RESUMEN
OBJECTIVES: Staphylococcal infective endocarditis (IE) remains a hard-to-treat infection with high mortality. Both the evaluation of new innovative therapies and research on alternative models mimicking human IE are therefore urgently needed to improve the prognosis of patients with diagnosed IE. Dalbavancin is a novel anti-staphylococcal lipoglycopeptide but there are limited data supporting its efficacy on biofilm infections. This antibiotic could be an alternative to current therapies for the medical treatment of IE but it needs to be further evaluated. METHODS: Here we developed an original ex vivo model of Staphylococcus aureus IE on human heart valves and assessed biofilm formation on them. After validating the model, the efficacy of two antistaphylococcal antibiotics, vancomycin and dalbavancin, was compared by measuring and visualizing their respective ability to inhibit and eradicate late-formed biofilm. RESULTS: Determination of the minimum biofilm inhibitory (MbIC) and eradicating (MbEC) concentrations in our ex vivo model identified dalbavancin as a promising drug with much lower MbIC and MBEC than vancomycin (respectively <0.01 versus 28 mg/L and 0.03 versus 32 mg/L). CONCLUSIONS: These data highlight a strong bactericidal effect of dalbavancin, particularly on an infected heart valve compared with vancomycin. Dalbavancin could be a realistic alternative treatment for the management of staphylococcal IE.
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Endocarditis Bacteriana , Endocarditis , Infecciones Estafilocócicas , Humanos , Vancomicina/farmacología , Vancomicina/uso terapéutico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Endocarditis Bacteriana/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana , Endocarditis/tratamiento farmacológicoRESUMEN
Voriconazole is a triazole antifungal indicated for invasive fungal infections that exhibits a high degree of inter-individual and intra-individual pharmacokinetic variability. Voriconazole pharmacokinetics is non-linear, making dosage adjustments more difficult. Therapeutic drug monitoring is recommended by measurement of minimum plasma concentrations. Several factors are responsible for the high pharmacokinetic variability of voriconazole: age, feeding (which decreases absorption), liver function, genetic polymorphism of the CYP2C19 gene, drug interactions and inflammation. Invasive fungal infections are indeed very frequently associated with inflammation, which engenders a risk of voriconazole overexposure. Many studies have reviewed this topic in both the adult and paediatric populations, but few studies have focused on the specific point of the prediction, to evaluate the influence of inflammation on voriconazole pharmacokinetics. Predicting the impact of inflammation on voriconazole pharmacokinetics could help optimize antifungal therapy and improve patient management. This review summarizes the existing data on the influence of inflammation on voriconazole pharmacokinetics in adult populations. We also evaluate the role of C-reactive protein, the impact of inflammation on patient metabolic phenotypes, and the tools that can be used to predict the effect of inflammation on voriconazole pharmacokinetics.
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Infecciones Fúngicas Invasoras , Voriconazol , Adulto , Niño , Humanos , Antifúngicos/farmacocinética , Inflamación , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Voriconazol/farmacocinéticaRESUMEN
A 53-year-old woman with a history of acute myeloid leukaemia received a second allogeneic haematopoietic stem cell transplant and was prescribed, among other medications, acyclovir and letermovir (480-mg daily oral dose) for prophylaxis of, respectively, herpes simplex and cytomegalovirus infection. The patient was admitted in the intensive care unit for dyspnoea and oliguria. Laboratory investigations revealed acute kidney injury but also a severe and progressive lactic acidosis. Liver function tests were within normal range. The combination of lactic acidosis, hypoglycaemia and acylcarnitine profile in plasma raised the suspicion of mitochondrial toxicity. Letermovir therapy was interrupted, and determination of plasma letermovir pharmacokinetics revealed a prolonged terminal half-life (38.7 h) that was not significantly influenced by continuous venovenous haemofiltration. Exploration for genetic polymorphisms revealed that the patient was SLCO1B1*5/*15 (c.521T>C homozygous carrier and c.388A>G heterozygous carrier) with a predicted nonfunctional organic anion transporting polypeptide 1B1 protein. The relationship between letermovir accumulation and development of lactic acidosis requires further observations.
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Acidosis Láctica , Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Femenino , Humanos , Persona de Mediana Edad , Acidosis Láctica/terapia , Acidosis Láctica/tratamiento farmacológico , Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Acetatos/farmacocinética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Transportador 1 de Anión Orgánico Específico del HígadoRESUMEN
BACKGROUND: After heart transplantation, calcineurin inhibitors (CNI) (cyclosporin A and tacrolimus) are key immunosuppressive drugs to prevent graft rejection. Whole-blood concentration (C blood )-guided therapeutic drug monitoring (TDM) is systematically performed to improve graft outcomes. However, some patients will still experience graft rejection and/or adverse events despite CNI C blood within the therapeutic range. Other pharmacokinetic parameters, such as the intragraft, or intracellular concentration at the CNI site of action could refine their TDM. Nonetheless, these remain to be explored. The objective of the INTRACAR study was to describe the relationship between whole blood, intragraft, and intracellular CNI concentrations as well as their efficacy in heart transplant recipients (HTR). METHODS: In a cohort of HTR, protocol endomyocardial biopsies (EMB) were collected to assess rejection by anatomopathological analysis. Part of the EMB was used to measure the intragraft concentrations of CNI (C EMB ). C blood and the concentration inside peripheral blood mononuclear cells, (C PBMC ), a cellular fraction enriched with lymphocytes, were also monitored. Concentrations in the 3 matrices were compared between patients with and without biopsy-proven acute rejection (BPAR). RESULTS: Thirty-four HTR were included, representing nearly 100 pharmacokinetic (PK) samples for each CNI. C blood , C EMB , and C PBMC correlated for both CNI. BPAR was observed in 74 biopsies (39.6%) from 26 patients (76.5%), all except one was of low grade. None of the PK parameters (C blood , C EMB , C PBMC , C EMB/blood , and C PBMC/blood ) was associated with BPAR. CONCLUSIONS: In this cohort of well-immunosuppressed patients, no association was observed for any of the PK parameters, including C blood , with the occurrence of BPAR. However, a trend was noticed for the C EMB and C EMB/blood of cyclosporin A. Further studies in higher-risk patients may help optimize the use of C EMB and C PBMC for CNI TDM in HTR.
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Inhibidores de la Calcineurina , Trasplante de Corazón , Humanos , Inhibidores de la Calcineurina/uso terapéutico , Ciclosporina/uso terapéutico , Leucocitos Mononucleares , Inmunosupresores/efectos adversos , Rechazo de Injerto/prevención & controlRESUMEN
PURPOSE: Therapeutic drug monitoring of tacrolimus using trough concentration (Cmin) is mandatory to ensure drug efficacy and safety in solid organ transplantation. However, Cmin is just a proxy for the area under the curve of drug concentrations (AUC) which is the best pharmacokinetic parameter for exposure evaluation. Some studies suggest that patients may present discrepancies between these two parameters. AUC is now easily available through mini-invasive microsampling approach. The aim of this study is to evaluate the relationship between AUC and Cmin in patients benefiting from a complete pharmacokinetic profile using a microsampling approach. METHODS: Fifty-one transplant recipients benefited from a complete pharmacokinetic profile using a microsampling approach, and their 24-h AUC were calculated using the trapezoidal method. The correlation with Cmin was then explored. In parallel, we estimated AUC using the sole Cmin and regression equations according to the post-transplantation days and the galenic form. RESULTS: Weak correlations were found between 24-h AUC observed and the corresponding Cmin (R2 = 0.60) and between AUC observed and expected using the sole Cmin (R2 = 0.62). Therapeutic drug monitoring of tacrolimus using Cmin leads to over- or under-estimate drug exposure in 40.3% of patients. CONCLUSION: Tacrolimus Cmin appears to be an imperfect reflection of drug exposure. Evaluating AUC using a microsampling approach offers a mini-invasive strategy to monitor tacrolimus treatment in transplant recipients.
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Trasplante de Órganos , Tacrolimus , Humanos , Tacrolimus/uso terapéutico , Tacrolimus/farmacocinética , Inmunosupresores/farmacocinética , Medicina de Precisión , Receptores de Trasplantes , Monitoreo de Drogas/métodos , Área Bajo la CurvaRESUMEN
BACKGROUND: Voriconazole (VRC), a widely used triazole antifungal, exhibits significant inter- and intra-individual pharmacokinetic variability. The main metabolite voriconazole N-oxide (NOX) can provide information on the patient's drug metabolism capacity. OBJECTIVES: Our objectives were to implement routine measurement of NOX concentrations and to describe the metabolic ratio (MR), and the contribution of the MR to VRC therapeutic drug monitoring (TDM) by proposing a suggested dosage-adjustment algorithm. PATIENTS AND METHODS: Sixty-one patients treated with VRC were prospectively included in the study, and VRC and NOX levels were assayed by LC-MS/MS. A mixed logistic model on repeated measures was implemented to analyse risk factors for the patient's concentration to be outside the therapeutic range. RESULTS: Based on 225 measurements, the median and interquartile range were 2.4 µg/ml (1.2; 4.2), 2.1 µg/ml (1.5; 3.0) and 1.0 (0.6; 1.9) for VRC, NOX and the MR, respectively. VRC Cmin <2 µg/ml were associated with a higher MR during the previous visit. MR values >1.15 and <0.48 were determined to be the best predictors for having a VRC Cmin lower than 2 µg/ml and above 5.5 µg/ml, respectively, at the next visit. CONCLUSIONS: Measurement of NOX resulted useful for TDM of patients treated with VRC. The MR using NOX informed interpretation and clinical decision-making and is very interesting for complex patients. VRC phenotyping based on the MR is now performed routinely in our institution. A dosing algorithm has been suggested from these results.
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Monitoreo de Drogas , Infecciones Fúngicas Invasoras , Humanos , Voriconazol , Monitoreo de Drogas/métodos , Cromatografía Liquida , Espectrometría de Masas en Tándem , Antifúngicos , Infecciones Fúngicas Invasoras/tratamiento farmacológico , ÓxidosRESUMEN
OBJECTIVES: Amoxicillin is the drug of choice in the management of streptococcal and enterococcal infective endocarditis (IE) but little is known regarding amoxicillin diffusion into infected heart valves. Herein, we assessed amoxicillin valvular distribution and related pharmacokinetic/pharmacodynamic (PK/PD) target attainment in IE patients undergoing heart valve surgery. PATIENTS AND METHODS: In this 2-year prospective study, patients with IE treated by continuous infusion of amoxicillin and undergoing a surgical valve replacement were included. Both amoxicillin plasma and tissue concentrations were measured the day of surgery. Amoxicillin concentration in plasma and crushed heart valves were measured by a validated liquid chromatography method coupled with ultra-violet and tandem mass spectrometry, respectively. MIC and MBC of amoxicillin were determined for all available isolates. The rate of achievement of PK/PD efficacy parameters were assessed. RESULTS: Twenty-two heart valves were removed from 20 patients. Bacterial aetiology was streptococcal (nâ=â17) and enterococcal (nâ=â3). Amoxicillin mean daily dose was 12â±â3â g/24â h, mean plasma concentration was 29â±â21â mg/L (nâ=â15), mean tissue concentration was 23â±â15â mg/L (nâ=â22). Median diffusion rate was 62%. Patients reached a plasma concentration target >4XCMI (nâ=â13). Tissue concentrations were bactericidal for all streptococcal IE but not for enterococcal IE. CONCLUSIONS: Amoxicillin intravalvular measurements in IE treated patients showed significant penetration into the infectious site. These data are reassuring that in situ bactericidal concentrations can be largely achieved in the management of streptococcal IE and support the need for combination antibiotic therapy for enterococcal IE.
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Endocarditis Bacteriana , Endocarditis , Humanos , Amoxicilina/uso terapéutico , Estudios Prospectivos , Endocarditis Bacteriana/tratamiento farmacológico , Endocarditis Bacteriana/microbiología , Válvulas Cardíacas/cirugía , Endocarditis/tratamiento farmacológico , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , StreptococcusRESUMEN
During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, clinical trials on antiviral or symptomatic drugs have been conducted very rapidly even for drugs with a poor pharmacological rationale for efficacy on SARS-CoV-2. Despite lacking basic pharmacological information, most of these clinical trials were also extremely redundant. Applying simple rules, (such as identifying a mechanistic rationale, confirming the ability to reach exposure targets at therapeutic dosage and ensuring tests show drug efficacy in appropriate in vitro and animal models before entering clinical trials) might have saved considerable amounts of time and money, and might have avoided useless research. Moreover, combining these simple rules with the implementation of a relevant policy at both an international and a national level, by limiting studies with a poor methodological/scientific approach and aggregating studies with similar design into single clinical trials, is potentially a far more-efficient strategy.
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COVID-19 , Pandemias , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , SARS-CoV-2RESUMEN
BACKGROUND: Ganciclovir pharmacokinetics is characterized by a high variability in drug exposure. Usually, monitoring of ganciclovir exposure is performed by measuring trough concentration. However, due to the specificity of pediatric pharmacokinetics, trough concentration measurements may not be a relevant surrogate of ganciclovir exposure. Area under the curve of concentration (AUC) may be a more appropriate biomarker. CASE PRESENTATION: We report the case of 3.6-year-old boy with Emberger syndrome with a cytomegalovirus reactivation occurring after allogenic hematopoietic stem cell transplantation. After a few days of treatment with intravenous ganciclovir, sub-therapeutic trough ganciclovir concentrations were measured (< 0.5 µg/mL) and viral load still increased. Ganciclovir dosage was increased by two-fold to deal with this treatment failure. Trough concentrations remained sub-therapeutic. The patient had hematologic disorder therefore it was decided to estimate ganciclovir AUC to assess more accurately drug exposure before any further dosage modification. AUC0-12 h was measured at 51 µg h/mL, which was within the therapeutic range (40-60 µg h/mL). Afterward, viral load decreased and became undetectable. CONCLUSIONS: This case report highlights that monitoring ganciclovir exposure based on AUC should be performed to tailor drug dosage in order to improve treatment efficacy and safety in pediatric patients.
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Infecciones por Citomegalovirus , Ganciclovir , Antivirales/uso terapéutico , Preescolar , Infecciones por Citomegalovirus/tratamiento farmacológico , Monitoreo de Drogas , Ganciclovir/uso terapéutico , Humanos , Masculino , Carga ViralRESUMEN
In the management of cystic fibrosis, treatments against Staphylococcus aureus and Haemophilus influenzae such as amoxicillin or cotrimoxazole have to be prescribed and the antibiotherapy's efficacy may be linked to the concentration that reaches the infected site. As cystic fibrosis patients present disturbed pharmacokinetics parameters, drug monitoring would be relevant to assess the lung distribution of antibiotics and to optimize dosing regimens. In this context, the aim of the study was to develop and validate HPLC-based methods for the determination of both antibiotics in bronchial sputum from cystic fibrosis patients, in order to assess the distribution of the drugs into the lungs. Plasma proteins were precipitated by acetonitrile and amoxicillin concentrations in sputum were determined by HPLC coupled with tandem-mass spectrometry. Following liquid extraction with ethyl acetate, cotrimoxazole was quantified by HPLC using ultraviolet detection. Both methods were rapid, specific, accurate and reproducible. The method was applied to patient samples. In three treated patients, concentrations of amoxicillin in sputum were similar and below the lower limit of quantification (0.1 µg/g) and in six patients, sputum concentrations up to 11.1 and 6.4 µg/g were measured for sulfamethoxazole and trimethoprim, respectively.
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Amoxicilina , Fibrosis Quística/tratamiento farmacológico , Esputo/química , Combinación Trimetoprim y Sulfametoxazol , Amoxicilina/análisis , Amoxicilina/química , Amoxicilina/uso terapéutico , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Humanos , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Combinación Trimetoprim y Sulfametoxazol/análisis , Combinación Trimetoprim y Sulfametoxazol/química , Combinación Trimetoprim y Sulfametoxazol/uso terapéuticoRESUMEN
In this study, the authors report the case of a patient diagnosed with hepatitis C virus who was treated with sofosbuvir-velpatasvir (400/100 mg). As the patient was unable to swallow whole tablets, therapeutic drug monitoring was performed to evaluate the effect of crushing sofosbuvir-velpatasvir tablets on drug absorption and global exposure.
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Antivirales/uso terapéutico , Carbamatos/uso terapéutico , Monitoreo de Drogas/métodos , Hepatitis C/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Sofosbuvir/uso terapéutico , Anciano , Antivirales/administración & dosificación , Antivirales/farmacocinética , Bencimidazoles/uso terapéutico , Carbamatos/administración & dosificación , Carbamatos/farmacocinética , Carcinoma Hepatocelular/cirugía , Combinación de Medicamentos , Femenino , Semivida , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Humanos , Neoplasias Hepáticas/cirugía , Pirrolidinas/uso terapéutico , Quinoxalinas/uso terapéutico , Sofosbuvir/administración & dosificación , Sofosbuvir/farmacocinética , Sulfonamidas/uso terapéutico , ComprimidosRESUMEN
BACKGROUND: Currently, the recommended tacrolimus (TAC) trough level (Cmin) after liver transplantation (LT) is 6-10 ng/mL (when associated in triple immunosuppressive therapy). However, few studies have achieved the lower limit of this range, especially below 7 ng/mL. This study evaluated the efficacy of a target TAC Cmin of 4-7 ng/mL after LT. METHODS: Of 1677 LTs performed between 2002 and 2017, 904 LT cases were analyzed. The cases were categorized into the following 3 groups and compared: low- (n = 247, 27.3%), intermediate- (n = 344, 37.9%), and high-exposure groups (n = 313, 34.5%) with TAC Cmin of 4-7 ng/mL, 7-10 ng/mL, and >10 ng/mL, respectively. In addition, propensity score matching was performed to reduce heterogeneity and population bias. RESULTS: At months 1 and 3, when compared with the 2 other groups, the low-exposure group had similar grafts (P = 0.75) and patient (P = 0.77) survival, but lower alanine aminotransferase (P < 0.001), bilirubin (P < 0.001), international normalized ratio (P = 0.046), and creatinine (P < 0.001) levels. After propensity score matching, the bilirubin (P < 0.001) and creatinine (P = 0.001) levels in the low-exposure group still improved at months 3, but the graft (P = 0.86) and patient (P = 0.99) survival were still similar. CONCLUSIONS: A TAC Cmin of 4-7 ng/mL seems safe and capable of improving graft and kidney function. This finding should be confirmed in a prospective randomized trial.
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Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Tacrolimus/efectos adversos , Tacrolimus/uso terapéutico , Adolescente , Adulto , Anciano , Esquema de Medicación , Monitoreo de Drogas/métodos , Femenino , Supervivencia de Injerto/efectos de los fármacos , Humanos , Trasplante de Riñón/métodos , Trasplante de Hígado/métodos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Regarding several cytotoxic agents, it was evidenced that genetic polymorphisms in genes encoding enzymes involved in their metabolism are associated with higher risk of toxicity. Genotyping these genes before treatment is a valuable strategy to prevent side effects and to predict individual response to drug therapy. This pharmacogenetic approach is recommended for chemotherapies such as thiopurines (azathioprine, 6-mercaptopurine, thioguanine), irinotecan, and fluoropyrimidines (capecitabine and 5-fluorouracil). In this study, we aimed at developing and validating a fast, cost-effective, and easily implementable multiplex genotyping method suitable for analyzing a panel of nine variants involved in the pharmacogenetics of widely prescribed anticancer drugs. We designed a multiplex-specific PCR assay where fragments were labeled by two different fluorescent dye markers (HEX/FAM) identifiable by fragment analysis. These two labels were used to discriminate bi-allelic variants, while the size of the fragment allowed the identification of a particular polymorphism location. Variants of interest were TPMT (rs1800462, rs1142345, rs1800460), NUDT15 (rs116855232), DPYD (rs55886062, rs3918290, rs67376798, rs75017182), and UGT1A1 (rs8175347). The assay was repeatable, and genotypes could be determined when DNA sample amounts ranged from 25 to 100 ng. Primers and dye remained stable in a ready-to-use mixture solution after five freeze-thaw cycles. Accuracy was evidenced by the consistency of 187 genotyping results obtained with our multiplex assay and a reference method. The developed method is fast and cost-effective in simultaneously identifying nine variants involved in the pharmacological response of anticancer drugs. This assay can be easily implemented in laboratories for widespread access to pharmacogenetics in clinical practice.
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Antineoplásicos/farmacología , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias/patología , Farmacogenética , Polimorfismo de Nucleótido Simple , Pruebas Genéticas , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
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
OBJECTIVES: In a new experimental model of carbapenemase-producing Klebsiella pneumoniae osteomyelitis we evaluated the efficacy of colistin alone and in various combinations and examined the emergence of colistin-resistant strains and cross-resistance to host defence peptides (HDPs). METHODS: KPC-99YC is a clinical strain with intermediate susceptibility to meropenem (MICâ=â4 mg/L) and full susceptibility to gentamicin, colistin and tigecycline (MICsâ=â1 mg/L) and fosfomycin (MICâ=â32 mg/L). Time-kill curves were performed at 4× MIC. Osteomyelitis was induced in rabbits by tibial injection of 2â×â108 cfu. Treatment started 14 days later for 7 days in seven groups: (i) control; (ii) colistin; (iii) colistin + gentamicin; (iv) colistin + tigecycline; (v) colistin + meropenem; (vi) colistin + meropenem + gentamicin; and (vii) colistin + fosfomycin. RESULTS: In vitro, colistin was rapidly bactericidal, but regrowth occurred after 9 h. Combinations of colistin with meropenem or fosfomycin were synergistic, whereas combination with tigecycline was antagonistic. In vivo, colistin alone was not effective. Combinations of colistin with meropenem or fosfomycin were bactericidal (Pâ<â0.001) and the addition of gentamicin enhanced the efficacy of colistin + meropenem (Pâ=â0.025). Tigecycline reduced the efficacy of colistin (Pâ=â0.007). Colistin-resistant strains emerged in all groups except colistin + fosfomycin and two strains showed cross-resistance to HDP LL-37. CONCLUSIONS: In this model, combinations of colistin plus meropenem, with or without gentamicin, or colistin plus fosfomycin were the only effective therapies. The combination of colistin and tigecycline should be administered with caution, as it may be antagonistic in vitro and in vivo.
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Antibacterianos/farmacología , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Colistina/farmacología , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/efectos de los fármacos , Osteomielitis/microbiología , Animales , Antibacterianos/uso terapéutico , Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Colistina/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana , Farmacorresistencia Bacteriana Múltiple , Sinergismo Farmacológico , Quimioterapia Combinada , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae/genética , Pruebas de Sensibilidad Microbiana , Osteomielitis/tratamiento farmacológico , ConejosRESUMEN
No drug-drug interaction study has been conducted to date for the combination of ombitasvir, paritaprevir/ritonavir, dasabuvir (3D), and mycophenolic acid (MPA). We here report the case of a hepatitis C virus-infected patient treated with 3D and MPA for vasculitis. In light of the threat of drug-drug interaction, the concentration of MPA was measured before, during, and 15 days after the end of the 3D treatment. Similar values were found at all 3 time points, thus indicating that there is probably no need to adapt MPA dosage to 3D.
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Anilidas/sangre , Carbamatos/sangre , Hepatitis C/sangre , Compuestos Macrocíclicos/sangre , Ácido Micofenólico/sangre , Ritonavir/sangre , Sulfonamidas/sangre , Uracilo/análogos & derivados , 2-Naftilamina , Anciano , Anilidas/administración & dosificación , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/sangre , Antivirales/administración & dosificación , Antivirales/sangre , Carbamatos/administración & dosificación , Ciclopropanos , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/sangre , Manejo de la Enfermedad , Interacciones Farmacológicas/fisiología , Monitoreo de Drogas/métodos , Quimioterapia Combinada , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Humanos , Lactamas Macrocíclicas , Compuestos Macrocíclicos/administración & dosificación , Masculino , Ácido Micofenólico/administración & dosificación , Prolina/análogos & derivados , Ritonavir/administración & dosificación , Sulfonamidas/administración & dosificación , Uracilo/administración & dosificación , Uracilo/sangre , ValinaRESUMEN
BACKGROUND: As a consequence of drug sequestration, increase in volume of distribution, or alteration of elimination, extracorporeal membrane oxygenation (ECMO) might lead to inadequate plasma concentrations of vital drugs. The aim of this experimental study was to develop an ex vivo model to better characterize the impact of ECMO procedure on beta-lactam antibiotics pharmacokinetics. METHODS: Plasma concentrations of cefotaxime, ceftazidime, cefepime, piperacillin, oxacillin, amoxicillin, and ceftriaxone were measured in an ex vivo ECMO circuit primed with whole human blood and compared with controls stored in glass tubes and polyvinyl chloride tubing. Serial blood samples were collected over 48 hours, and the concentrations of beta-lactam antibiotics were quantified using a validated high-performance liquid chromatography assay. The concentrations' decay rate over time was compared between the ECMO circuits and controls using nonlinear mixed-effect modeling. RESULTS: Cefotaxime concentrations decreased markedly: 86% of the initial concentration remained after 4 hours and only 21% after 48 hours (P < 0.05 for the comparison in rate of decrease with both glass and polyvinyl chloride controls). There was no difference in the rate of decrease between ECMO circuit and controls for the other beta-lactam antibiotics. The average drug recoveries from the ECMO circuits at 48 hours were as follows: ceftazidime, 73%; cefepime, 67%; piperacillin, 71%; oxacillin, 46%; and amoxicillin, 72%. Concentrations of ceftriaxone remained stable throughout the 48-hour study both in ECMO circuits and in controls. CONCLUSIONS: Significant losses of cefotaxime were observed, whereas ceftazidime, cefepime, piperacillin, oxacillin, and amoxicillin decrease was moderate and similar to that of the control group, and ceftriaxone concentrations remained unchanged. These results are reassuring for the use of beta-lactam antibiotics in critically ill patients treated with ECMO.
Asunto(s)
Antibacterianos/sangre , Antibacterianos/farmacocinética , beta-Lactamas/sangre , beta-Lactamas/farmacocinética , Oxigenación por Membrana Extracorpórea/métodos , Humanos , CinéticaRESUMEN
Knowledge regarding antimicrobial therapy strategies in deep sternal wound infections (DSWI) following cardiac surgery is limited. Therefore, we aimed to determine the steady-state plasma and mediastinal concentrations of oxacillin administered by continuous infusion in critically ill patients with DSWI and to compare these concentrations with the susceptibility of staphylococci recovered. A continuous infusion of oxacillin (150 to 200 mg/kg of body weight/24 h) was administered after a loading dose (50 mg/kg). Plasma and mediastinal concentrations of total and unbound oxacillin were determined 4 h after the loading dose (H4) and then at day 1 (H24) and day 2 (H48). Twelve patients were included. Nine patients exhibited bacteremia, 5 were in septic shock, 8 were positive for Staphylococcus aureus, and 4 were positive for coagulase-negative staphylococci. The median MIC (first to third interquartile range) was 0.25 (0.24 to 0.41) mg/liter. Median plasma concentrations of total and unbound oxacillin at H4, H24, and H48 were, respectively, 64.4 (41.4 to 78.5) and 20.4 (12.4 to 30.4) mg/liter, 56.9 (31.4 to 80.6) and 21.7 (6.5 to 27.3) mg/liter, and 57.5 (32.2 to 85.1) and 20 (14.3 to 35.7) mg/liter. The median mediastinal concentrations of total and unbound oxacillin at H4, H24, and H48 were, respectively, 2.3 (0.7 to 25.9) and 0.9 (<0.5 to 15) mg/liter, 29.1 (19.7 to 38.2) and 12.6 (5.9 to 19.8) mg/liter, and 31.6 (14.9 to 42.9) and 17.1 (6.7 to 26.7) mg/liter. High-dose oxacillin delivered by continuous infusion is a valuable strategy to achieve our pharmacokinetic target (4× MIC) at the site of action at H24. But concerns remain in cases of higher MICs, emphasizing the need for clinicians to obtain the MICs for the bacteria and to monitor oxacillin concentrations, especially the unbound forms, at the target site.
Asunto(s)
Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Oxacilina/administración & dosificación , Oxacilina/farmacocinética , Infección de Heridas/tratamiento farmacológico , Anciano , Enfermedad Crítica , Femenino , Humanos , Infusiones Intravenosas/métodos , Masculino , Pruebas de Sensibilidad Microbiana/métodos , Estudios Prospectivos , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Infección de Heridas/microbiologíaRESUMEN
Objectives: Assessing the therapeutic potential of a novel antimicrobial pseudopeptide, Pep16, both in vitro and in vivo for the treatment of septic arthritis caused by Staphylococcus aureus. Methods: Seven clinical isolates of S. aureus (two MRSA and five MSSA) were studied. MICs of Pep16 and comparators (vancomycin, teicoplanin, daptomycin and levofloxacin) were determined through the broth microdilution method. The intracellular activity of Pep16 and levofloxacin was assessed in two models of infection using non-professional (osteoblasts MG-63) or professional (macrophages THP-1) phagocytic cells. A mouse model of septic arthritis was used to evaluate the in vivo efficacy of Pep16 and vancomycin. A preliminary pharmacokinetic (PK) analysis was performed by measuring plasma concentrations using LC-MS/MS following a single subcutaneous injection of Pep16 (10â mg/kg). Results: MICs of Pep16 were consistently at 8â mg/L for all clinical isolates of S. aureus (2- to 32-fold higher to those of comparators) while MBC/MIC ratios confirmed its bactericidal activity. Both Pep16 and levofloxacin (when used at 2â×âMIC) significantly reduced the bacterial load of all tested isolates (two MSSA and two MRSA) within both osteoblasts and macrophages. In MSSA-infected mice, Pep16 demonstrated a significant (â¼10-fold) reduction on bacterial loads in knee joints. PK analysis following a single subcutaneous administration of Pep16 revealed a gradual increase in plasma concentrations, reaching a peak of 5.6â mg/L at 12â h. Conclusions: Pep16 is a promising option for the treatment of septic arthritis due to S. aureus, particularly owing to its robust intracellular activity.