In this review, we provide an updated summary on colistin pharmacokinetics and pharmacodynamics. Colistin is an old molecule that is frequently used as last-line treatment for infections caused by multidrug-resistant Gram-negative bacteria. Colistin is a decapeptide administered either as a prodrug, colistin methanesulfonate (CMS), when used intravenously, or as colistin sulfate when used orally. Because colistin binds to laboratory materials, many experimental issues are raised and studies on colistin can be tricky. Due to its large molecular weight and its cationic properties at physiological pH, colistin passes through physiological membranes poorly and is mainly distributed within the extracellular space. Renal clearance of colistin is very low, but the dosing regimen should be adapted to the renal function of the patient because CMS is partly eliminated by the kidney. Therapeutic drug monitoring of colistin is warranted because the pharmacokinetics of colistin are very variable, and because its therapeutic window is narrow. Resistance of bacteria to colistin is increasing worldwide in parallel to its clinical and veterinary uses and a plasmid-mediated resistance mechanism (MCR-1) was recently described in animals and humans. In vitro, bacteria develop various resistance mechanisms rapidly when exposed to colistin. The use of a loading dose might reduce the emergence of resistance but the use of colistin in combination also seems necessary.

Valganciclovir, the ganciclovir prodrug, is an antiviral agent administered orally to prevent or treat cytomegalovirus infection in solid-organ transplant recipients. The valganciclovir dosing regimen in children is still controversial, as the number of patients reaching the area under the concentration-time curve at steady state (AUCss) target (40 to 60 mg·h/liter) remains highly variable. The aim of this study was to determine the population pharmacokinetics of valganciclovir in pediatric renal transplant recipients and propose an appropriate dosing regimen. Children with renal transplant who received valganciclovir to prevent or treat cytomegalovirus infection at the Robert Debré University Hospital were included. Plasma ganciclovir concentrations were determined by high-performance liquid chromatography and UV detection. Population pharmacokinetic analysis was performed with NONMEM software. A total of 104 patients aged 2 to 20 years treated with valganciclovir, administered at a mean dose of 17.3 ± 6.1 mg/kg of body weight to prevent and/or treat cytomegalovirus infection after renal transplantation, were included. A total of 1,212 samples were available. A two-compartment model with first-order elimination best fitted the data: ganciclovir clearance increased with body surface area, was 15% higher in boys than in girls, and decreased with increasing creatinine concentration. The central volume of distribution increased with body surface area and was 14% higher in boys than in girls. According to the personalized dosing regimen, 65.7% and 65.4% of the children were predicted to achieve the AUCss target for cytomegalovirus prophylaxis and treatment, respectively. A new pharmacokinetic model that allows the proposal of an individualized dose adapted to the characteristics of pediatric patients with renal transplant was built.

Objectives: An important clindamycinerifampicin pharmacokinetic (PK) interaction has been reported, but the potential influence of the clindamycin administration route on that interaction is unknown. This prospective, observational, comparative PK study was undertaken to characterize and analyse the impact of the route, comparing the rifampicin enzyme-inductor effects on clindamycin clearance (CLclin) for oral versus intravenous (IV) administration. Methods: Patients with bone-and-joint infections (BJIs) were treated with clindamycin monotherapy (n ¼ 20) or clindamycinerifampicin combination therapy (n ¼ 19). Patients received continuous IV clindamycin infusion for 2e6 weeks, followed by an oral regimen. Liquid chromatographyemass spectrometry was used to measure plasma clindamycin concentrations at the end of IV and after 2 weeks of oral treatment. The ratios of the mean CLclin for the combination and monotherapy groups were calculated for IV (Riv) and oral (Rpo) routes, with the final ratio, Rf ¼ Rpo/Riv, representing the fold change of the rifampicin-inducing effect from the IV to the oral route. Results: Comparing monotherapy with combination-therapy groups, the former's median steady-state concentration was two-fold higher after IV administration (8.49 versus 3.82 mg/L, p < 0.001) and its median AUC 0e8h was 12 times higher after oral intake (37.7 versus 3.1 mg.h/L, p < 0.001). Riv, Rpo and Rf were 2.68, 18.8 and 7.0 respectively. Conclusion:The magnitude of this interaction was markedly increased by oral intake, questioning the use of oral treatment for difficult-to-treat infections like BJIs. Nevertheless, the clindamycinerifampicin combination seems possible provided that clindamycin is administered by continuous IV infusion.

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