Abstract
Currently, polymyxin B has been widely used in the treatment of multidrug-resistant Gram-negative pathogen infections. Due to the limited pharmacokinetic/pharmacodynamic data, the optimal dosage regimen for the recently proposed therapeutic target of the area under the concentration-time curve over 24 h in steady state divided by the minimum inhibitory concentration 50–100 mg⋅h/L has not yet been established. Moreover, most studies have focused on critically ill patients, yet there have been no studies in the field of renal transplantation. To optimize the dosage strategy and reduce the risk of toxicity, a population pharmacokinetics model of polymyxin B with the Phoenix NLME program was developed in our study. A total of 151 plasma samples from 50 patients were collected in the present study. Polymyxin B plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. A one-compartment model adequately described the data, and the clearance and volume of distribution were 1.18 L/h and 12.09 L, respectively. A larger creatinine clearance was associated with increased clearance of polymyxin B (p < 0.01). Monte Carlo simulation showed that a regimen of a 75 mg loading dose with a 50 mg maintenance dose was a better option to achieve an optimal therapeutic effect (minimum inhibitory concentration ≤1 mg/L) and to reduce the incidence of side effects for patients with renal impairments. The developed model suggested that dosing adjustment should be based on renal function in renal transplant patients.
Highlights
Infection due to multidrug-resistant (MDR) Gram-negative bacteria has become an extreme challenge, as MDR organisms have become resistant to most currently available antibiotics, resulting in limited treatment options
PMB population PK (PPK) Renal Transplant Patients concentration-time curve over 24 h in steady state divided by the minimum inhibitory concentration (AUC0–24h/MIC) (Mohamed et al, 2012)
As polymyxin B was excreted unchanged in urine, some studies found no correlation between polymyxin B clearance (CL) and creatinine clearance (CrCL), whereas Wang et al found that CrCL was a significant covariable for the CL of polymyxin B (Wang et al, 2020)
Summary
Infection due to multidrug-resistant (MDR) Gram-negative bacteria has become an extreme challenge, as MDR organisms have become resistant to most currently available antibiotics, resulting in limited treatment options. According to the results from previous pharmacokinetics and pharmacodynamics (PK/PD) studies, the bactericidal activity of polymyxin B is best correlated with the area under the PMB PPK Renal Transplant Patients concentration-time curve over 24 h in steady state divided by the minimum inhibitory concentration (AUC0–24h/MIC) (Mohamed et al, 2012). Previous population PK (PPK) studies of polymyxin B showed significant individual differences across patients (Zavascki et al, 2008; Kwa et al, 2011; Sandri et al, 2013a; Sandri et al, 2013b; Avedissian et al, 2018; Kubin et al, 2018; Manchandani et al, 2018; Miglis et al, 2018; Lakota et al 2018) found that when given the recommended dosage, only 71% of patients could achieve the AUC0–24h target, which might either lead to a poor response or a higher incidence of renal injury (Lakota et al, 2018). Further studies are warranted to determine the characteristics of polymyxin B pharmacokinetics
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