Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria

Objectives: The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death. Methods: Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) 2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03–1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19–1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen. Discussion: The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations

Uridine Metabolism in HIV-1-Infected Patients: Effect of Infection, of Antiretroviral Therapy and of HIV-1/ART-Associated Lipodystrophy Syndrome

Background Uridine has been advocated for the treatment of HIV-1/HAART-associated lipodystrophy (HALS), although its metabolism in HIV-1-infected patients is poorly understood. Methods Plasma uridine concentrations were measured in 35 controls and 221 HIV-1-infected patients and fat uridine in 15 controls and 19 patients. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Uridine was measured by a binary gradient-elution HPLC method. Analysis of genes encoding uridine metabolizing enzymes in fat was performed with TaqMan RT-PCR. Results Median plasma uridine concentrations for HIV-1-infected patients were 3.80 µmol/l (interquartile range: 1.60), and for controls 4.60 µmol/l (IQR: 1.8) (P = 0.0009). In fat, they were of 6.0 (3.67), and 2.8 (4.65) nmol/mg of protein, respectively (P = 0.0118). Patients with a mixed HALS form had a median plasma uridine level of 4.0 (IC95%: 3.40-4.80) whereas in those with isolated lipoatrophy it was 3.25 (2.55-4.15) µmol/l/l (P = 0.0066). The expression of uridine cytidine kinase and uridine phosphorylase genes was significantly decreased in all groups of patients with respect to controls. A higher expression of the mRNAs for concentrative nucleoside transporters was found in HIV-1-infected patients with respect to healthy controls. Conclusions HIV-1 infection is associated with a decrease in plasma uridine and a shift of uridine to the adipose tissue compartment. Antiretroviral therapy was not associated with plasma uridine concentrations, but pure lipoatrophic HALS was associated with significantly lower plasma uridine concentrations

Antibiotic research and development: business as usual?

This article contends that poor economic incentives are an important reason for the lack of new drugs and explains how the DRIVE-AB intends to change the landscape by harnessing the expertise, motivation and diversity of its partner

Synthesis, characterization and antibacterial activity studies of new 2‑pyrral‑L‑amino acid Schif base palladium (II) complexes.

Three new 2-pyrral amino acid Schif base palladium (II) complexes were synthesized, characterized and their activity against six bacterial species was investigated. The ligands: Potassium 2-pyrrolidine-L-methioninate (L1), Potassium 2-pyrrolidine-L-histidinate (L2) and Potassium 2-pyrrolidine-L-tryptophanate (L3) were synthesized and reacted with dichloro(1,5- cyclooctadiene)palladium(II) to form new palladium (II) complexes C1, C2 and C3, respectively. 1 NMR, FTIR, UV–Vis,elemental analysis and conductivity measurements were used to characterize the products. The antibacterial activities of the compounds were evaluated against Gram-positive Staphylococcus aureus (S. aureus, ATCC 25923), methicillin-resistant Staphylococcus aureus (MRSA, ATCC 33591), Staphylococcus epidermidis (S. epidermidis, ATCC 12228) and Streptococcus pyogenes (S. pyogenes, ATCC 19615) and, gram-negative Pseudomonas aeruginosa (P. aeruginosa, ATCC 27853) and Klebsiella pneumoniae (K. pneumoniae, ATCC 13883) using the agar well difusion assay and microtitre plate serial dilution method. The palladium complexes were active against the selected bacteria with the imidazole ring containing complex C2 and indole heterocyclic ring containing complex C3 showing the highest activity