melatonin (60 mg once daily) or a matching placebo, initiated concurrently with colistin therapy. All patients will receive standard antimicrobial treatment and supportive care according to institutional protocols.

The primary objective is to evaluate the effect of adjunctive melatonin on oxidative stress, measured by changes in serum malondialdehyde (MDA) levels. Secondary objectives include assessment of microbiological eradication, clinical response, inflammatory markers, renal safety (including the incidence of acute kidney injury), and overall clinical outcomes such as length of stay.

This study aims to determine whether melatonin can serve as a safe and effective adjunctive therapy to improve outcomes and potentially restore the efficacy of colistin in the treatment of multidrug-resistant Gram-negative infections.

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Aalaa Kamal Shata, MD; Phone Number: +201129214940; Email: aalaashata@yahoo.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• • Confirmed diagnosis of infection caused by multidrug-resistant Gram-negative bacteria based on microbiological culture and sensitivity testing

  • Patients receiving intravenous colistin therapy according to institutional protocols
  • Clinical diagnosis of sepsis or severe infection in accordance with established critical care criteria

Exclusion Criteria:

• • Pregnancy or lactation

  • Terminal medical or surgical illness (e.g., advanced malignancy)
  • Severe chronic liver disease or end-stage renal failure
  • Impaired cognitive function or active psychiatric illness under treatment
  • Known hypersensitivity to melatonin
  • Use of melatonin within 48 hours prior to enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: melatonin; Patients will receive oral melatonin 60 mg once daily, initiated concurrently with the administration of the colistin loading dose	Drug: Melatonin; Patients will receive oral melatonin 60 mg once daily, initiated concurrently with the administration of the colistin loading dose
Placebo Comparator: Placebo; Patients will receive matching placebo capsules following the same dosing schedule.	Other: Placebo; Patients will receive matching placebo capsules following the same dosing schedule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxidative stress marker	serum malondialdehyde (MDA) levels	day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
microbiological eradication	Clearance of the baseline MDR Gram-negative pathogen, confirmed by negative follow-up culture	Day 7
inflammatory response	C reactive protein will be measured	Day 7

Collaborators and Investigators

• Sponsor: Ain Shams University

Publications and helpful links

General Publications

• Mansilla-Rosello A, Hernandez-Magdalena J, Dominguez-Bastante M, Olmedo-Martin C, Comino-Pardo A, Escames G, Acuna-Castroviejo D. A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in surgical patients with severe sepsis admitted to the intensive care unit. J Pineal Res. 2023 Mar;74(2):e12845. doi: 10.1111/jpi.12845. Epub 2022 Dec 2.

Study record dates

Study Major Dates

• Study Start (Estimated): March 26, 2026
• Primary Completion (Estimated): August 26, 2026
• Study Completion (Estimated): August 26, 2026

Study Registration Dates

• First Submitted: March 26, 2026
• First Submitted That Met QC Criteria: March 26, 2026
• First Posted (Actual): March 31, 2026

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 26, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: multidrug resistance; colistin; Gram-Negative Infections; gram negative infections
• Additional Relevant MeSH Terms: Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indoles; Tryptamines; Melatonin
• Other Study ID Numbers: REC-FPFUE-NO 5/2026

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