Development and validation of a dosing nomogram for continuous infusion cloxacillin in infective endocarditis.

BACKGROUND: Cloxacillin is the first-line treatment for methicillin-susceptible staphylococcal infective endocarditis (IE). The recommended dose is 12 g per day regardless of the patient characteristics, despite the importance of renal function on its pharmacokinetics. OBJECTIVES: We sought to build a population pharmacokinetics model of continuous infusion cloxacillin in IE patients to evaluate the influence of multiple covariates and then develop a nomogram based on significant covariates for individual adaptation. PATIENTS AND METHODS: We included patients of a local IE cohort who were treated with cloxacillin administered by continuous infusion, excluding those who received intermittent or continuous dialysis, extracorporeal membrane oxygenation or extracorporeal circulation. The population pharmacokinetic analysis was performed using Pmetrics. The influence of weight, ideal weight, height, body mass index, body surface area, glomerular filtration rate (GFR) calculated with the Chronic Kidney Disease Epidemiology Collaboration formula (both expressed in mL/min/1.73 m² and in mL/min) and serum protein level on cloxacillin pharmacokinetics was assessed. Accounting for relevant covariates, a dosing nomogram was developed to determine the optimal daily dose required to achieve a steady-state plasma concentration range of 20-50 mg/L with a probability ≥0.9. RESULTS: A total of 114 patients (331 plasma concentrations) were included. A one-compartment model including GFR expressed in mL/min as a covariate was chosen. Using the nomogram, achieving the cloxacillin concentration target requires a daily dose ranging from 3.5 to 13.1 g for a GFR ranging from 20 to 125 mL/min. CONCLUSIONS: This work provided a practical tool for cloxacillin dose adjustment in IE according to renal function.

A multifaceted strategy to optimize pharmacokinetics of antimicrobial therapy in patients with hospital-acquired infections-a monocentre quality improvement project.

OBJECTIVE: We assessed the efficacy of a quality improvement programme to optimize the delivery of antimicrobial therapy in critically ill patients with hospital-acquired infections (HAI). PATIENTS AND METHODS: Before-after trial in a university hospital in France. Consecutive adults receiving systemic antimicrobial therapy for HAI were included. Patients received standard care during the pre-intervention period (June 2017 to November 2017). The quality improvement programme was implemented in December 2017. During the intervention period (January 2018 to June 2019), clinicians were trained to dose adjustment based on therapeutic drug monitoring and continuous infusion of ß-lactam antibiotics. The primary endpoint was the mortality rate at day 90. RESULTS: A total of 198 patients were included (58 pre-intervention, 140 intervention). The compliance with the therapeutic drug monitoring-dose adaptation increased from 20.3% to 59.3% after the intervention (P < 0.0001). The 90-day mortality rate was 27.6% in the pre-intervention period and 17.3% in the intervention group (adjusted relative risk 0.53, 95%CI 0.27-1.07, P = 0.08). Treatment failures were observed in 22 (37.9%) patients before and 36 (25.7%) patients after the intervention (P = 0.07). CONCLUSIONS: Recommendations for therapeutic drug monitoring-dose adaptation and continuous infusion of ß-lactam antibiotics were not associated with a reduction in the 90-day mortality rate in patients with HAI.

Dalbavancin plasma concentrations in 133 patients: a PK/PD observational study.

OBJECTIVES: Limited pharmacokinetics data support dalbavancin long-term use in off-label indications and the optimal dosing regimen is debated. We aimed to describe dalbavancin concentrations in an observational retrospective multicentre study. METHODS: Patients from 13 French hospitals, treated with 1500 mg doses of dalbavancin and for whom therapeutic drug monitoring was performed from June 2018 to March 2021 were included. Dalbavancin plasma concentrations were described at peak and 1, 2, 3, 4, 6 and 8 weeks after the last 1500 mg dose. Concentrations in patients weighing more or less than 75 kg and with a GFR greater or less than 60 mL/min were compared. Microbiological data were collected and dalbavancin MIC was measured when possible. RESULTS: One hundred and thirty-three patients were included (69% treated for bone and joint infections, 16% for endocarditis). Thirty-five patients received a single dose of dalbavancin and 98 received several administrations. Two, 3 and 4 weeks after the last dose, median plasma concentrations were respectively 25.00, 14.80 and 9.24 mg/L for the first doses and 34.55, 22.60 and 19.20 mg/L for the second or subsequent doses. Weight and renal function had an impact on pharmacokinetics. Infection was documented in 105 patients (Staphylococcus spp. in 68% of cases). Staphylococcus aureus was isolated in 32.5% of cases (median MIC: 0.047 mg/L) and Staphylococcus epidermidis in 27% of cases (median MIC of 0.047 mg/L). CONCLUSIONS: Plasma concentrations of dalbavancin were consistent with those described in clinical trials and those sought during the industrial development of the molecule.

Pantoprazole promotes sustained intestinal carriage of multidrug-resistant Escherichia coli in amoxicillin-treated mice.

AIMS: The main objective of this study was to compare extended-spectrum ß-lactamase (ESBL) Escherichia coli fecal titers during 12 days between two groups: mice who received proton pump inhibitors (PPIs) and those that did not. METHODS AND RESULTS: We tested three different in vivo models: model 1, high inoculum (106 CFU ml-1); model 2, low inoculum (102 CFU ml-1); and model 3, low inoculum and 2-day amoxicillin wash-out. There was no significant difference between the two groups in fecal ESBL E. coli titers in models 1 and 2. The fecal titers of ESBL E. coli were probably too high to show differences in colonization related to PPI treatment. By introducing a 2-day wash-out period after stopping amoxicillin (model 3), the fecal ESBL E. coli titers were higher in the PPI-treated mice during 12 days (3 log versus 11 log day CFU g-1; P < 0.05). This result highlighted that PPIs promote stable ESBL E. coli digestive carriage in mice. Fecal quantitative PCR showed that mice with low ESBL E. coli fecal titers had a much higher concentration of equol-producing bacteria, Muribaculum sp., and Adlercreutzia caecimuris. CONCLUSIONS: Pantoprazole treatment promotes sustained digestive carriage of ESBL E. coli in amoxicillin-treated mice.

Efficacy of Nanoencapsulated Daptomycin in an Experimental Methicillin-Resistant Staphylococcus aureus Bone and Joint Infection Model.

Staphylococcus aureus bone infections remain a therapeutic challenge, leading to long and expensive hospitalizations. Systemic antibiotic treatments are inconsistently effective, due to insufficient penetration into the infectious site. In an osteomyelitis model, the single local administration of nanoparticle-encapsulated daptomycin allows sterilization of the infectious sites after 4 and 14 days of treatment, while daily systemic daptomycin treatment for 4 days was not effective. These results demonstrate the great potential of this local antibiotic treatment.

Pharmacokinetics and Safety of XAV-19, a Swine Glyco-humanized Polyclonal Anti-SARS-CoV-2 Antibody, for COVID-19-Related Moderate Pneumonia: a Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study.

We assessed the pharmacokinetics and safety of XAV-19, a swine glyco-humanized polyclonal antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in coronavirus disease 2019 (COVID-19)-related moderate pneumonia. The objective was to evaluate the optimal dose and safety of XAV-19 during this first administration to patients with COVID-19-related moderate pneumonia. In this phase IIa trial, adults with COVID-19-related moderate pneumonia with a duration of ≤10 days were randomized to receive an infusion of XAV-19 at 0.5 mg/kg of body weight at day 1 and day 5 (group 1), 2 mg/kg at day 1 and day 5 (group 2), or 2 mg/kg at day 1 (group 3) or placebo. Eighteen patients (n = 7 for group 1, n = 1 for group 2, n = 5 for group 3, and n = 5 for placebo) were enrolled. Baseline characteristics were similar across groups; median XAV-19 serum concentrations (ranges) at the time of the maximum serum concentration of the drug (Cmax) and at day 8 were 9.1 (5.2 to 18.1) and 6.4 (2.8 to 11.9) µg/ml, 71.5 and 47.2 µg/ml, and 50.4 (29.1 to 55.0) and 20.3 (12.0 to 22.7) µg/ml for groups 1, 2, and 3, respectively (P = 0.012). The median terminal half-life (range) was estimated at 11.4 (5.5 to 13.9) days for 2 mg/kg of XAV-19 at day 1. Serum XAV-19 concentrations were above the target concentration of 10 µg/ml (2-fold the in vitro 100% inhibitory concentration [IC100]) from the end of perfusion to more than 8 days for XAV-19 at 2 mg/kg at day 1. No hypersensitivity or infusion-related reactions were reported during treatment, and there were no discontinuations for adverse events and no serious adverse events related to the study drug. A single intravenous dose of 2 mg/kg of XAV-19 demonstrated high serum concentrations, predictive of potent durable neutralizing activity with good tolerability. (This study has been registered at ClinicalTrials.gov under identifier NCT04453384.).

Effect of High-Dose Baclofen on Agitation-Related Events Among Patients With Unhealthy Alcohol Use Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Unhealthy alcohol use can lead to agitation in the intensive care unit (ICU). Objective: To assess whether high-dose baclofen reduces agitation-related events compared with placebo in patients with unhealthy alcohol use receiving mechanical ventilation. Design, Settings, and Participants: This phase 3, double-blind, placebo-controlled, randomized clinical trial conducted in 18 ICUs in France recruited adults receiving mechanical ventilation who met criteria for unhealthy alcohol use. Patients were enrolled from June 2016 to February 2018; the last follow-up was in May 2019. Interventions: Baclofen (n = 159), adjusted from 50 to 150 mg per day based on estimated glomerular filtration rate, or placebo (n = 155) during mechanical ventilation up to a maximum of 15 days before gradual dose reduction over 3 to 6 days. Main Outcomes and Measures: The primary end point was the percentage of patients with at least 1 agitation-related event over the treatment period. Secondary outcomes included duration of mechanical ventilation, length of ICU stay, and 28-day mortality. Results: Among 314 patients who were randomized (mean age, 57 years; 60 [17.2%] women), 313 (99.7%) completed the trial. There was a statistically significant decrease in the percentage of patients who experienced at least 1 agitation-related event in the baclofen group vs the placebo group (31 [19.7%] vs 46 [29.7%]; difference, -9.93% [95% CI, -19.45% to -0.42%]; adjusted odds ratio, 0.59 [95% CI, 0.35-0.99]). Of 18 prespecified secondary end points, 14 were not significantly different. Compared with the placebo group, the baclofen group had a significantly longer median length of mechanical ventilation (9 vs 8 days; difference, 2.00 [95% CI, 0.00-3.00]; hazard ratio [HR] for extubation, 0.76 [95% CI, 0.60-0.97]) and stay in the ICU (14 vs 11 days; difference, 2.00 [95% CI, 0.00-4.00]; HR for discharge, 0.70 [95% CI, 0.54-0.90]). At 28 days, there was no significant difference in mortality in the baclofen vs placebo group (25.3% vs 21.6%; adjusted odds ratio, 1.24 [95% CI, 0.72-2.13]). Delayed awakening (no eye opening at 72 hours after cessation of sedatives and analgesics) occurred in 14 patients (8.9%) in the baclofen group vs 3 (1.9%) in the placebo group. Conclusions and Relevance: Among patients with unhealthy alcohol use receiving mechanical ventilation, treatment with high-dose baclofen, compared with placebo, resulted in a statistically significant reduction in agitation-related events. However, considering the modest effect and the totality of findings for the secondary end points and adverse events, further research is needed to determine the possible role of baclofen in this setting and to potentially optimize dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT02723383.

Development and validation of a dosing nomogram for amoxicillin in infective endocarditis.

BACKGROUND: Amoxicillin is the first-line treatment for streptococcal or enterococcal infective endocarditis (IE) with a dose regimen adapted to weight. OBJECTIVES: Covariates influencing pharmacokinetics (PK) of amoxicillin were identified in order to develop a dosing nomogram based on identified covariates for individual adaptation. PATIENTS AND METHODS: Patients treated with amoxicillin administered by continuous infusion for IE were included retrospectively. The population PK analysis was performed using the Pmetrics package for R (NPAG algorithm). Influence of weight, ideal weight, height, BMI, body surface area, glomerular filtration rate adapted to the body surface area and calculated by the CKD-EPI method (mL/min), additional ceftriaxone treatment and serum protein level on amoxicillin PK was tested. A nomogram was then developed to determine the daily dose needed to achieve a steady-state free plasma concentration above 4× MIC, 100% of the time, without exceeding a total plasma concentration of 80 mg/L. RESULTS: A total of 160 patients were included. Population PK analysis was performed on 540 amoxicillin plasma concentrations. A two-compartment model best described amoxicillin PK and the glomerular filtration rate covariate significantly improved the model when included in the calculation of the elimination constant Ke. CONCLUSIONS: This work allowed the development of a dosing nomogram that can help to increase achievement of the PK/pharmacodynamic targets in IE treated with amoxicillin.

Population Pharmacokinetic Study of Cefazolin Dosage Adaptation in Bacteremia and Infective Endocarditis Based on a Nomogram.

Optimal dosing of continuous-infusion cefazolin can be challenging in patients being treated for bacteremia or infective endocarditis. The aim of this work is to describe and analyze the pharmacokinetics of cefazolin in those patients using a population pharmacokinetics modeling approach and to establish a nomogram to determine the optimal daily dose. Population pharmacokinetics were modeled using the Pmetrics package for R. Plasma concentrations were collected retrospectively from patients treated with continuous-infusion cefazolin for bacteremia or infective endocarditis. The influence of multiple parameters, including renal function, total body weight, body mass index, body surface area (BSA), ideal weight, lean body weight, height, and age, was tested. The probabilities of target attainment for selected target concentrations (40, 60, and 80 mg/liter) were calculated. A dosing nomogram was then developed, using the absolute value of the glomerular filtration rate (aGFR), to determine the optimal daily dose required to achieve the target concentrations in at least 90% of patients. In total, 346 cefazolin plasma concentrations from 162 patients were collected. A one-compartment model best described the data set. The only covariate was aGFR, calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and the patient's body surface area, for the rate of elimination. Using the nomogram, achieving a cefazolin concentration target of 40 mg/liter with a success rate of at least 90% and with an aGFR of 30, 60, 90, and 120 ml/min requires a daily dose of 2.6, 4.3, 6.1, and 8.0 g/day, respectively. These results confirm the interest of posology adaptation of cefazolin according to aGFR.

High-Dosage Cefazolin Achieves Sufficient Cerebrospinal Diffusion To Treat an External Ventricular Drainage-Related Staphylococcus aureus Ventriculitis.

A patient received continuous infusion of cefazolin 10 g then 8 g daily for an external ventricular drainage-related methicillin-susceptible Staphylococcus aureus (MSSA) ventriculitis. Median free concentrations in the cerebrospinal fluid were 11.9 and 6.1 mg/liter after 10- and 8-g doses, respectively. Free concentrations in the cerebrospinal fluid were always above the MIC usually displayed by methicillin-susceptible Staphylococcus aureus (MSSA) isolates. These results support the use of high-dose cefazolin to achieve sufficient meningeal concentrations.

High-Dose Ceftriaxone for Bacterial Meningitis and Optimization of Administration Scheme Based on Nomogram.

High dosages of ceftriaxone are used to treat central nervous system (CNS) infections. Dosage adaptation according to the glomerular filtration rate is currently not recommended. Ceftriaxone pharmacokinetics (PK) was investigated by a population approach in patients enrolled in a French multicenter prospective cohort study who received high-dose ceftriaxone for CNS infection as recommended by French guidelines (75 to 100 mg/kg of body weight/day without an upper limit). Only those with suspected bacterial meningitis were included in the PK analysis. A population model was developed using Pmetrics. Based on this model, a dosing nomogram was developed, using the estimated glomerular filtration rate (eGFR) and total body weight as covariates to determine the optimal dosage allowing achievement of targeted plasma trough concentrations. Efficacy and toxicity endpoints were based on previous reports, as follows: total plasma ceftriaxone concentrations of ≥20 mg/liter in >90% of patients for efficacy and ≤100 mg/liter in >90% of patients for toxicity. Based on 153 included patients, a two-compartment model including eGFR and total body weight as covariates was developed. The median value of the unbound fraction was 7.57%, and the median value of the cerebral spinal fluid (CSF)/plasma ratio was 14.39%. A nomogram was developed according to a twice-daily regimen. High-dose ceftriaxone administration schemes, used to treat meningitis, should be adapted to the eGFR and weight, especially to avoid underdosing using current guidelines. (This study has been registered at ClinicalTrials.gov under identifier NCT01745679.).

Tolerability of high-dose ceftriaxone in CNS infections: a prospective multicentre cohort study.

BACKGROUND: Ceftriaxone is widely used to treat community-acquired CNS bacterial infections. French guidelines for meningitis in adults promote 75-100 mg/kg/day ceftriaxone without an upper limit for dosage, yet little is known about the pharmacology and tolerability of such regimens. PATIENTS AND METHODS: A multicentre prospective cohort study was conducted in adult patients to assess the adverse drug reactions (ADRs) of high-dose ceftriaxone (i.e. daily dosage ≥4 g or ≥75 mg/kg) in CNS infections and to analyse their related factors. Drug causality was systematically assessed by an expert committee who reviewed the medical charts of all included patients. RESULTS: A total of 196 patients were enrolled over a 31 month period. Median dosage and duration of ceftriaxone were 96.4 mg/kg/day (7 g/day) and 8 days, respectively. Nineteen ceftriaxone-related ADRs (mainly neurological) occurred in 17 patients (8.7%), with only one case of treatment discontinuation (biliary pseudolithiasis). In univariate analysis, older age, male gender, renal impairment and high trough ceftriaxone plasma concentration were associated with ceftriaxone-related ADRs. CONCLUSIONS: High-dose ceftriaxone for CNS infection administered as recommended by French guidelines in adults was well tolerated overall, suggesting these recommendations could be applied and generalized. In patients with advanced age or renal insufficiency, prescription should be done with caution and therapeutic drug monitoring could be useful.

Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d'Anesthésie et Réanimation-SFAR).

BACKGROUND: Beta-lactam antibiotics (ßLA) are the most commonly used antibiotics in the intensive care unit (ICU). ICU patients present many pathophysiological features that cause pharmacokinetic (PK) and pharmacodynamic (PD) specificities, leading to the risk of underdosage. The French Society of Pharmacology and Therapeutics (SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (SFAR) have joined forces to provide guidelines on the optimization of beta-lactam treatment in ICU patients. METHODS: A consensus committee of 18 experts from the two societies had the mission of producing these guidelines. The entire process was conducted independently of any industry funding. A list of questions formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes) was drawn-up by the experts. Then, two bibliographic experts analysed the literature published since January 2000 using predefined keywords according to PRISMA recommendations. The quality of the data identified from the literature was assessed using the GRADE® methodology. Due to the lack of powerful studies having used mortality as main judgement criteria, it was decided, before drafting the recommendations, to formulate only "optional" recommendations. RESULTS: After two rounds of rating and one amendment, a strong agreement was reached by the SFPT-SFAR guideline panel for 21 optional recommendations and a recapitulative algorithm for care covering four areas: (i) pharmacokinetic variability, (ii) PK-PD relationship, (iii) administration modalities, and (iv) therapeutic drug monitoring (TDM). The most important recommendations regarding ßLA administration in ICU patients concerned (i) the consideration of the many sources of PK variability in this population; (ii) the definition of free plasma concentration between four and eight times the Minimal Inhibitory Concentration (MIC) of the causative bacteria for 100% of the dosing interval as PK-PD target to maximize bacteriological and clinical responses; (iii) the use of continuous or prolonged administration of ßLA in the most severe patients, in case of high MIC bacteria and in case of lower respiratory tract infection to improve clinical cure; and (iv) the use of TDM to improve PK-PD target achievement. CONCLUSIONS: The experts strongly suggest the use of personalized dosing, continuous or prolonged infusion and therapeutic drug monitoring when administering ßLA in critically ill patients.

Pharmacokinetics of Tedizolid in an Obese Patient after Bariatric Surgery.

An obese woman was treated with oral tedizolid 200 mg once daily for pseudoarthrosis 10 years after Roux-en-Y bypass surgery. Total plasma peak concentration was 2.12 mg/liter 3 h after intake, and area under the concentration-time curve from 0 to 24 h (AUC0-24) was 28.3 mg/liter · h. The AUC0-24/MIC ratio for unbound concentrations and for sensitive Staphylococcus and Streptococcus strains was ≥10.8, higher than the target ratio of 3. These results support the use of tedizolid without adjustment after bariatric surgery.

Comparison Between an Automated and Manual Extraction for the Determination of Immunosuppressive Drugs Whole Blood Concentrations by Liquid Chromatography Tandem Mass Spectrometry.

BACKGROUND: The whole blood extraction for liquid chromatography tandem mass spectrometry (LC-MS/MS) of simultaneous quantification of cyclosporine A (Cys A), tacrolimus (Tacrs), sirolimus (Siros), and everolimus (Evers) is still performed manually in many laboratories. The analytical results obtained with an automated method using a liquid handler versus a classical manual preparation were compared. METHODS: Cys A (n = 36), Tacrs (n = 50), Siros (n = 34), Evers (n = 38) whole blood samples of patients were analyzed by LC-MS/MS assay after manual preparation and automated process using a liquid handling platform including a centrifugation step. RESULTS: The comparison between manual and automated extraction investigated by a linear regression showed a high correlation between results [(Tacrs "automated") = 1.0927 × (Tacrs "manual") - 0.36; (Cys A "automated") = 1.0284 × (Cys A "manual") + 0.0312; (Siros "automated") = 0.9923 × (Siros "manual") + 0.4001; (Evers "automated") = 1.0000 × (Evers "manual") - 0.0600]. CONCLUSION: The results obtained by the automated and manual preparation are consistent. The automated method is applied for high-throughput therapeutic drug monitoring of immunosuppressive drugs in routine practice, leading to an increase in quality.

Influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1.

OBJECTIVES: The metabolic pathways of dolutegravir and nevirapine suggest a potential pharmacokinetic interaction between these drugs. The objective of this study was to investigate the influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1. PATIENTS AND METHODS: This study was an investigator-initiated trial registered at ClinicalTrials.gov under identifier NCT02067767. Dolutegravir (50 mg once daily) was added to the antiretroviral regimen (400 mg of nevirapine once daily + 600/300 mg of abacavir/lamivudine once daily) in 10 adult patients for 5 days. After discontinuation of nevirapine, the combination of dolutegravir + abacavir/lamivudine was continued. Full pharmacokinetic profiles were assessed on the day of nevirapine discontinuation and 2 weeks after discontinuation of nevirapine. The pharmacokinetic parameters of dolutegravir were calculated by non-compartmental analysis. The log-transformed values of these parameters were compared between periods with and without nevirapine co-administration. RESULTS: The co-administration of nevirapine led to a significant decrease (P < 0.05) in the area under the plasma concentration-time curve for dolutegravir from the time the dose was administered until the end of the dosing interval (-19%, P = 0.011), as well as decreases in trough plasma concentration (-34%, P = 0.018) and terminal half-life (-15%, P = 0.039), and a significant increase (P < 0.05) in apparent oral clearance for dolutegravir (+23%, P = 0.011). CONCLUSIONS: The decrease in dolutegravir exposure in combination with nevirapine suggests that the metabolism of dolutegravir is induced by nevirapine. According to therapeutic drug monitoring for dolutegravir, some patients may need a higher dose than 50 mg of dolutegravir once daily to maintain the therapeutic plasma concentration throughout the dosing interval.

Efficacy of an inulin-based treatment on intestinal colonization by multidrug-resistant E. coli: insight into the mechanism of action.

Inulin, an increasingly studied dietary fiber, alters intestinal microbiota. The aim of this study was to assess whether inulin decreases intestinal colonization by multidrug resistant E. coli and to investigate its potential mechanisms of action. Mice with amoxicillin-induced intestinal dysbiosis mice were inoculated with extended spectrum beta-lactamase producing E. coli (ESBL-E. coli). The combination of inulin and pantoprazole (IP) significantly reduced ESBL-E. coli fecal titers, whereas pantoprazole alone did not and inulin had a delayed and limited effect. Fecal microbiome was assessed using shotgun metagenomic sequencing and qPCR. The efficacy of IP was predicted by increased abundance of 74 taxa, including two species of Adlercreutzia. Preventive treatments with A. caecimuris or A. muris also reduced ESBL-E. coli fecal titers. Fecal microbiota of mice effectively treated by IP was enriched in genes involved in inulin catabolism, production of propionate and expression of beta-lactamases. They also had increased beta-lactamase activity and decreased amoxicillin concentration. These results suggest that IP act through production of propionate and degradation of amoxicillin by the microbiota. The combination of pantoprazole and inulin is a potential treatment of intestinal colonization by multidrug-resistant E. coli. The ability of prebiotics to promote propionate and/or beta-lactamase producing bacteria may be used as a screening tool to identify potential treatments of intestinal colonization by multidrug resistant Enterobacterales.

Evaluation of the QMS® Teicoplanin Immunoassay (ThermoFisher Scientific) on Cobas® 8000 System (Roche Diagnostics) and comparison to fluorescence polarization immunoassay for the determination of teicoplanin concentrations in human plasma.

BACKGROUND: The performances of the QMS(®) Teicoplanin immunoassay recently developed on Cobas(®) 6000/8000 systems were evaluated and compared to a fluorescence polarization immunoassay (FPIA) [Teicoplanin Innofluor(®) Assay (Thermo Fisher Scientific, Indianapolis, IN)] on FLX analyzer (Abbott Laboratories, Abbott Park, IL)]. METHODS: The validation was performed according to the Cofrac (French Accreditation Committee) document SH GTA 04. For the comparison, 48 plasma samples were analyzed by FPIA and QMS assays. RESULTS: The QMS assay is accurate (intra assay and inter assay inaccuracy ≤ 2.4%) and precise (intra assay and inter assay imprecision ≤ 10.2%). A linear relationship [QMS = 1.0319 × FPIA - 2.8518, r(2) = 0.9246 (P < 0.001)] between FPIA and QMS was found. In the Bland-Altman plots, no systematic bias was found even if QMS results trends to be lower (mean of the ratio QMS concentration/FPIA concentration = 0.91). CONCLUSION: These results between QMS and FPIA are consistent, which indicates that QMS(®) Teicoplanin immunoassay on Cobas(®) 8000 System is an alternative to FPIA.

Development of a Predictive Dosing Nomogram to Achieve PK/PD Targets of Amikacin Initial Dose in Critically Ill Patients: A Non-Parametric Approach.

French guidelines recommend reaching an amikacin concentration of ≥8 × MIC 1 h after beginning infusion (C1h), with MIC = 8 mg/L for probabilistic therapy. We aimed to elaborate a nomogram guiding clinicians in choosing the right first amikacin dose for ICU patients in septic shock. A total of 138 patients with 407 observations were prospectively recruited. A population pharmacokinetic model was built using a non-parametric, non-linear mixed-effects approach. The total body weight (TBW) influenced the central compartment volume, and the glomerular filtration rate (according to the CKD-EPI formula) influenced its clearance. A dosing nomogram was produced using Monte Carlo simulations of the amikacin amount needed to achieve a C1h ≥ 8 × MIC. The dosing nomogram recommended amikacin doses from 1700 mg to 4200 mg and from 28 mg/kg to 49 mg/kg depending on the patient's TBW and renal clearance. However, a Cthrough ≤ 2.5 mg/L 24 h and 48 h after an optimal dose of amikacin was obtained with probabilities of 0.20 and 0.81, respectively. Doses ≥ 30 mg/kg are required to achieve a C1h ≥ 8 × MIC with MIC = 8 mg/L. Targeting a MIC = 8 mg/L should depend on local ecology.