Pharmacokinetics of Polymyxin B in Hospitalized Adults with Cystic Fibrosis

Abstract

Background: The optimal polymyxin B dosage needed to achieve an efficacy target of 50-100 mg·h/L when treating multi-drug-resistant bacterial infections in adult cystic fibrosis (CF) patients is unclear. The pharmacokinetics of intravenous polymyxin B were evaluated to better inform dosing. Methods: This was a prospective, observational pharmacokinetic (PK) study of nine CF adults receiving intravenous polymyxin B as part of usual clinical care. Doses preceding PK sampling ranged from 50-100 mg every 12 hours. Five PK samples were collected following the fourth or fifth dose and concentrations of polymyxin subcomponents, B1 and B2, were quantified using Liquid Chromatography Mass Spectrometry (LC-MS). Population PK (NONMEM® software) analysis was performed using pooled polymyxin B1+B2 concentrations. Results: Participants were Caucasian, predominantly male, with mean age and weight of 31 years (range 21-57 years) and 58.0kg (range 38.3-70.4kg), respectively. A 1-compartment zero-order infusion and linear elimination model adequately described the data with estimated clearance and volume of distribution, 2.09 L/hr and 12.7 L, respectively, corresponding to a 4.1 hour mean half-life (t 1/2 ). Although body weight was observed to influence the volume of distribution, a fixed dose of 75 mg every 12 hours was predicted to achieve the target steady-state exposure. Neurotoxicities were reported in all patients; acute kidney injury events in two patients. These events resolved within 2-4 days after discontinuing polymyxin B. Conclusions: Fixed maintenance dosing of polymyxin B without loading is predicted to achieve the targeted therapeutic exposure in CF adults. Treatment-limiting neurotoxicities are very common in this population.

Population pharmacokinetics of polymyxin B in patients with liver dysfunction

“…Based on the final PopPK model in our study, the population estimate of CL was 2.43 L/h and V was 23.11 L, which was not significantly different from the findings of previous studies on the one‐compartment PopPK model of PMB (range, CL: 1.18–2.5 L/h and V: 12.09–34.4 L) 18,19,22,23,37 . In addition, in the present study, CrCL was identified as a significant covariate of PMB CL, which corresponds with the results of studies by Yu et al and Li et al 22,23 Nevertheless, our results differed from those of the studies of Manchandani et al and Kubin et al, which did not indicate that the effect was clinically insignificant 18,19 .…”

“…12.09-34.4 L). 18,19,22,23,37 In addition, in the present study, CrCL was identified as a significant covariate of PMB CL, which corresponds with the results of studies by Yu et al and Li et al 22,23 Nevertheless, our results differed from those of the studies of Manchandani et al…”

Effects of Aerosol Inhalation Combined with Intravenous Drip of Polymyxin B on Bacterial Clearance, Symptoms Improvement, and Serum Infection Indexes in Patients with Pneumonia Induced by Multidrug-Resistant Gram-Negative Bacteria

“…CRP is a protein that rises sharply in plasma when the body is infected or tissue damaged, which can activate complement and enhance the phagocytosis of phagocytes to play an opsonizing role. PCT can reflect the active degree of systemic inflammation in the body, and it is significantly increased in severe bacterial, fungal, and parasitic infections and sepsis [ 14 , 15 ]. Pathogenic bacteria and airway secretions in patients with MDR Gram-negative ( G −) pneumonia accumulate in the lungs, stimulate the production of mononuclear macrophages and neutrophils, and cause the body to secrete a large amount of IL-6, leading to systemic inflammatory response, and CRP and PCT were significantly increased.…”

Higher incidence of neurotoxicity and skin hyperpigmentation in renal transplant patients treated with polymyxin B

“…Neurotoxicity was less common (7–27%) in earlier studies and usually manifests as dizziness, muscle weakness, facial and peripheral paraesthesia, partial deafness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia and neuromuscular blockade 4,14 . Nevertheless, Liu and Crass recently reported higher neurotoxic adverse reactions in both healthy subjects (85%) and patients with cystic fibrosis (100%) 15,16 . Compared to highly sedated patients in earlier studies, these patients were conscious and presented a better capacity to perceive the symptoms of neurotoxicity, which might be the reason for the higher incidence rates.…”

“…4,14 Nevertheless, Liu and Crass recently reported higher neurotoxic adverse reactions in both healthy subjects (85%) and patients with cystic fibrosis (100%). 15,16 Compared to highly sedated patients in earlier studies, these patients were conscious and presented a better capacity to perceive the symptoms of neurotoxicity, which might be the reason for the higher incidence rates. In addition, intravenous polymyxin B treatment was recently found to cause skin hyperpigmentation (SH), and the D-phenylalanine residue at position 6 might be the critical structure involved in this reaction, but the incidence and mechanism of this effect are still unknown.…”