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AIMS: Dolutegravir (DTG) and rilpivirine (RPV) dual therapy is now recommended as a switch option in virologically suppressed HIV patients. Literature suggests that virological failure with dual therapy could possibly relate to subtherapeutic drug concentrations. In this study, we aimed at describing the DTG and RPV trough plasma concentrations (Cmin) and plasma HIV-1 RNA viral load (VL) during maintenance dual therapy. METHODS: We performed a retrospective analysis of DTG and RPV therapeutic drug monitoring in people living with HIV/AIDS (PLWHA) with dual therapy in 9 French centres. DTG and RPV trough plasma concentrations were estimated using a Bayesian approach to predict Cmin. The relationship between the pharmacokinetics of DTG and RPV and VL > 50 copies (cp)/mL was explored using joint nonlinear mixed models. The frequency of subtherapeutic threshold (DTG Cmin below 640 ng/mL and RPV Cmin below 50 ng/mL) were compared between PLWHA presenting VL > 50 cp/mL or not during the study. RESULTS: At baseline, 209 PLWHA were enrolled in the study. At week 48, 19 people living with HIV/AIDS (9.1%) discontinued their treatment and 15 PLWHA (7.1%) exhibited VL > 50 cp/mL. Six PLWHA out of 15 (40.0%) with VL > 50 cp/mL during the follow-up had at least 1 Cmin below the respective thresholds while only 26/194 patients (13.4%) without virological replication had at least 1 concentration below the threshold (P = .015). CONCLUSION: A majority of PLWHA receiving DTG/RPV maintenance dual therapy demonstrated VL < 50 cp/mL but virological replication was more frequent in people living with HIV/AIDS with subtherapeutic Cmin.
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Síndrome de Inmunodeficiencia Adquirida , Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Fármacos Anti-VIH/uso terapéutico , Estudios Retrospectivos , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Teorema de Bayes , Monitoreo de Drogas , Rilpivirina/uso terapéutico , Oxazinas , Piridonas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Carga ViralRESUMEN
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.
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Endocarditis Bacteriana , Endocarditis , Humanos , Cloxacilina/uso terapéutico , Antibacterianos/uso terapéutico , Nomogramas , Endocarditis Bacteriana/tratamiento farmacológico , Endocarditis/tratamiento farmacológicoRESUMEN
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 (Pâ<â0.0001). 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, Pâ=â0.08). Treatment failures were observed in 22 (37.9%) patients before and 36 (25.7%) patients after the intervention (Pâ=â0.07). 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.
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Antiinfecciosos , Infección Hospitalaria , Adulto , Humanos , Antibacterianos , Mejoramiento de la Calidad , Antiinfecciosos/uso terapéutico , Infección Hospitalaria/tratamiento farmacológico , beta-Lactamas/farmacocinética , HospitalesRESUMEN
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 1500â 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 8â weeks after the last 1500â mg dose. Concentrations in patients weighing more or less than 75â kg and with a GFR greater or less than 60â 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 4â weeks after the last dose, median plasma concentrations were respectively 25.00, 14.80 and 9.24â mg/L for the first doses and 34.55, 22.60 and 19.20â 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: 0.047â mg/L) and Staphylococcus epidermidis in 27% of cases (median MIC of 0.047â 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.
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Antibacterianos , Infecciones Estafilocócicas , Humanos , Teicoplanina/farmacocinética , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureusRESUMEN
Echinocandins are noncompetitive inhibitors of the GSC1 subunit of the enzymatic complex involved in synthesis of 1,3-beta-d-glucan, a cell wall component of most fungi, including Pneumocystis spp. Echinocandins are widely used for treating systemic candidiasis and rarely used for treating Pneumocystis pneumonia. Consequently, data on P. jirovecii gsc1 gene diversity are still scarce compared to that for the homologous fks1 gene of Candida spp. In this study, we analyzed P. jirovecii gsc1 gene diversity and the putative selection pressure of echinocandins on P. jirovecii. gsc1 gene sequences of P. jirovecii specimens from two patient groups were compared. One group of 27 patients had prior exposure to echinocandins, whereas the second group of 24 patients did not, at the time of P. jirovecii infection diagnoses. Two portions of the P. jirovecii gsc1 gene, HS1 and HS2, homologous to hot spots described in Candida spp., were sequenced. Three single-nucleotide polymorphisms (SNPs) at positions 2204, 2243, and 2303 close to the HS1 region and another SNP at position 4540 more distant from the HS2 region were identified. These SNPs represent synonymous mutations. Three gsc1 HS1 alleles, A, B, and C, and two gsc1 HS2 alleles, a and b, and four haplotypes, Ca, Cb, Aa, and Ba, were defined, without significant difference in haplotype distribution in both patient groups (P = 0.57). Considering the identical diversity of P. jirovecii gsc1 gene and the detection of synonymous mutations in both patient groups, no selection pressure of echinocandins among P. jirovecii microorganisms can be pointed out so far.
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Pneumocystis carinii , Pneumocystis , Neumonía por Pneumocystis , Pared Celular , Equinocandinas/farmacología , Equinocandinas/uso terapéutico , Humanos , Pneumocystis carinii/genética , Neumonía por Pneumocystis/tratamiento farmacológico , Neumonía por Pneumocystis/microbiologíaRESUMEN
Smoking cessation is underestimated in terms of drug interactions. Abrupt smoking cessation is common in cases of emergency hospitalization and restrictions of movement. Tobacco is a known cytochrome P450 1A2 (CYP1A2) inducer, its consumption and withdrawal can lead to major pharmacokinetic drug interactions. Nevertheless, references do exist, but may have different results between them. The objective of our work was to establish the broadest and most consensual list as possible of CYP1A2 substrates treatments and propose a pharmacological approach. We searched the widest possible list of CYP1A2 substrates based on various international references. We compared the references and defined probability and reliability scores of our results to sort the substances based on the scores. For the 245 substances identified as CYP1A2 substrates, we focused on the 63 CYP1A2 substrates with both probability and reliability scores >50%. Our work establishes adaptive pharmacological approaches for the management of patients initiating smoking cessation which must be integrated into the management of smoking cessation. Pharmacologists can now adopt adaptive pharmacological approaches to complement patient-specific clinical information about smoking cessation by considering pharmacokinetic risk. This work establishes an unprecedented list. It should guide in the care of patients initiating smoking cessation to prevent pharmacokinetic drug interactions.
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Citocromo P-450 CYP1A2 , Cese del Hábito de Fumar , Citocromo P-450 CYP1A2/farmacología , Interacciones Farmacológicas , Humanos , Reproducibilidad de los Resultados , Cese del Hábito de Fumar/métodos , NicotianaRESUMEN
BACKGROUND AND OBJECTIVES: Pneumococcal meningitis is a devastating disease that requires adequate meningeal antibiotic penetration to limit the mortality. Despite a large usage in this indication, data about CSF concentration of cefotaxime during pneumococcal meningitis in adults are scarce. Therefore, we aimed to describe the CSF concentration obtained after high-dose cefotaxime administration in adult patients treated for Streptococcus pneumoniae meningitis. PATIENTS AND METHODS: In this multicentre, observational, retrospective study, cases of adult patients with S. pneumoniae meningitis hospitalized between January 2013 and October 2019 for whom cefotaxime concentration was measured in CSF were reviewed. RESULTS: Cefotaxime concentration was analysed in 44 CSF samples collected among 31 patients. Median (IQR) age was 61 years (52-69). Dexamethasone was administered in 27 subjects. Median (IQR) cefotaxime daily dosage was 15 g (12-19), corresponding to 200 mg/kg (150-280). CSF samples were collected approximately 5 days after cefotaxime initiation. Median (IQR, range) cefotaxime CSF concentration was 10.3 mg/L (4.8-19.3, 1.2-43.4). Median (range) MIC for Streptococcus pneumoniae was 0.25 mg/L (0.008-1) (n = 22). The median (IQR, range) CSF/MIC ratio was 38 (12-146, 4-1844). Twenty-five CSF concentrations (81%) were above 10 times the MIC. Cefotaxime was discontinued in two patients for toxicity. In-hospital mortality rate was 29%. CONCLUSIONS: Adult patients with pneumococcal meningitis treated with a high dose of cefotaxime (200 mg/kg/day) had elevated CSF concentrations with satisfying pharmacokinetics/pharmacodynamics parameters and tolerability profile. This study brings reassuring pharmacological data regarding the use of high-dose cefotaxime monotherapy for treating pneumococcal meningitis with susceptible strains to cefotaxime.
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Meningitis Neumocócica , Adulto , Anciano , Antibacterianos/uso terapéutico , Cefotaxima , Humanos , Meningitis Neumocócica/tratamiento farmacológico , Persona de Mediana Edad , Estudios Retrospectivos , Streptococcus pneumoniaeRESUMEN
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.
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Amoxicilina , Endocarditis , Antibacterianos/uso terapéutico , Endocarditis/tratamiento farmacológico , Humanos , Nomogramas , Estudios RetrospectivosRESUMEN
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.
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Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Bacteriemia/tratamiento farmacológico , Cefazolina/administración & dosificación , Cefazolina/farmacocinética , Endocarditis Bacteriana/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Endocarditis/tratamiento farmacológico , Endocarditis Bacteriana/microbiología , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , NomogramasRESUMEN
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.
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Cefazolina/uso terapéutico , Ventriculitis Cerebral/tratamiento farmacológico , Staphylococcus aureus/patogenicidad , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Cefazolina/administración & dosificación , Ventriculitis Cerebral/microbiología , Humanos , Meningitis/tratamiento farmacológico , Meningitis/microbiología , Pruebas de Sensibilidad Microbiana , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacosRESUMEN
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.).
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Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Ceftriaxona/administración & dosificación , Ceftriaxona/farmacocinética , Meningitis Bacterianas/tratamiento farmacológico , Nomogramas , Antibacterianos/uso terapéutico , Peso Corporal , Ceftriaxona/uso terapéutico , Estudios de Cohortes , Infección Hospitalaria/tratamiento farmacológico , Esquema de Medicación , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana Edad , Método de Montecarlo , Estudios Prospectivos , Resultado del TratamientoRESUMEN
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.
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Antibacterianos/administración & dosificación , Ceftriaxona/administración & dosificación , Infecciones del Sistema Nervioso Central/tratamiento farmacológico , Infecciones del Sistema Nervioso Central/microbiología , Farmacorresistencia Bacteriana , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/farmacocinética , Ceftriaxona/farmacocinética , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
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.
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Cirugía Bariátrica , Obesidad/tratamiento farmacológico , Oxazolidinonas/farmacocinética , Tetrazoles/farmacocinética , Anciano , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Femenino , Humanos , Pruebas de Sensibilidad Microbiana , Obesidad/metabolismo , Oxazolidinonas/farmacología , Staphylococcus/efectos de los fármacos , Streptococcus/efectos de los fármacos , Tetrazoles/farmacologíaRESUMEN
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.
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Cromatografía Liquida/métodos , Monitoreo de Drogas/métodos , Procesamiento Automatizado de Datos/métodos , Inmunosupresores/sangre , Espectrometría de Masas en Tándem/métodos , Femenino , Humanos , Modelos Lineales , MasculinoAsunto(s)
Betacoronavirus , Infecciones por Coronavirus/sangre , Lopinavir/sangre , Neumonía Viral/sangre , Ritonavir/sangre , Anciano , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/sangre , Quimioterapia Combinada , Femenino , Humanos , Lopinavir/administración & dosificación , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/tratamiento farmacológico , Ritonavir/administración & dosificación , SARS-CoV-2RESUMEN
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 dailyâ+â600/300 mg of abacavir/lamivudine once daily) in 10 adult patients for 5 days. After discontinuation of nevirapine, the combination of dolutegravirâ+âabacavir/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 (Pâ<â0.05) 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%, Pâ=â0.011), as well as decreases in trough plasma concentration (-34%, Pâ=â0.018) and terminal half-life (-15%, Pâ=â0.039), and a significant increase (Pâ<â0.05) in apparent oral clearance for dolutegravir (+23%, Pâ=â0.011). 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.
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Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Nevirapina/administración & dosificación , Adulto , Anciano , Interacciones Farmacológicas , Femenino , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Oxazinas , Piperazinas , Estudios Prospectivos , PiridonasAsunto(s)
Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Infecciones Bacterianas/tratamiento farmacológico , Ceftriaxona/administración & dosificación , Ceftriaxona/farmacocinética , Antibacterianos/líquido cefalorraquídeo , Infecciones Bacterianas/epidemiología , Infecciones Bacterianas/microbiología , Ceftriaxona/líquido cefalorraquídeo , Estudios de Cohortes , Monitoreo de Drogas , Francia/epidemiología , Humanos , Resultado del TratamientoRESUMEN
OBJECTIVES: To identify the current practices with long half-life lipoglycopeptides (LGPs) and potential use/position of oritavancin. RESULTS: Despite their indication being limited to skin and soft tissue infections (SSTIs), long half-life lipoglycopeptides are mainly used off-label to treat bone and joint infections (BJIs) and infective endocarditis. Oritavancin and dalbavancin are both semisynthetic lipoglycopeptide antibiotics with activity against Gram-positive organisms. The game-changing property of these two antibiotics is their one-time dosing. Due to its shorter half-life, oritavancin might have an advantage over dalbavancin for a treatment duration of less than 2 weeks, as it could be used both in prolonged treatments of complicated patients in BJIs or administered as a single-dose treatment for Gram-positive cocci infections usually treated by a 5- to 10-day antibiotic course. These infections include urinary tract infections, bacteremias, catheter-related infections, etc. In addition to the possibility of being used as an end-of-treatment injection, oritavancin could be used as an empiric therapy treatment in the postoperative period in the context of device-associated especially prosthetic joint infections to allow for the early discharge of the patient. METHODS: A qualitative survey was conducted in March 2022 including sixteen infectiologists, one internist, five hospital pharmacists, and one pharmacologist. CONCLUSION: Long half-life lipoglycopeptides contribute to changing the paradigm in the management of acute bacterial infections, as infectiologists now consider a range of indications and patient profiles for one single drug. Oritavancin strengthens the therapeutic arsenal in numerous infections from BJIs to urinary tract infections and could help to manage specific clinical situations, on top of providing potential benefits for the hospital's budget.