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

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.

Conditions

• Bacteremia
• Healthcare-associated Pneumonia
• Ventilator-associated Pneumonia

Interventions

DRUG

Polymyxin B

Intravenous polymyxin B will be started on a standard dose of 25,000U/kg body weight, in 2 divided doses each day, infused over 2 hours. The duration of intravenous antibiotic treatment for subjects with either bacteremia or VAP or HAP will be at least 10 days. The duration of intravenous polymyxin B can be prolonged based on clinical indication, e.g., deep-seated source of infection, etc. For patients with VAP, nebulized colistin at the dose of 2 MU 8 hourly for 5 days will be prescribed.

DRUG

Polymyxin B + Doripenem

Standard dose of intravenous polymyxin B at 25,000U/kg body weight will be given in 2 divided doses each day with each dose infused over 2 hours and intravenous doripenem 500mg, with each dose infused over 4 hours. For patients with VAP, nebulized colistin at the dose of 2 MU 8 hourly for 5 days will be prescribed.

Sponsors & Collaborators

• Singapore General Hospital

  collaborator OTHER

• National University Hospital, Singapore

  collaborator OTHER

• Changi General Hospital

  collaborator OTHER

• Tan Tock Seng Hospital

  lead OTHER

Principal Investigators

• David Lye, MBBS, FRACP · Tan Tock Seng Hospital

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

21 Years

Max Age

90 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2015-01-31

Primary Completion

2015-10-31

Completion

2015-12-31

Countries

• Singapore

Study Locations