Effect of Different Dosage Frequency of Polymyxin B on Rat Nephrotoxicity

Abstract

Background Polymyxin B, as the final treatment against multidrug-resistant Gram-negative bacilli, is widely used in clinical practice. However, little is known about the nephrotoxicity of polymyxin B. The purpose of this study was to elucidate the relationship between polymyxin B nephrotoxicity and daily administration frequency. Methods Sprague–Dawley rats were randomly divided into three groups: 18 mg/kg/q24 h group (Group A, once daily), 9 mg/kg/q12 h group (Group B, twice daily), and normal saline control group (Group C). The rats were injected subcutaneously for 5 consecutive days with the same daily total dose and different frequency of administration. The serum creatinine (SCr) and blood urea nitrogen (BUN) of each group before administration (0 h), and 8 and 24 h after administration, were measured by tail vein blood sampling. On the sixth day, the rats in each group were killed, the left kidney was taken for pathological section observation, and the results of each group were compared. Results After 96 h of administrated polymyxin B, the total average level of SCr in Group A was 56.98±12.42 μmol/L, that of Group B was 52.02±8.68 μmol/L, and that of Group C was 34.36±5.39 μmol/L. BUN was 9.86±4.58, 10.54±4.08, and 3.55±0.73 mmol/L in Groups A, B, and C, respectively. The daily urinary protein excretion was 5004.45±1333.84 μg in Group A, 4608.04±1444.42 μg in Group B, and 2096.33±215.28 μg in Group C. In addition, according to the observation of pathological slices, compared with Group A, the number of exfoliated and necrotic cells of renal tubules in Group B was higher, and the morphological changes were more serious. Conclusion The experimental results showed that the renal toxicity in rats treated with a twice-daily subcutaneous dose of polymyxin B was higher than that in rats treated with once-daily dose of polymyxin B.

Urinary Metabolomics from a Dose-Fractionated Polymyxin B Rat Model of Acute Kidney Injury

“…rats receiving fractionated dosing schemes had slightly higher degrees of kidney injury than those receiving once daily administration. 14,15 AKI was very common in all of the human and preclinical studies, and kidney injury rates and extents were reasonably similar between groups. Thus, it is unlikely that toxicity will be ameliorated by simply changing the dosing scheme (of the same total daily dose); attention must be focused on early identification and prevention of toxicity.…”

Pharmacokinetics and Nephrotoxicity of Polymyxin MRX-8 in Rats: A Novel Agent against Resistant Gram-Negative Bacteria

“…One study in rats showed that polymyxin=-induced nephrotoxicity was related to the frequency of dosing [28]. A 10-year cohort study found that nephrotoxicity is related to the dose and the number of days of administration [29].…”

An inflammation-targeted nanoparticle with bacteria forced release of polymyxin B for pneumonia therapy

“…On the other hand, it also protonates under physiological conditions and interacts with phosphate anions in the cell membranes of healthy cells, especially in the kidney, where PMB accumulates. 7 That is the most critical mechanism of PMB-induced nephrotoxicity: PMB increases the permeability of tubular epithelial cell membranes, leading to an influx of cations, anions and water. 8 In the last two decades of the twentieth century, several approaches have been used to encapsulate PMB through electrostatic interactions, shielding the cationic portion or reducing the number of cationic residues.…”