Randomized-controlled Trial (RCT) on Combination Antibiotic for Infections Caused by Gram-negative Bacteria

• Status: Withdrawn
• Trial end date: 2015-12-01
• Target enrollment: 0
• Participant gender: All

Summary

Background and rationale:

Antimicrobial resistance is a global public health threat. An increasing number of Gram-negative bacteria isolates worldwide are resistant to virtually all antibiotics including carbapenems. Although polymyxins are the current gold standard antibiotic for treatment of severe extensively drug-resistant Gram-negative bacteria (XDR-GNB - defined in Appendix I) infections, resistance development on therapy and treatment failures are common. Combination antibiotics therapy have better in vitro efficacy, but have not been formally tested in a prospective trial.

We will conduct a Phase IIB, prospective, open-label, randomized-controlled trial in 4 major Singaporean hospitals, with balanced treatment assignments achieved by permuted block randomization, stratified by hospital. There will be 75 subjects per arm, with the subjects in the comparator arm receiving standard-dose polymyxin B while the intervention arm will receive a second antibiotic, doripenem, with polymyxin B against the bacterial isolate in question. Subjects with ventilator-associated pneumonia (VAP) will additionally receive nebulized colistin. The primary outcome is 30-day mortality while secondary outcomes include microbiological clearance, time to defervescence, and toxicity of therapy, presence of secondary infections due to new multi-drug resistant bacteria and length of ICU stay. Plasma drug levels will be measured by liquid chromatography-mass spectrometry.

Hypothesis:

The underlying primary hypothesis is that combination antibiotic therapy (IV polymyxin B + IV doripenem) is superior to mono-antibiotics therapy (IV polymyxin B) in reducing 30-day mortality from XDR-GNB infections.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Tan Tock Seng Hospital
• Collaborators: Changi General Hospital; National University Hospital, Singapore; Singapore General Hospital
• Treatments: Anti-Bacterial Agents; Antibiotics, Antitubercular; Colistin; Doripenem; Polymyxin B; Polymyxins

Criteria

Inclusion Criteria:

• Monomicrobial XDR-GNB bacteremia.

• Monomicrobial XDR-GNB ventilator-associated pneumonia OR healthcare-associated pneumonia.

Exclusion Criteria (will be excluded if subjects meet one or more of the following criteria):

• Allergy to any of the study medications.

• For female patients, the patients is pregnant.

• Unable to provide consent and have no legally authorized representatives.

• Currently enrolled in another trial.

• >48 hours after XDR-GNB confirmation by the microbiology laboratory.

• Palliative care or with less than 24 hours of life expectancy, as discussed with their primary physicians.

• Co-infection with other aerobic Gram-negative bacteria.

• Severe renal impairment (creatinine clearance <30 milliliters (mL)/min).

• Concurrent infection not involving the lungs or bloodstream is not an exclusion criterion for the study.