Optimizing Clinical Use of Polymyxin B
Optimizing Clinical Use of Polymyxin B
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.
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.
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 a bloodstream infection (according
 to CDC criteria 55) and/or pneumonia

 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