Optimizing Clinical Use of Polymyxin B

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

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.

Study Overview

• Status: Completed
• Conditions: Pneumonia; Sepsis; Urinary Tract Infections; Blood Stream Infection; Respiratory Tract Infection (Including Tracheobronchitis)

Detailed 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.

• Study Type: Observational
• Enrollment (Actual): 155

Contacts and Locations

• Study Contact: Name: Jolene Daniel; Phone Number: 732-235-7713; Email: jd1557@rwjms.rutgers.edu

Study Locations

• Brazil
  • Porto Alegre, Brazil, 90035-001
    • Hospital Moinhos de Vento
  • Porto Alegre, Brazil, 10032
    • Hospital Sao Lucas da - PUC / RS
• Singapore
  • Singapore, Singapore, 16908
    • Singapore General Hospital
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10065
      • New York Presbyterian-Weill Cornell Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The human subjects involved in this study will be receiving intravenous polymyxin B as part of their routine clinical care because of infection due to bacteria resistant to all other first-line antibiotics.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Study cohort; Patients receiving IV polymyxin B for treatment of bacteremia and/or urinary tract infection and/or respiratory tract infection (including tracheobronchitis) or sepsis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Polymyxin B plasma concentrations	28 days after enrollment

Secondary Outcome Measures

Outcome Measure	Time Frame
Changes in serum creatinine	28 days after enrollment
Clinical response based on resolution of signs and symptoms of infection	28 days after enrollment
Microbiologic response based on eradication of pathogens from blood and respiratory cultures	28 days after enrollment

Collaborators and Investigators

• Sponsor: Rutgers, The State University of New Jersey
• Investigators: Principal Investigator: Keith S Kaye, MD, MPH, Rutgers University

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): May 31, 2022
• Study Completion (Actual): August 3, 2022

Study Registration Dates

• First Submitted: January 11, 2016
• First Submitted That Met QC Criteria: February 10, 2016
• First Posted (Estimated): February 15, 2016

Study Record Updates

• Last Update Posted (Estimated): November 21, 2023
• Last Update Submitted That Met QC Criteria: November 17, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Urologic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Sepsis; Infections; Communicable Diseases; Urinary Tract Infections; Respiratory Tract Infections
• Other Study ID Numbers: R01AI119446-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No