RESUMEN

This study was aimed at increasing the clinical usefulness of clinical pharmacological advice (CPA) for personalized drug dosing based on therapeutic drug monitoring (TDM). Educational and organizational interventions focused on improving the knowledge of clinical pharmacology among hospital healthcare workers and reducing the incidence of errors throughout the process were planned. After a pre-interventional period of risk assessment, different list forms of the types of error occurring in the various phases of the process (Phase 1, request for CPA and blood sampling for TDM; Phase 2, sample delivery to and check in at the CPU; Phase 3, TDM execution and CPA production) were created. In the interventional period, the errors were collected daily and educational programmes were carried out. The pre-intervention error rate was 19.5%, and resulted significantly higher for the requests coming from the medical wards compared with those from the surgical wards or the ICUs (26.0% versus 10.5% versus 13.7%, p < 0.001). The educational programme trained 303 nurses and 145 physicians. Afterwards, the error percentage progressively dropped (15.5% in the 2nd trimester; 12.3% in the 3rd one; 10.5% in the 4th one). The adopted strategy resulted in significant improvements which may be useful both to improve quality of patient care and to reduce waste in healthcare costs.

Asunto(s)

Monitoreo de Drogas/métodos , Errores de Medicación/prevención & control , Medicina de Precisión/métodos , Calidad de la Atención de Salud , Relación Dosis-Respuesta a Droga , Educación Médica Continua/métodos , Educación Continua en Enfermería/métodos , Humanos , Estudios Prospectivos , Medición de Riesgo/métodos

RESUMEN

The worrisome increase in Gram-negative bacteria with borderline susceptibility to carbapenems and of carbapenemase-producing Enterobacteriaceae has significantly undermined their efficacy. Continuous infusion may be the best way to maximize the time-dependent activity of meropenem. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CL(Cr)) estimates for use in daily clinical practice to target the steady-state concentrations (C(ss)s) of meropenem during continuous infusion at 8 to 16 mg/liter (after the administration of an initial loading dose of 1 to 2 g over 30 min). The correlation between meropenem clearance (CL(m)) and CL(Cr) was retrospectively assessed in a cohort of critically ill patients (group 1, n = 67) to create a formula for dosage calculation to target C(ss). The performance of this formula was validated in a similar cohort (group 2, n = 56) by comparison of the observed and the predicted C(ss)s. A significant relationship between CL(m) and CL(Cr) was observed in group 1 (r = 0.72, P < 0.001). The application of the formula to meropenem dosing in group 2, infusion rate (g/24 h) = [0.078 × CL(Cr) (ml/min) + 2.85] × target C(ss) × (24/1,000), led to a significant correlation between the observed and the predicted C(ss)s (r = 0.92, P < 0.001). Dosing nomograms based on CL(Cr) were created to target the meropenem C(ss) at 8, 12, and 16 mg/liter in critically ill patients. These nomograms could be helpful in improving the treatment of severe Gram-negative infections with meropenem, especially in the presence of borderline susceptible pathogens or even of carbapenemase producers and/or of pathophysiological conditions which may enhance meropenem clearance.

Asunto(s)

Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Enfermedad Crítica/terapia , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Tienamicinas/administración & dosificación , Tienamicinas/uso terapéutico , Anciano , Algoritmos , Antibacterianos/farmacocinética , Proteínas Bacterianas/metabolismo , Cromatografía Líquida de Alta Presión , Estudios de Cohortes , Creatinina/metabolismo , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/genética , Femenino , Humanos , Infusiones Intravenosas , Masculino , Meropenem , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Nomogramas , Espectrofotometría Ultravioleta , Tienamicinas/farmacocinética , beta-Lactamasas/metabolismo

RESUMEN

OBJECTIVES: Prolonged treatment with linezolid may cause toxicity. The purpose of this study was to define pharmacodynamic thresholds for improving safety outcomes of linezolid. METHODS: We performed a retrospective study of patients who had trough (C(min)) and peak (C(max)) plasma levels measured during prolonged linezolid treatment. Dosage adjustments were performed when C(min) ≥10 mg/L and/or AUC24 ≥400 mg/L ·â€Šh. Patients were divided into two subgroups according to the absence or presence of co-treatment with rifampicin (the linezolid group and the linezolid + rifampicin group, respectively). Data on demographic characteristics, disease, microbiology and haematochemical parameters were collected and outcomes in relation to drug exposure were compared between groups. RESULTS: A total of 45 patients were included. Dosage adjustments were needed in 40% versus 0% of patients in the linezolid group (n = 35) versus the linezolid + rifampicin group (n = 10), respectively. Patients in the linezolid group had either significantly higher C(min) [3.71 mg/L (1.43-6.38) versus 1.37 mg/L (0.67-2.55), P < 0.001] or AUC24 [212.77 mg/L ·â€Šh (166.67-278.42) versus 123.33 mg/L ·â€Šh (97.36-187.94), P < 0.001]. Thrombocytopenia appeared in 51.4% versus 0% of cases in the linezolid group versus the linezolid + rifampicin group, respectively. In 33.3% of those patients who were experiencing thrombocytopenia, therapeutic drug monitoring (TDM)-guided dosage reductions allowed recovery from toxicity and prosecution of therapy with good outcome. A logistic regression model for thrombocytopenia estimated a probability of 50% in the presence of C(min) of 6.53 mg/L and/or of AUC24 of 280.74 mg/L ·â€Šh. CONCLUSIONS: Maintenance over time of C(min) between 2 and 7 mg/L and/or of AUC24 between 160 and 300 mg/L ·â€Šh may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.

Asunto(s)

Acetamidas/administración & dosificación , Acetamidas/efectos adversos , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Infecciones Bacterianas/tratamiento farmacológico , Monitoreo de Drogas/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Oxazolidinonas/administración & dosificación , Oxazolidinonas/efectos adversos , Adulto , Femenino , Humanos , Linezolid , Masculino , Persona de Mediana Edad , Plasma/química , Estudios Retrospectivos , Rifampin/administración & dosificación , Resultado del Tratamiento

RESUMEN

Cerebral nocardiosis is a severe infection that carries the highest mortality rate among all bacterial cerebral abscesses. We report on a case in an immunocompromised patient which was successfully treated with unexpectedly low doses of linezolid. Therapeutic drug monitoring was very helpful in highlighting issues of poor compliance and of drug-drug interactions.

Asunto(s)

Acetamidas/uso terapéutico , Antibacterianos/uso terapéutico , Absceso Encefálico/tratamiento farmacológico , Nocardiosis/tratamiento farmacológico , Oxazolidinonas/uso terapéutico , Acetamidas/administración & dosificación , Anciano , Antibacterianos/administración & dosificación , Femenino , Humanos , Huésped Inmunocomprometido , Linezolid , Oxazolidinonas/administración & dosificación

Asunto(s)

Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Endocarditis/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/patogenicidad , Vancomicina/farmacología , Vancomicina/uso terapéutico , Animales

RESUMEN

OBJECTIVE: To describe a case of severe cellulitis, successfully treated with high-dose daptomycin plus continuous infusion meropenem, in a patient with morbid obesity and renal failure, in whom drug exposure over time was optimized by means of real-time therapeutic drug monitoring (TDM). CASE SUMMARY: A 63-year-old man with morbid obesity (body mass index 81.6 kg/m²) and renal failure was admitted to the emergency department because of severe cellulitis. The patient had an admission Laboratory Risk Indicator for Necrotizing Fasciitis score of 9, and broad-spectrum antimicrobial therapy with daptomycin and meropenem was started. Because of rapidly changing renal function, dosage adjustments were guided by an intensive program of TDM (daptomycin ranging from 1200 mg every 48 hours over 30 minutes to 1200 mg every 36 hours over 30 minutes; meropenem ranging from 0.25 g every 8 hours over 6 hours to 500 mg every 4 hours by continuous infusion). Clinical response was observed within 72 hours. However, a sudden increase of serum creatine kinase (SCK) raised questions about the need for discontinuation of daptomycin. The drug concentrations were not toxic; therefore, we decided to continue therapy. Significant clinical improvement, with SCK normalization, was observed within a few days. Antimicrobial therapy was switched on day 29 to amoxicillin/clavulanate plus levofloxacin, and then discontinued at discharge on day 53. DISCUSSION: High-dose daptomycin plus continuous infusion meropenem may ensure adequate empiric antimicrobial coverage in patients with possible early necrotizing fasciitis. However, in patients with morbid obesity and changing renal function, significant challenges may arise because of the hydrophilic nature of these drugs and the inaccuracy of standard methods of estimating renal function. CONCLUSIONS: Real-time TDM may represent an invaluable approach in optimizing drug exposure with high-dose daptomycin plus continuous infusion meropenem in patients with severe cellulitis, morbid obesity, and changing renal function.

Asunto(s)

Antibacterianos/efectos adversos , Celulitis (Flemón)/tratamiento farmacológico , Daptomicina/efectos adversos , Monitoreo de Drogas , Obesidad Mórbida/complicaciones , Insuficiencia Renal/complicaciones , Tienamicinas/efectos adversos , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Celulitis (Flemón)/sangre , Celulitis (Flemón)/complicaciones , Celulitis (Flemón)/fisiopatología , Creatina Quinasa/sangre , Daptomicina/sangre , Daptomicina/uso terapéutico , Quimioterapia Combinada/efectos adversos , Fascitis Necrotizante/etiología , Fascitis Necrotizante/prevención & control , Humanos , Masculino , Meropenem , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Tienamicinas/sangre , Tienamicinas/uso terapéutico , Resultado del Tratamiento

RESUMEN

BACKGROUND AND OBJECTIVES: Combination therapy with interferon-α and ribavirin is considered the treatment of choice for chronic hepatitis C. However, interferon-α may induce severe depression. It has been suggested that interferon-α is able to modify cytochrome P450 (CYP) 1A2 and 2D6 activity. We therefore decided to study the effects of the interferon-α-2b pegylated derivative on fluoxetine disposition in patients receiving combination chemotherapy for chronic hepatitis C. METHODS: After approval by the institutional ethics committee, 20 adult patients with chronic hepatitis C, but with no history of other liver diseases, were prospectively admitted to the study, which included phenotyping by means of a dextromethorphan test and evaluation of fluoxetine and norfluoxetine pharmacokinetic parameters (the area under the serum concentration-time curve, maximum serum concentration, time to reach the maximum serum concentration and terminal elimination half-life) before and after 2 months of continuous peginterferon-α-2b therapy. RESULTS: The only statistically significant difference we observed was a significant reduction in the terminal elimination half-life of fluoxetine (from 47.30 to 33.23 hours; p = 0.014) after peginterferon-α-2b treatment. CONCLUSION: These data suggest that interferon-α may induce, rather than inhibit, the biotransformation of fluoxetine.

Asunto(s)

Antidepresivos de Segunda Generación/farmacocinética , Antivirales/uso terapéutico , Fluoxetina/farmacocinética , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/metabolismo , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Adulto , Antidepresivos de Segunda Generación/sangre , Antidepresivos de Segunda Generación/uso terapéutico , Área Bajo la Curva , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Fluoxetina/sangre , Fluoxetina/uso terapéutico , Semivida , Hepacivirus/genética , Hepatitis C Crónica/genética , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Fenotipo , Proteínas Recombinantes , Ribavirina/uso terapéutico , Adulto Joven

RESUMEN

The objective of the present retrospective observational study carried out in patients receiving a standard dosage of linezolid and undergoing routine therapeutic drug monitoring (TDM) was to assess the interindividual variability in plasma exposure, to identify the prevalence of attainment of optimal pharmacodynamics, and to define if an intensive program of TDM may be warranted in some categories of patients. Linezolid plasma concentrations (trough [C(min)] and peak [C(max)] levels) were analyzed by means of a high-performance liquid chromatography (HPLC) method, and daily drug exposure was estimated (daily area under the plasma concentration-time curve [AUC(24)]). The final database included 280 C(min) and 223 C(max) measurements performed in 92 patients who were treated with the fixed 600-mg dose every 12 h (q12h) intravenously (n = 58) or orally (n = 34). A wide variability was observed (median values [interquartile range]: 3.80 mg/liter [1.75 to 7.53 mg/liter] for C(min), 14.70 mg/liter [10.57 to 19.64] for C(max), and 196.08 mg·h/liter [144.02 to 312.10 mg·h/liter] for estimated AUC(24)). Linezolid C(min) was linearly correlated with estimated AUC(24) (r(2) = 0.85). Optimal pharmacodynamic target attainment (defined as C(min) of ≥2 mg/liter and/or AUC(24)/MIC(90) ratio of >80) was obtained in about 60 to 70% of cases, but potential overexposure (defined as C(min) of ≥10 mg/liter and/or AUC(24) of ≥400 mg·h/liter) was documented in about 12% of cases. A significantly higher proportion of cases with potential overexposure received cotreatment with omeprazole, amiodarone, or amlodipine. Our study suggests that the application of TDM might be especially worthwhile in about 30% of cases with the intent of avoiding either the risk of dose-dependent toxicity or that of treatment failure.

Asunto(s)

Acetamidas/farmacocinética , Antibacterianos/farmacocinética , Monitoreo de Drogas/métodos , Oxazolidinonas/farmacocinética , Acetamidas/sangre , Adulto , Anciano , Antibacterianos/sangre , Peso Corporal , Femenino , Humanos , Linezolid , Masculino , Persona de Mediana Edad , Oxazolidinonas/sangre , Estudios Retrospectivos

Asunto(s)

Antibacterianos/administración & dosificación , Neumonía Bacteriana/tratamiento farmacológico , Vancomicina/administración & dosificación , Heridas y Lesiones/microbiología , Antibacterianos/farmacocinética , Disponibilidad Biológica , Creatinina/metabolismo , Enfermedad Crítica , Humanos , Neumonía Bacteriana/complicaciones , Neumonía Bacteriana/metabolismo , Insuficiencia Renal/inducido químicamente , Vancomicina/farmacocinética , Heridas y Lesiones/metabolismo , Heridas y Lesiones/terapia

Asunto(s)

Antifúngicos/administración & dosificación , Micosis/tratamiento farmacológico , Triazoles/administración & dosificación , Administración Oral , Antifúngicos/efectos adversos , Antifúngicos/sangre , Antifúngicos/farmacocinética , Área Bajo la Curva , Esquema de Medicación , Interacciones Alimento-Droga , Mucosa Gástrica/metabolismo , Humanos , Triazoles/efectos adversos , Triazoles/sangre , Triazoles/farmacocinética

RESUMEN

The efficacy of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA)-related infections has been called into question by recent findings of higher rates of failure of vancomycin treatment of infections caused by strains with high MICs. Continuous infusion may be the best way to maximize the time-dependent activity of vancomycin. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CL(Cr)) estimates for use in daily clinical practice to target the steady-state concentrations (C(ss)s) of vancomycin during continuous infusion at 15 to 20 mg/liter (after the administration of an initial loading dose of 15 mg/kg of body weight over 2 h). The correlation between vancomycin clearance (CL(v)) and CL(Cr) was retrospectively assessed in a cohort of critically ill patients (group 1, n = 70) to create a formula for dosage calculation to target C(ss) at 15 mg/liter. The performance of this formula was prospectively validated in a similar cohort (group 2, n = 63) by comparison of the observed and the predicted C(ss)s. A significant relationship between CL(v) and CL(Cr) was observed in group 1 (P < 0.001). The application of the calculated formula to vancomycin dosing in group 2 {infusion rate (g/24 h) = [0.029 x CL(Cr) (ml/min) + 0.94] x target C(ss) x (24/1,000)} led to a significant correlation between the observed and the predicted C(ss)s (r = 0.80, P < 0.001). Two dosing nomograms based on CL(Cr) were created to target the vancomycin C(ss) at 15 and 20 mg/liter in critically ill patients. These nomograms could be helpful in improving the vancomycin treatment of MRSA infections, especially in the presence of borderline-susceptible pathogens and/or of pathophysiological conditions which may enhance the clearance of vancomycin, while potentially avoiding the increased risk of nephrotoxicity observed with the use of high intermittent doses of vancomycin.

Asunto(s)

Enfermedad Crítica , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Nomogramas , Infecciones Estafilocócicas/tratamiento farmacológico , Vancomicina , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Estudios de Cohortes , Creatinina/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Monitoreo de Drogas , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Infecciones Estafilocócicas/microbiología , Factores de Tiempo , Resultado del Tratamiento , Vancomicina/administración & dosificación , Vancomicina/farmacocinética , Vancomicina/uso terapéutico

RESUMEN

A rapid, selective and sensitive isocratic reversed-phase HPLC assay coupled with MS/MS detection for simultaneous quantification of fluoxetine and its major active metabolite in serum samples has been developed. Analytes were extracted with a simple three step liquid-liquid procedure and chromatographic separation was achieved on a C18 column. Because of its sensitivity, this HPLC/MS/MS method is suitable both for routine therapeutic drug monitoring and for pharmacokinetic studies, due to its low limits of quantification.

Asunto(s)

Antidepresivos de Segunda Generación/sangre , Antidepresivos de Segunda Generación/farmacocinética , Fluoxetina/análogos & derivados , Fluoxetina/sangre , Fluoxetina/farmacocinética , Antidepresivos de Segunda Generación/metabolismo , Área Bajo la Curva , Calibración , Cromatografía Líquida de Alta Presión/instrumentación , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Fluoxetina/metabolismo , Semivida , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Espectrometría de Masas/métodos , Control de Calidad , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Factores de Tiempo

RESUMEN

The purpose of this study was to assess the clinical efficacy of high-dose levofloxacin plus rifampicin in the empirical treatment of non-tuberculous spondylodiscitis in an epidemiological context of low incidence of staphylococcal fluoroquinolone resistance. All consecutive adult patients with spondylodiscitis (January 2003 to December 2006) were empirically treated with high-dose levofloxacin (500 mg every 12 h normalised to renal function and optimised by means of therapeutic drug monitoring whenever feasible) plus rifampicin 600 mg every 24 h. Trough and peak plasma concentrations were targeted at 1-3 mg/L and 6-9 mg/L, respectively, to maximise the concentration-dependent activity of levofloxacin in bone. Follow-up was performed until 9 months after the end of therapy. Forty-eight patients were included. Eleven patients underwent a surgical approach for spine stabilisation. Among the 29 bacterial isolates, Staphylococcus aureus was the most frequent (65.5%) (all meticillin-susceptible strains). Tailored levofloxacin plasma exposure over time was ensured in most cases. Median treatment duration was 15.1 weeks. Overall response rates were: 77.1% at the intent-to-treat analysis; 84.1% among patients who completed therapy (N=44); and 96.3% among those receiving targeted therapy against documented levofloxacin-susceptible isolates (N=27). No patient had evidence of disease relapse at follow-up. Our findings suggest that high-dose levofloxacin regimens may be highly effective in the treatment of non-tuberculous spondylodiscitis and support its putative role in combination with rifampicin against S. aureus.

Asunto(s)

Antibacterianos/uso terapéutico , Discitis/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Levofloxacino , Ofloxacino/uso terapéutico , Rifampin/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Monitoreo de Drogas , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Ofloxacino/administración & dosificación , Rifampin/administración & dosificación , Resultado del Tratamiento , Adulto Joven

RESUMEN

OBJECTIVES: The aim of the study was to assess the biliary penetration of linezolid and the probabilities of attaining optimal pharmacodynamic exposure against vancomycin-resistant enterococci (VRE) in the bile of liver transplant (LTx) patients who received linezolid for the treatment of multidrug-resistant Gram-positive hospital infections. METHODS: After at least 2 days of standard 600 mg twice-daily therapy, simultaneous bile and blood samples for linezolid assay were collected from six LTx patients just prior to drug administration to determine trough concentrations (Cmin) at steady-state in both sites. Linezolid concentrations in plasma and in bile were analysed by means of HPLC. Biliary penetration of linezolid was calculated as the ratio between Cmin in bile and in plasma. Optimal theoretical pharmacodynamic exposure of linezolid against VRE in bile was defined as biliary Cmin>MIC90. RESULTS: C(min) of linezolid in bile achieved very high values at steady-state, which were significantly higher than in plasma (median of 21.77 versus 8.08 mg/L, P=0.021). The very high biliary penetration of linezolid (median value of 1.93; range 1.31-4.83) enabled achievement of optimal theoretical pharmacodynamic exposure against VRE in bile (Cmin>2 mg/L) on all of the occasions. CONCLUSIONS: These preliminary data suggest a potential role for linezolid in the treatment of cholangitis due to VRE in LTx patients. Obviously, further confirmatory data assessing also the AUC/MIC ratio of linezolid in bile are needed.

Asunto(s)

Acetamidas/farmacocinética , Acetamidas/uso terapéutico , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Conductos Biliares/química , Oxazolidinonas/farmacocinética , Oxazolidinonas/uso terapéutico , Colangitis/tratamiento farmacológico , Cromatografía Líquida de Alta Presión , Femenino , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Humanos , Linezolid , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Plasma/química , Resistencia a la Vancomicina

RESUMEN

Solid organ transplantation in HIV-infected individuals requires concomitant use of immunosuppressants and antiretrovirals that may cause significant drug interactions. Here we report on a peculiar pharmacokinetic interaction between tacrolimus and protease inhibitors (PIs) which occurred in four HIV-infected liver transplant patients who had to shift PI therapy from nelfinavir to fosamprenavir as a consequence of regulatory restrictions. After the switch, tacrolimus trough blood concentrations significantly dropped in all patients (mean +/- SD 6.9 +/- 2.6 versus 3.2 +/- 2.0 ng/ml before and after the switch, respectively; P=0.01), so that a marked dosage increase was needed (0.29 +/- 0.14 versus 0.88 +/- 0.48 mg/day, 1-3 days before and 3 weeks after the switch, respectively; P=0.046) to attain the desired target (8.7 +/- 2.3 ng/ml). Consistently, marked changes of the concentration/dose ratio of tacrolimus were observed in all cases (27.2 +/- 9.7 ng/ml per mg/kg/day versus 9.7 +/- 4.0 ng/ml per mg/kg/day before and after the switch, respectively; P<0.001). Our findings suggest that fosamprenavir may be less potent than nelfinavir in inhibiting tacrolimus clearance and support the need for higher tacrolimus dosage to avoid insufficient immunosuppression in HIV-infected liver transplant patients when switching from nelfinavir to fosamprenavir or even when directly starting antiretroviral therapy with fosamprenavir.

Asunto(s)

Carbamatos/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/administración & dosificación , Inmunosupresores/farmacocinética , Trasplante de Hígado , Nelfinavir/administración & dosificación , Organofosfatos/administración & dosificación , Sulfonamidas/administración & dosificación , Tacrolimus/farmacocinética , Adulto , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Furanos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Masculino , Persona de Mediana Edad , Tacrolimus/administración & dosificación , Tacrolimus/sangre

RESUMEN

OBJECTIVE: To describe the management of a pharmacokinetic interaction between azole antifungals (fluconazole and voriconazole) and everolimus in a patient who underwent an orthotopic liver transplant. CASE SUMMARY: A 65-year-old male who received an orthotopic liver transplant experienced an iatrogenic retroperitoneal duodenal perforation on postoperative day 55. His condition was subsequently complicated by severe sepsis and acute renal failure. Intravenous fluconazole 400 mg, followed by 100 mg every 24 hours according to impaired renal function, was immediately started; to avoid further nephrotoxicity, immunosuppressant therapy was switched from cyclosporine plus mycophenolate mofetil to oral everolimus 0.75 mg every 12 hours. Satisfactory steady-state minimum concentration (C(min)) of everolimus was achieved (approximately 5 ng/mL). On day 72 posttransplant, because of invasive aspergillosis, antifungal therapy was switched to intravenous voriconazole 400 mg every 12 hours on the first day, followed by 200 mg every 12 hours; to prevent drug toxicity, the everolimus dosage was promptly lowered to 0.25 mg every 24 hours. At that time, the everolimus C(min) averaged approximately 3 ng/mL. The concentration/dose ratio of everolimus (ie, C(min) reached at steady-state for each milligram per kilogram of drug administered) was markedly lower during fluconazole versus voriconazole cotreatment (mean +/- SD, 3.49 +/- 0.29 vs 11.05 +/- 0.81 ng/mL per mg/kg/daily; p < 0.001). Despite intensive care, the patient's condition continued to deteriorate and he died on day 84 posttransplant. DISCUSSION: Both azole antifungals were considered probable causative agents of an interaction with everolimus according to the Drug Interaction Probability Scale. The interaction is due to the inhibition of CYP3A4-mediated everolimus clearance. Of note, prompt reduction of the everolimus dosage since the first azole coadministration, coupled with intensive therapeutic drug monitoring, represented a useful strategy to prevent drug overexposure. CONCLUSIONS: Our data suggest that during everolimus-azole cotreatment, a dose reduction of everolimus is needed to avoid overexposure. According to the different inhibitory potency of CYP3A4 activity, the reduction should be lower during fluconazole than during voriconazole cotreatment.

Asunto(s)

Fluconazol/farmacocinética , Trasplante de Hígado/efectos adversos , Pirimidinas/farmacocinética , Sirolimus/análogos & derivados , Triazoles/farmacocinética , Anciano , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Interacciones Farmacológicas , Everolimus , Resultado Fatal , Fluconazol/uso terapéutico , Humanos , Inmunosupresores/sangre , Inmunosupresores/farmacocinética , Inmunosupresores/uso terapéutico , Masculino , Pirimidinas/uso terapéutico , Sirolimus/sangre , Sirolimus/farmacocinética , Sirolimus/uso terapéutico , Triazoles/uso terapéutico , Voriconazol

RESUMEN

Pharmacokinetics is a discipline aimed at predicting the best dosage and dosing regimen for each single drug in order to ensure and maintain therapeutically effective concentrations at the action sites. In cardiac critical care patients, various pathophysiological conditions may significantly alter the pharmacokinetic behaviour of drugs. Gastrointestinal drug absorption may be erratic and unpredictable in the early postoperative period, and so patients may be unresponsive to oral therapy; thus the intravenous route should be preferred for life-saving drugs whenever feasible. Variations in the extracellular fluid content as a response to the trauma of surgery and the fluid load or significant drug loss through thoracic drainages may significantly lower plasma concentrations of extracellularly distributed hydrophilic antimicrobials (beta-lactams, aminoglycosides and glycopeptides). Drug metabolism may be altered by the systemic inflammatory response and/or multiple organ failure and/or drug-drug pharmacokinetic interactions that can potentially occur during polytherapy, especially in immunosuppressed cardiac transplant patients. Instability of renal function may promote significant changes in body fluid concentrations of renally eliminated drugs, even in a brief period of hours. Finally, the application of extracorporeal circulation by means of cardiopulmonary bypass may significantly alter the disposition of several drugs during the operation because of acute haemodilution, hypoalbuminaemia, hypothermia and/or adsorption to the bypass equipment. Accordingly, to avoid either overexposure and the consequent increased risk of toxicity or underexposure and the consequent risk of therapeutic failure in critically ill cardiac patients, the dosing regimens of several drugs are expected to be significantly different from those suggested for clinically stable patients. Additionally, therapeutic drug monitoring may be helpful in the management of drug therapy and should be routinely used to guide individualized dose adjustments for (i) immunosuppressants whenever cytochrome P450 3A4 isoenzyme inhibitors (e.g. macrolide antibacterials, azole antifungals) or inducers (e.g. rifampicin [rifampin]) are added to or withdrawn from the regimen; and (ii) glycopeptide and aminoglycoside antibacterials whenever haemodynamically active agents (such as dopamine, dobutamine and furosemide [frusemide]) are added to or withdrawn from the regimen, and also whenever significant changes of haemodynamics and/or of renal function occur.

Asunto(s)

Procedimientos Quirúrgicos Cardíacos , Cuidados Críticos , Farmacocinética , Puente Cardiopulmonar , Humanos , Absorción Intestinal/fisiología , Periodo Intraoperatorio , Preparaciones Farmacéuticas/metabolismo , Distribución Tisular

RESUMEN

Continuous renal replacement therapy (CRRT), particularly continuous venovenous haemofiltration (CVVH) and continuous venovenous haemodiafiltration (CVVHDF), are gaining increasing relevance in routine clinical management of intensive care unit patients. The application of CRRT, by leading to extracorporeal clearance (CL(CRRT)), may significantly alter the pharmacokinetic behaviour of some drugs. This may be of particular interest in critically ill patients presenting with life-threatening infections, since the risk of underdosing with antimicrobial agents during this procedure may lead to both therapeutic failure and the spread of breakthrough resistance. The intent of this review is to discuss the pharmacokinetic principles of CL(CRRT) of antimicrobial agents during the application of CVVH and CVVHDF and to summarise the most recent findings on this topic (from 1996 to December 2006) in order to understand the basis for optimal dosage adjustments of different antimicrobial agents. Removal of solutes from the blood through semi-permeable membranes during RRT may occur by means of two different physicochemical processes, namely, diffusion or convection. Whereas intermittent haemodialysis (IHD) is essentially a diffusive technique and CVVH is a convective technique, CVVHDF is a combination of both. As a general rule, the efficiency of drug removal by the different techniques is expected to be CVVHDF > CVVH > IHD, but indeed CL(CRRT) may vary greatly depending mainly on the peculiar physicochemical properties of each single compound and the CRRT device's characteristics and operating conditions. Considering that RRT substitutes for renal function in clearing plasma, CL(CRRT) is expected to be clinically relevant for drugs with dominant renal clearance, especially when presenting a limited volume of distribution and poor plasma protein binding. Consistently, CL(CRRT) should be clinically relevant particularly for most hydrophilic antimicrobial agents (e.g. beta-lactams, aminoglycosides, glycopeptides), whereas it should assume much lower relevance for lipophilic compounds (e.g. fluoroquinolones, oxazolidinones), which generally are nonrenally cleared. However, there are some notable exceptions: ceftriaxone and oxacillin, although hydrophilics, are characterised by primary biliary elimination; levofloxacin and ciprofloxacin, although lipophilics, are renally cleared. As far as CRRT characteristics are concerned, the extent of drug removal is expected to be directly proportional to the device's surface area and to be dependent on the mode of replacement fluid administration (predilution or postdilution) and on the ultrafiltration and/or dialysate flow rates applied.Conversely, drug removal by means of CVVH or CVVHDF is unaffected by the drug size, considering that almost all antimicrobial agents have molecular weights significantly lower (<2000Da) than the haemofilter cut-off (30,000-50,000Da). Drugs that normally have high renal clearance and that exhibit high CL(CRRT) during CVVH or CVVHDF may need a significant dosage increase in comparison with renal failure or even IHD. Conversely, drugs that are normally nonrenally cleared and that exhibit very low CL(CRRT) during CVVH or CVVHDF may need no dosage modification in comparison with normal renal function. Bearing these principles in mind will almost certainly aid the management of antimicrobial therapy in critically ill patients undergoing CRRT, thus containing the risk of inappropriate exposure. However, some peculiar pathophysiological conditions occurring in critical illness may significantly contribute to further alteration of the pharmacokinetics of antimicrobial agents during CRRT (i.e. hypoalbuminaemia, expansion of extracellular fluids or presence of residual renal function). Accordingly, therapeutic drug monitoring should be considered a very helpful tool for optimising drug exposure during CRRT.

Asunto(s)

Antiinfecciosos/farmacocinética , Infecciones Bacterianas/tratamiento farmacológico , Enfermedad Crítica , Terapia de Reemplazo Renal , Antiinfecciosos/uso terapéutico , Infecciones Bacterianas/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Riñón/metabolismo , Riñón/fisiopatología , Modelos Biológicos

RESUMEN

Because of a possible relationship between tamoxifen (T) concentrations and clinical effects, we initiated a preliminary investigation on serum and tissue concentrations of T and its main active metabolites, and 4-hydroxytamoxifen, in women with positive breast cancer estrogen receptor. One hundred forty-eight patients were studied: 80 were admitted for monitoring of therapeutic serum drug concentrations, 22 had tissue concentrations taken at surgery, and 46 patients had uterine mucosa levels measured at diagnostic hysteroscopy. Steady-state serum concentrations were reached after 1 month of continuous treatment, with desmethyltamoxifen being the highest represented derivative from the third week onward. There was no relationship between dose (in mg/kg body weight) and steady-state serum concentrations during therapeutic drug monitoring of patients. The highest tissue concentrations were observed in breast lymph-nodes, cancer tissue, and uterine mucosa. On the basis of these data, we speculate that T and its active metabolites may exert both a defensive role (ie, an obstacle to the diffusion of malignant cells through the local lymphatic system) and a harmful one (induction of uterine malignancies).

Asunto(s)

Neoplasias de la Mama/metabolismo , Ganglios Linfáticos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/metabolismo , Tamoxifeno/metabolismo , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Cromatografía Líquida de Alta Presión , Monitoreo de Drogas/métodos , Femenino , Humanos , Persona de Mediana Edad , Moduladores Selectivos de los Receptores de Estrógeno/sangre , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/sangre , Tamoxifeno/uso terapéutico , Distribución Tisular

RESUMEN

We report a case of acute bacterial meningitis due to Listeria monocytogenes whose successful treatment was mainly attributable to high-dose levofloxacin therapy (500 mg iv bid). This supports the hypothesis that levofloxacin may be an effective option for the treatment of listerial meningitis.

Asunto(s)

Antibacterianos/uso terapéutico , Levofloxacino , Listeria monocytogenes/efectos de los fármacos , Meningitis por Listeria/tratamiento farmacológico , Ofloxacino/uso terapéutico , Anciano , Líquido Cefalorraquídeo/microbiología , Femenino , Humanos , Listeria monocytogenes/aislamiento & purificación , Listeriosis/tratamiento farmacológico , Listeriosis/microbiología , Meningitis por Listeria/microbiología , Resultado del Tratamiento