Different Dosing Strategies of Colistin in Multidrug-Resistant Gram-Negative Bacilli Infections

Mansoura University

Status and phase: Enrolling; Phase 3; Phase 2

Conditions: Multi Drug Resistant; Critical Ill Patients

Treatments: Drug: US FDA colistin dosing strategy; Drug: EMA colistin dosing strategy

Study type: Interventional

Funder types: Other

Identifiers

NCT06843668

H-04-Q001

Details and patient eligibility

About

Nosocomial infections caused by multi-drug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative pathogens represent a major threat worldwide. The increasing trend of multi-drug resistance in Gram-negative bacteria (MDR-GNB) poses a particularly acute challenge to health systems especially in critically ill patients.

Patients in intensive care units (ICUs) have encountered an increasing emergence and spread of antibiotic-resistant pathogens. In Saudi Arabia mainly MDR-GNB such as Acinetobacter Baumannii, Pseudomonas Aeruginosa, Klebsiella Pnemoniae and Enterobacter are observed in ICUs.

Polymyxins are the last line therapy in the treatment of infection caused by these MDR-GNB. Colistin is the most widely used polymyxin antibiotic, it is administered as inactive prodrug colistimethate sodium (CMS) that is hydrolyzed to an active moiety of colistin base activity (CBA). It acts as cationic detergent and damages bacterial cytoplasmic membrane causing leaking of intracellular substances and then cell death.

During the first years of their use, polymyxin-associated neurotoxicity occurred in patients with an incidence as high as 27% following parenteral administration. However, other retrospective clinical trials have not exposed neurotoxicity to be a major concern. On the other hand, nephrotoxicity is by far the most common and dose-limiting side effect associated with parenteral polymyxins, with incidence rates in patients as high as 60%. Despite the high incidence of colistin induced nephrotoxicity, in 2012, the World Health Organization (WHO) reclassified polymyxins as critically important for the management of MDR-GNB infection, renewing the interest in these antibiotics.

To the best of our knowledge no study compared the efficacy and safety of both dosing strategies in critically ill patients. Moreover, there is still a lack of evidence on the efficacy and safety of both dosing strategies in obese patients. Therefore, this study aims at comparing the efficacy and toxicity of both strategies in colistin dosing (the fixed dose and the weight-based dosing) in obese patients and non- obese patients.

Enrollment: 120 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Patients age ≥ 18 years old.
• Patients who will be treated with CMS for MR GNB infections.
• Patients who are admitted to the ICUs.

Exclusion criteria

• Known hypersensitivity to colistin.
• Pregnant and lactating women.
• Patients who are treated with colistin for < 24 hours.
• Patients with myasthenia gravis or concomitant anesthetics or neuromuscular blocking drugs.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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120 participants in 2 patient groups

The EMA (fixed dose) colistin group

Experimental group

Description:

The EMA colistin group will receive I.V colistin using fixed dose strategy.

Treatment:

Drug: EMA colistin dosing strategy

US FDA (weight-based dose) colistin group

Active Comparator group

Description:

The weight-based colistin group will receive I.V. colistin using weight based dosing strategy.

Treatment:

Drug: US FDA colistin dosing strategy