Abstract Pharmacokinetic studies of daptomycin in septic patients indicate that pharmacokinetic parameters may be altered. The purpose of this clinical investigation is to determine the ...pharmacokinetics of daptomycin in a population of hospitalized patients with clinically significant gram-positive infections and receiving daptomycin. Daptomycin was measured using an isocratic HPLC technique. Thirty-five patients suffering from gram-positive severe infections and receiving daptomycin were included in the study. Patients were divided into two groups, depending on the dose of daptomycin received: group A, including 24 patients receiving 6 mg/kg/day daptomycin and group B, 11 patients receiving 8 mg/kg/day. Patients receiving a daptomycin dosage of 8 mg/kg/day had significantly higher values of mean Cmax and AUC0–24 . Each group was further divided into three subgroups, according to the creatinine clearance (CrCl) values: (1) patients with a CrCl >80 ml/min, (2) patients with CrCl ranging between 80 and 40 ml/min, and (3) patients with CrCl <40 ml/min. Compared to patients with normal renal function, those with CrCl <40 ml/min had higher mean values of minimum concentration ( Cmin ) ( p < 0.001), AUC0–24 ( p = 0.03), and prolonged plasma half-time ( p < 0.001). These differences were present both in patients receiving 6 and those with 8 mg/kg/day. However, in each of the three subgroups with different degrees of renal function a marked variability of pharmacokinetics parameters was observed. The factors associated with increased mortality were an infection acquired in the ICU, hypoalbuminemia, and AUC/MIC <666. The marked variability that characterizes daptomycin pharmacokinetics in these patients suggest the monitoring of the main pharmacokinetic parameters in this clinical setting.
Low plasma levels of first-line antitubercular drugs can be counted among the main causes of poor response to antitubercular therapy, and therapeutic drug monitoring has been proposed as a method to ...promote tailored treatments for both child and adult patients. The main aim of the study was to evaluate serum concentrations of isoniazid (INH) and rifampicin (RIF) and to investigate reasons for sub-therapeutic plasma concentrations in order to fix dosages. Children with TB were prospectively enrolled from January to August 2019. Two venous blood samples were collected (the first at least 15 days after the beginning of antitubercular treatment, and the second between 1 and 8 weeks later). Plasma concentrations were determined by a validated high-performance liquid chromatography method. In all, 45 children were included. Seventy blood samples for INH plasma concentration were collected between 120 and 240 min after drug intake. Adjusting for dose (mg/kg/day) and time of INH administration, when considering three different age groups (less than or equai to 2 years, 2-12 years, > 12 years), a statistically significant lower INH plasma concentration was observed in younger children compared to the older age groups in the multivariate analysis (p < 0.001 and p < 0.001). A total of 68 blood samples were evaluated for RIF concentrations. Both for INH and RIF a statistically significant lower plasma concentration was also observed in adolescents (p < 0.001). Fifteen children (15/45, 33%) presented drug concentrations under the referral therapeutic range. Based on our findings, monitoring patients' drug plasma concentrations in children under 2 years of age and in adolescents can make treatment more patient-tailored.
Abstract Pharmacokinetics and pharmacodynamics are significantly altered in critically ill septic patients and the risk of prolonged periods with concentrations below the minimum inhibitory ...concentration (MIC) and of low area under the serum concentration–time curve/MIC (AUC/MIC) ratios is of concern. We compared the pharmacokinetic/pharmacodynamic (PK/PD) profile of linezolid administered by intermittent or continuous infusion in critically ill septic patients. Patients were divided into two groups: intermittent infusion (Group I) (600 mg/12 h); or continuous infusion (Group C) (300 mg intravenous loading dose +900 mg continuous infusion on Day 1, followed by 1200 mg/daily from Day 2). Linezolid serum levels were monitored for 72 h and microbiological data were collected. The clinical outcome was monitored. Sixteen patients completed the study. MICs of susceptible pathogens were 2 mg/L for 80% of the isolates. In Group I, linezolid trough serum levels ( Cmin ) varied widely and were below the susceptibility breakpoint (4 mg/L) during the study period; in 50% of patients Cmin was <1 mg/L. In Group C, mean linezolid serum levels were more stable and, starting from 6 h, were significantly higher than Cmin levels observed in Group I and were always above the susceptibility breakpoint. Time that the free drug concentration was above the MIC ( Tfree > MIC) of > 85% was more frequent in Group C than in Group I ( P < 0.05). Finally, with continuous infusion it was possible to achieve AUC/MIC values of 80–120 more frequently than with intermittent infusion ( P < 0.05). According to PK/PD parameters, continuous infusion has theoretical advantages over intermittent infusion in this population of patients.
Linezolid is a new drug from the oxazolidinone class of antibiotics used against mycobacteria and multi-drug resistant (MDR) Gram-positive bacterial infections, which may are also ...glycopeptide-resistant. The drug usage in pediatric age needs an accurate drug monitoring for effective patient management. The aim of this study was to evaluate the use of dried blood spot (DBS) specimens to determinate linezolid levels during treatment. Advantages of DBS include short collection time, low invasiveness, ease and low cost of sample collection, transport and storage. The analysis was performed in LC–MS/MS operating in positive ion mode and multiple reaction monitoring (MRM) mode. The calibration curve in matrix was linear in the concentration range of 1–100mg/L with correlation coefficient value of 0.9987. Intraday and interday coefficients of variation were within 3.6% and 13.0%, respectively. We also tested the thermal and temporal drug stability in dried blood spots at four different temperatures to evaluate the risks of sample delivery in different conditions. The short term stability studies showed that linezolid concentration remained stable for at least one month under all the conditions tested.
This new assay has favorable characteristics being highly precise and accurate and allows a fast linezolid analysis with a total run time 22min long, in gradient analysis. Concentration data for plasma and DBS samples from patients after treatment were compared showing a good correlation.
Correlation between DBS data and serum samples measured by HPLC–UV was satisfactory.
The benefit for patients is the ability to monitor the treatment with a simple and convenient sample collection at home.
The pharmacokinetics of valganciclovir were studied in 8 infants ranging in age from 4 to 90 days (mean 20 days). We suggest that doses of 15 mg/kg given twice daily may be suitable for neonates and ...young infants.
This paper reports on a 71- year-old Caucasian male who underwent neurosurgery for an oligodendroglioma, followed by a cranial-sinus fistula and cerebrospinal fluid rhinorrhea. The clinical course ...was complicated due to an extensively drug-resistant Acinetobacter baumannii meningitis. The patient was treated with colistin methanesulfonate, intrathecal for 24 days and intravenous for 46 days. In addition, the patient received meropenem and teicoplanin to treat a urinary tract infection and a bacterial aspiration pneumonia. Cerebrospinal fluid trough colistin levels resulted above the MIC of A. baumannii. Colistin cerebrospinal fluid concentration did not increase over the treatment period. Meningitis was cured and A. baumannii eradicated. No side effects from the antimicrobial therapy were observed. In conclusion, this case highlights the issues in treating infections caused by resistant Gram negative bacteria and supports previous findings on the efficacy, pharmacokinetic and tolerability of intravenous and intrathecal colistin treatments.
Due to the so‐called “antibiotic resistance crisis” new antibacterial agents are urgently sought to treat multidrug‐resistant pathogens. A group of gold‐ or silver‐based complexes, of general formula ...M(PEt3)X (with M=Au or Ag, and X=Cl, Br or I), alongside with three complexes bearing a positive or negative charge—Au(PEt3)2Cl, KAu(CN)2 and Ag(PEt3)2NO3—were prepared and comparatively tested with auranofin on a representative panel of pathogens including Gram‐positive, Gram‐negative and Candida strains. Interestingly, all the gold and silver complexes tested were active on Gram‐positive strains, with the gold complexes having greater efficacy. The effects of the gold compounds were potentiated to a larger extent than silver compounds when tested in combination with a permeabilizing agent. A number of relevant structure–activity relationships emerged from the comparative analysis of the observed antibacterial profiles, shedding new light on the underlying molecular mechanisms of the action of these compounds.
Test your metal: The antimicrobial properties of a small group of metal complexes with general formula M(PEt3)X (M=Au or Ag, X=Cl, Br or I) are measured and compared with three complexes bearing a positive or negative charge, that is, Au(PEt3)2Cl, KAu(CN)2 and Ag(PEt3)2NO3. The stability of complexes under the experimental conditions is shown to be a key parameter and a principal mechanism for resistance in Gram‐negative bacterial strains is reduced uptake. The results should aid the design of metal‐based antimicrobial agents.
Auranofin, (AF), a gold(I) complex in clinical use for the therapy of rheumatoid arthritis, is reported here to produce remarkable bactericidal effects in vitro against
Staphylococcus
sp. Noticeably, ...a similar antimicrobial action and potency are also noticed toward a few methicillin-resistant
Staphylococcus aureus
strains but not toward
Escherichia coli
. The time and concentration dependencies of the antimicrobial actions of AF have been characterized through recording time kill curves, and a concentration dependent profile highlighted. Overall, the present results point out that auranofin might be quickly and successfully repurposed for the treatment of severe bacterial infections due to resistant Staphylococci.
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