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.).

Fungal Prophylaxis with a Gastro-Resistant Posaconazole Tablet for Patients with Hematological Malignancies in the POSANANTES Study.

Posaconazole is an antifungal drug used in both prophylaxis and treatment of invasive fungal infections. Its oral formulation requires therapeutic drug monitoring. To overcome gastric acidity, a gastro-resistant posaconazole tablet has recently been developed. POSANANTES was a prospective noninterventional study that aimed to monitor plasma concentration trough level (Cmin) of posaconazole tablets used prophylactically in patients with hematological malignancies. Fifty patients were included. Group A (n = 31) included patients receiving induction chemotherapy for myeloid malignancies, and group B (n = 19) included patients treated for graft-versus-host disease after allogeneic hematopoietic stem cells transplantation. In multivariate analysis, female sex, group B assignment, and evaluation of Cmin at day 8 (versus any other day planned by the analysis) were associated with a higher Cmin, while diarrhea was associated with a lower Cmin (P < 0.05). Thirty-four percent (n = 17) of all included patients had to prematurely stop treatment, mainly in group A. In conclusion, this real-life prospective study showed good absorption of posaconazole tablets used for prophylaxis in patients with hematological malignancies, even though this strategy was somewhat limited due to the high number of patients in group A who had to stop their treatment in an untimely fashion.

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.

Pharmacokinetics of linezolid treatment using intravenous and oral administrations in extremely premature infants.

INTRODUCTION: Vancomycin is the usual antibiotic treatment in coagulase-negative staphylococcus sepsis in premature infants but causes renal toxicity. As linezolid is effective in Gram-positive cocci infection, and devoid of renal side-effects, it has been used in Nantes neonatal intensive care units and linezolid plasma concentrations were monitored. AIM: The aims of this study are to report data on linezolid concentrations in premature infants, describe clinical and bacteriological evolution during treatment, and determine potential side effects. METHODS: A retrospective observational study of premature infants treated with linezolid in Nantes Hospital from January 2008 through November 2011 was conducted. Linezolid plasma concentrations, possible side effects due to linezolid, and clinical response to linezolid treatment were collected from folder review. RESULTS: Twenty-four linezolid plasma concentrations were monitored in 16 premature patients, at steady state for continuous intravenous administration or 7 ± 1.5 h after last oral administration. Except for one case, linezolid plasma concentrations were ≥minimal inhibition concentration (MIC) for linezolid for both parenteral and oral administrations. We observed three cases of thrombocytopenia, two of leukopenia, three of neutropenia, and one of severe hyperlactacidemia, resolving after discontinuation of treatment. Clinical signs of infection resolved in 13/16 cases. Bacteria were coagulase-negative Staphylococci in 12/16 cases and were eradicated in 9/12 evaluable cases. CONCLUSIONS: This study reports an adequate linezolid plasma concentration with regard to the linezolid MIC in extremely premature infants. However, considering adverse events reported, its use should be cautious and may concern only oral administration during the late phase of infection, to limit paradoxical catheter use to treat nosocomial infections. Moreover, safe and efficient anti-Staphylococcus therapies should be identified to treat this vulnerable population.

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.

[Level of evidence for therapeutic drug monitoring of ceftriaxone]. / Niveau de preuve du suivi thérapeutique pharmacologique de la ceftriaxone.

Ceftriaxone is a third generation cephalosporin with an original pharmacokinetics based on a long elimination half-life among cephalosporins, a high protein binding and a dual renal and biliary elimination. Also the pharmacokinetic parameters of ceftriaxone are highly variable in clinical situations such as severe renal insufficiency, liver and renal insufficiency, the elderly, the neonates less than 1 week of age and critically ill patients. In these clinical situations associated or not with high minimal inhibitory concentration (MIC) level, the relationship concentration-clinical outcome based on the ratio between trough plasma concentration and MIC can allow a dose adjustment. Consequently, therapeutic drug monitoring (TDM) of ceftriaxone could be possibly useful in these situations, whereas the necessity of TDM has still to be demonstrated to monitor toxicity.

Impact of Inflammation on Midazolam Metabolism in Severe COVID-19 Patients.

Midazolam is a benzodiazepine frequently used for sedation in patients hospitalized in the intensive care unit (ICU) for coronavirus disease 2019 (COVID-19). This drug is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes. Several studies have suggested that inflammation, frequently observed in these patients, could modulate CYP3A activity. The objective of this work was to study the impact of inflammation on midazolam pharmacokinetics in patients with COVID-19. Forty-eight patients hospitalized in the ICU for COVID-19 and treated with midazolam administered by continuous infusion were included in this study. Midazolam and α-hydroxymidazolam concentrations were measured and patient data, including the use of CYP3A inhibitors, were collected. Total and unbound concentrations of midazolam and α-hydroxymidazolam were measured in plasma using a validated liquid-chromatography coupled with mass spectrometry method. Inflammatory condition was evaluated by C-reactive protein (CRP) level measurement. Both drug concentrations and CRP measurements were performed on 354 plasma samples. CRP elevation was significantly associated with the α-hydroxymidazolam/midazolam plasma ratio decrease, whether for the unbound fraction or for the total fraction. Conversely, inflammation was not associated with protein binding modifications. Logically, α-hydroxymidazolam/midazolam plasma ratio was significantly reduced when patients were treated with CYP3A inhibitors. In this study, we showed that inflammation probably reduces the metabolism of midazolam by CYP3A. These results suggest that molecules with narrow therapeutic margins and metabolized by CYP3A should be administrated with care in case of massive inflammatory situations.

Colchicine-induced rhabdomyolysis in a heart/lung transplant patient with concurrent use of cyclosporin, pravastatin, and azithromycin.

We report a case of colchicine-induced rhabdomyolysis in a heart/lung-transplanted man treated with cyclosporin. A treatment was to resolve an acute gouty arthritis and was started with 3 mg of colchicine the first day, then 2 mg the second and the third day, and finally 1 mg/d during 6 days. Eight days later, the patient developed multiple organ failure and rhabdomyolysis. The concentration of colchicine analyzed was greater than the standard 153 hours after his last intake. Pharmacokinetic interactions are responsible of this toxicity. Cyclosporin, pravastatin, and azithromycin are known to inhibit P-glycoprotein, which will enhance the intracellular colchicine level by acting in its bioavailability and moderating hepatic and renal excretion. Moreover, long-term treatment by cyclosporin generates chronic renal failure that will, in the same time, decrease colchicine elimination. Even short-term administration of therapeutic colchicine dose may cause colchicine-related toxicity, especially in the setting of a renal failure and/or polymedicinal treatment.

Cannabis intoxication after accidental ingestion in infants: urine and plasma concentrations of Δ-9-tetrahydrocannabinol (THC), THC-COOH and 11-OH-THC in 10 patients.

Introduction: Accidental cannabis poisoning after oral ingestion in infants is an emerging cause of intoxication with well-known clinical aspects but few data exist regarding the levels of cannabinoids in plasma and urine. Here, we present data on the concentrations of Δ-9-tetrahydrocannabinol (THC) and metabolites in plasma and/or urine in 10 infants after cannabis intoxication.Materials and methods: Cannabinoids were detected using an automated immunochemical method and quantified using liquid chromatography coupled with mass spectrometry.Results: Ten infants were admitted after cannabis poisoning. THC, THC-COOH and 11-OH-THC plasma levels ranged from 4.4 to 127 ng/mL, from 28 to 433 ng/mL and from 2 to 59.8 ng/mL, respectively. THC-COOH urine levels ranged from 748 to 5689 ng/mL. The most common symptoms were drowsiness, hypotonia, behavioural disorder and tachycardia.Discussion: No correlation between plasma concentrations and symptoms could be found, but the concentration of THC-COOH in the two patients who experienced seizures was higher than 3000 ng/mL. This series of cases of accidental intoxication in infants showed high THC and metabolites concentrations in urine and plasma.

Simultaneous determination of eight ß-lactam antibiotics in human plasma and cerebrospinal fluid by liquid chromatography coupled to tandem mass spectrometry.

Therapeutic drug monitoring of ß-lactam antibiotics is increasingly used for dose optimization in the individual patient to increase efficacy and reduce the risk of toxicity. The objective of this work is to develop and validate a fast and reliable method using liquid chromatography coupled to tandem mass spectrometric detection to quantify simultaneously amoxicillin, cloxacillin, cefazolin, cefotaxime, ceftazidime, cefepime, meropenem and piperacillin in plasma and cerebrospinal fluid (CSF). Sample clean-up included protein precipitation with acetonitrile followed by evaporation of the supernatant and reconstitution of the residue with mobile phase solvents. Eight deuterated ß-lactam antibiotics were used as internal standards. Chromatographic separation was performed on a C18 column (50 mm x 2.1 mm) using a binary gradient elution of water and acetonitrile both containing 0.1% (v/v) formic acid. The total run time was 8 min. The method was then used to perform therapeutic drug monitoring on 2221 patient plasma samples. 32 CSF samples were also analyzed. This method, with its simple sample preparation provides sensitive, accurate and precise quantification of the plasma and cerebrospinal fluid concentration of ß-lactam antibiotics and can be used for therapeutic drug monitoring.

Pharmacokinetics and toxicity of high-dose baclofen in ICU patients.

BACKGROUND: High-dose baclofen could prove beneficial in patients with unhealthy alcohol use in intensive care units (ICU). However, the pharmacokinetic properties of baclofen are unknown in this population. Our objectives were to investigate the pharmacokinetics of baclofen and the relationship between baclofen exposure and its toxicity in the ICU. MATERIALS AND METHODS: As part of a healthcare quality improvement project, we conducted a prospective, single-center study in a surgical intensive care unit at Nantes University Hospital in order to assess our local protocol of sedation in patients with consumption of alcohol above the recommended limits by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Baclofen pharmacokinetics were investigated by a non-compartment analysis and a population approach in 20 patients under mechanical ventilation. After a baclofen loading dose on day 1, daily doses were divided into 3 intakes adapted to glomerular filtration rate (GFR) and blood samples were withdrawn on day 3 for pharmacokinetic analysis. Baclofen was administered until extubation or tracheostomy and agitation-related events as well as the potential side effects of baclofen were noted. RESULTS: In this population, pharmacokinetic parameters [absorption latency time = 0.37 h, absorption constant rate = 2.2 h-1, apparent volume of distribution = 105 L, apparent clearance (l/h) = 13.5 × (GFR/103)0.839] were characterized by modified absorption and the influence of renal function: renal failure significantly increased baclofen exposure (p = .007) and significantly decreased baclofen clearance (p = .007) compared with patients without renal failure. When comparing patients with or without possible signs of baclofen toxicity, no difference was found regarding baclofen exposure (p = .34) and plasma peak concentration (p = .26). CONCLUSIONS: The a priori planned algorithm for dose adaptation according to renal clearance appeared to be suitable in our population. Daily administration of 150 mg of baclofen in ICU patients with preserved renal function did not lead to toxic concentrations in the plasma. A dose reduction of approximately 40%, 60% and 70% in patients with mild, moderate and severe renal failure could be suggested.

Pharmacokinetic data on high dose baclofen administration in unhealthy alcohol user in the ICU.

In the intensive care unit, alcohol intake above the NIAAA recommendations regardless of the existence of an Alcohol Use Disorder (AUD), was associated with an increased risk of death and longer time on ventilator. This rises the hypothesis that unhealthy alcohol use may lead to specific issues when weaning the mechanical ventilation (i.e. agitation or its related complications) regardless of AUD or withdrawal syndrome. Thus, we proposed to use baclofen off-label to avoid agitation. The data presented in this article is related to the research article entitled: "Pharmacokinetics and toxicity of high-dose baclofen in ICU patients" Vourc'h et al., 2019 Data provided in this submission includes 1) the detailed methods for baclofen assay by mass spectrometric detection, 2) the supplementary population pharmacokinetic analysis presenting observed concentration vs. population or individual predicted concentration (raw data of the latter is also available), and 3) the algorithm for the adaptation of baclofen daily doses according of the renal clearance to assess the risk of toxicity in critically ill patients.

Influence of glomerular filtration rate on the clearance of vancomycin administered by continuous infusion in burn patients.

The relationship between clearance of vancomycin administered by continuous infusion and the glomerular filtration rate (GFR) estimated by creatinine clearance (CL(Cr)) was investigated in a large cohort of burn patients. Individual vancomycin clearance (CL(Van)) was estimated from the ratio between the rate of infusion and the plasma concentration at steady state for 70 patients (149 samples). The average value of CL(Van) (7.03+/-3.79 L/h) was higher than normal values in non-burn patients. A significant relationship between CL(Van) versus CL(Cr) was found (r=0.506; P<0.001): CL(Van) (L/h)=0.0205CL(Cr)(mL/min)+3.47. From this result, a simple formula is proposed to adapt vancomycin dosage: rate of vancomycin continuous infusion (g/day)=[0.0205CL(Cr) (mL/min)+3.47] x [target vancomycin concentration at steady state (mg/L)] x (24/1000). The limits of the predictive performance of this formula are discussed, since factors other than GFR can affect vancomycin elimination. This formula could help clinicians to define the optimum vancomycin dosage, particularly in patients with disturbed renal function.