Polymyxin T1

The optimal polymyxin B dosage needed to achieve an efficacy target of 50 to 100 mg · h/liter when treating multidrug-resistant bacterial infections in adult cystic fibrosis (CF) patients is unclear. The pharmacokinetics of intravenous polymyxin B were evaluated to better inform dosing. 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 to 100 mg every 12 h. 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. Participants were Caucasian, predominantly male, with mean age and weight of 31 years (range 21 to 57 years) and 58.0 kg (range 38.3 to 70.4 kg), respectively. A 1-compartment zero-order infusion and linear elimination model adequately described the data with estimated clearance and volume of distribution being 2.09 liters/h and 12.7 liters, respectively, corresponding to a 4.1 h mean half-life (t1/2). Although body weight was observed to influence the volume of distribution, a fixed dose of 75 mg every 12 h was predicted to achieve the target steady-state exposure. Neurotoxicities were reported in all patients, with acute kidney injury events in two patients. These events resolved within 2 to 4 days after discontinuing polymyxin B. 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.

The combination of polymyxins and chloramphenicol possesses synergistic killing activity against New Delhi metallo-β-lactamase (NDM)-producing Klebsiella pneumoniae. This systems study examined the transcriptomic responses to the polymyxin/chloramphenicol combination in clinical NDM-producing K. pneumoniae isolate S01. Klebsiella pneumoniae S01 (initial inoculum ~108 CFU/mL) was treated with polymyxin B (1 mg/L, continuous infusion) or chloramphenicol [maximum concentration (Cmax) = 8 mg/L, half-life (t1/2) = 4 h], alone or in combination, using an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model to mimic their pharmacokinetics in patients. Transcriptomic profiles of bacterial samples collected at 0, 0.25, 1, 4 and 24 h were examined using RNA sequencing (RNA-Seq). Chloramphenicol monotherapy significantly increased the expression of genes involved in ribosomal synthesis across the entire 24-h treatment, reflective of chloramphenicol-mediated inhibition of protein synthesis. The effect of polymyxin B was rapid and no major pathways were perturbed at later time points (4 h and 24 h). Combination treatment yielded the highest number of differentially expressed genes, including a large number observed following chloramphenicol monotherapy, in particular carbohydrate, nucleotide, amino acid and cell wall metabolism. Notably, chloramphenicol alone and in combination with polymyxin B significantly inhibited the expression of the arn operon that is responsible for lipid A modification and polymyxin resistance. These results indicate that the polymyxin/chloramphenicol combination displayed persistent transcriptomic responses over 24 h mainly on cell envelope synthesis and metabolism of carbohydrates, nucleotides and amino acids.

The study aimed to investigate the role of magnesium sulfate prophylaxis in nephrotoxicity caused by colistin. Thirty Wistar Albino rats were divided into four groups: control, colistin, magnesium (Mg), and Mg+colistin. The drugs were administered to the groups for seven days. Urea-creatinine values were measured at the beginning (T0) and end (T1) of the study. Malondialdehyde (MDA) levels were measured in plasma and kidney tissue, glutathione (GSH) levels were analyzed in the erythrocyte and kidney tissues. At the end of the study, the semiquantitative score (SQS) was calculated by the histopathological examination of the kidneys. Urea values significantly decreased in Mg and Mg+colistin groups compared to the baseline (p=0.013 and p=0.001). At the time of T1, these groups had significantly lower urea values than the colistin and control groups. Creatinine value was significantly increased in the colistin group compared to baseline (p=0.005), the creatinine value in the colistin group was significantly higher than the Mg+colistin group (p=0.011). Plasma MDA levels were significantly higher in the colistin group compared to the other groups at the time of T1 (p<0.001). The Mg+colistin group had lower renal MDA levels than the colistin group. The colistin group had significantly higher renal tubular grade (p=0.035), renal affected area (p<0.001), and SQS (p=0.001) than the Mg+colistin group. The results of the study suggested that Mg sulfate may have a nephrotoxicity-reducing effect on colistin.