Optimizing Clinical Use of Polymyxin B

Sepsis Clinical Trial

Official title:

Optimizing Clinical Use of Polymyxin B: Teaching an Old Drug to Treat Superbugs

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02682355
• Other study ID #: R01AI119446-01
• Status: Completed
• Start date: February 2016
• Est. completion date: August 3, 2022

Study information

• Verified date: November 2023
• Source: Rutgers, The State University of New Jersey
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Polymyxin B is already being used extensively in the USA and other parts of the world; its use is likely to rapidly increase due to the greater burden of infections caused by MDR Gram-negative bacteria and the growing awareness of the limitations inherent in the clinical pharmacology of CMS/colistin. Cross resistance exists between the two polymyxins and thus both must be dosed optimally; but the recently generated scientifically-based dosage regimens for CMS/colistin cannot be extrapolated to polymyxin B. It is essential that an adequately powered study is conducted to define the clinical PK/PD/TD relationships of polymyxin B and identify, using next-generation proteomics, biomarkers for early detection of kidney injury. This will allow the development of scientifically-based dosage regimens for various categories of patients and an adaptive feedback control clinical tool for optimized dosing of polymyxin B in future individual patients.

Description:

Multidrug-resistant (MDR) Gram-negative 'superbugs' are rapidly spreading around the world, and polymyxin B and colistin (polymyxin E) are often the only effective antibiotics. Since polymyxin B was released in the 1950s, its pharmacokinetics, pharmacodynamics, toxicodynamics (PK/PD/TD) have never been defined. Recent pharmacological research on polymyxins has predominantly focused on colistin methanesulfonate (CMS, an inactive prodrug of colistin) and demonstrates that CMS has significant limitations. Thus, polymyxin B is increasingly being viewed as the preferred polymyxin. Unfortunately, recently developed scientifically-based dosing recommendations for CMS cannot and should not be applied to polymyxin B, as the latter is administered as its active entity. Therefore, it is essential to determine the PK/PD/TD of polymyxin B in critically-ill patients, refine optimal dosage regimens, and develop the user-friendly adaptive feedback control (AFC) clinical tool.

The Specific Aims are:

1. To develop a population PK model for polymyxin B;

2. To investigate relationships between the PK of polymyxin B, duration of therapy and patient characteristics, with the development and timing of nephrotoxicity; and to use next-generation proteomics to identify the most predictive biomarker(s) of polymyxin B associated nephrotoxicity; and to develop the population PK/TD model;

3. To establish the relationships between polymyxin B PK, bacterial susceptibility and patient characteristics, with the probability of attaining and time to achieving clinical and bacteriological outcomes; and

4. To employ the models from Aims 1-3 and Monte Carlo simulation to develop scientifically-based dosage regimens of polymyxin B and to develop an AFC algorithm for future individual patients.

Research Design: Patients being treated with intravenous polymyxin B will be identified at three clinical sites in the USA and one in Singapore. Patients (n = 250) will have blood collected at various times surrounding a dose of polymyxin B between days 1 and 5 of therapy. Development of nephrotoxicity, clinical response, and bacteriological response will be examined. Total and free plasma concentrations of polymyxin B will be determined. Bacterial isolates will be examined for the emergence of polymyxin resistance. The relationships between polymyxin B PK, PD and TD end-points (e.g. clinical and bacteriological responses, development of toxicity and resistance) will be assessed using pharmacometric analyses. Finally, the obtained information will be used to apply Monte Carlo simulation to examine the impact of various patient characteristics and other factors on polymyxin B PK, PD and TD, in order to establish optimal dosage regimens and AFC algorithms for individual critically-ill patients.

Significance: No new antibiotics will be available for Gram-negative 'superbugs' for many years. This landmark multicenter study will provide essential information for optimizing polymyxin B use in critically-ill patients, while minimizing resistance and toxicity. This proposal aligns perfectly with the NIAID priority "To teach old drugs new tricks" and the recent Executive Order of the White House to combat antibiotic resistance.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 155
• Est. completion date: August 3, 2022
• Est. primary completion date: May 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patient of 18 years of age or older

2. Expectation of hospitalization and receipt of polymyxin B of = 48 hours

3. Receipt of intravenous polymyxin B for treatment of bacteremia and/or urinary tract infection and/or respiratory tract infection (including tracheobronchitis) or sepsis

4. Provision of written informed consent by the patient or by the patient's health care proxy if the patient cannot give consent

5. Adequate venous access to enable collection of blood for determination of concentrations of polymyxin B and co-administered antibiotics

Exclusion Criteria:

1. Age <18 years

2. Currently incarcerated

3. Concomitant use of polymyxin B delivered directly into the respiratory tract

4. Cystic fibrosis

5. Known allergy to CMS/colistin or polymyxin B

6. Anticipated death within 48 h of commencing polymyxin B therapy

Related Conditions & MeSH terms

• Blood Stream Infection
• Communicable Diseases
• Infections
• Pneumonia
• Respiratory Tract Infections
• Sepsis
• Urinary Tract Infections

Locations

Country	Name	City	State
Brazil	Hospital Moinhos de Vento	Porto Alegre
Brazil	Hospital Sao Lucas da - PUC / RS	Porto Alegre
Singapore	Singapore General Hospital	Singapore
United States	Northwestern University	Chicago	Illinois
United States	Columbia University Medical Center	New York	New York
United States	New York Presbyterian-Weill Cornell Medical Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Rutgers, The State University of New Jersey

Countries where clinical trial is conducted

United States,  Brazil,  Singapore, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Polymyxin B plasma concentrations		28 days after enrollment
Secondary	Changes in serum creatinine		28 days after enrollment
Secondary	Clinical response based on resolution of signs and symptoms of infection		28 days after enrollment
Secondary	Microbiologic response based on eradication of pathogens from blood and respiratory cultures		28 days after enrollment