RESUMO
OBJECTIVES: The overall study aim was to identify the relevant preclinical teicoplanin pharmacokinetic (PK)/pharmacodynamic (PD) indices to predict efficacy and suppression of resistance in MRSA infection. METHODS: A hollow-fibre infection model and a neutropenic murine thigh infection model were developed. The PK/PD data generated were modelled using a non-parametric population modelling approach with Pmetrics. The posterior Bayesian estimates derived were used to study the exposure-effect relationships. Monte Carlo simulations from previously developed population PK models in adults and children were conducted to explore the probability of target attainment (PTA) for teicoplanin dosage regimens against the current EUCAST WT susceptibility range. RESULTS: There was a concentration-dependent activity of teicoplanin in both the in vitro and in vivo models. A total in vivo AUC/MIC of 610.4 (total AUC of 305.2 mg·h/L) for an MRSA strain with an MIC of 0.5 mg/L was needed for efficacy (2 log10 cell kill) against a total bacterial population. A total AUC/MIC ratio of â¼1500 (total AUC of â¼750 mg·h/L) was needed to suppress the emergence of resistance. The PTA analyses showed that adult and paediatric patients receiving a standard regimen were only successfully treated for the in vivo bactericidal target if the MIC was ≤0.125 mg/L in adults and ≤0.064 mg/L in children. CONCLUSIONS: This study improves our understanding of teicoplanin PD against MRSA and defines an in vivo AUC/MIC target for efficacy and suppression of resistance. Additional studies are needed to further corroborate the PK/PD index in a variety of infection models and in patients.
Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Teicoplanina/farmacologia , Teicoplanina/farmacocinética , Animais , Área Sob a Curva , Modelos Animais de Doenças , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Modelos Teóricos , Método de Monte Carlo , Infecções Estafilocócicas/microbiologiaAssuntos
Claritromicina/farmacologia , Claritromicina/farmacocinética , Everolimo/farmacocinética , Everolimo/uso terapêutico , Transplante de Coração/efeitos adversos , Pneumonia Bacteriana/tratamento farmacológico , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Claritromicina/administração & dosagem , Interações Medicamentosas , Everolimo/administração & dosagem , Everolimo/sangue , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Imunossupressores/farmacocinética , Imunossupressores/uso terapêuticoRESUMO
We describe the case of an intravenous drug user affected by life-threatening Staphylococcus aureus-complicated skin and soft tissue infection with associated bacteraemia who, while on replacement therapy with methadone, required 11 mg/kg/day daptomycin to achieve trough (Cmin) and peak (Cmax) plasma levels similar to those observed with the standard dosage of 6 mg/kg in healthy volunteers (mean ± standard deviation: Cmin 12.35 ± 0.80 mg/L, Cmax 63.90 ± 8.71 mg/L). Clinical pharmacological advice based on real time therapeutic drug monitoring may be helpful for optimizing daptomycin exposure in these patients. Physicians should take into account that dosages much higher than the standard ones may be needed, probably as a consequence of augmented drug clearance.
Assuntos
Antibacterianos/farmacocinética , Bacteriemia/tratamento farmacológico , Daptomicina/farmacocinética , Metadona/administração & dosagem , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Abuso de Substâncias por Via Intravenosa/tratamento farmacológico , Analgésicos Opioides/administração & dosagem , Antibacterianos/administração & dosagem , Bacteriemia/complicações , Daptomicina/administração & dosagem , Interações Medicamentosas , Usuários de Drogas , Humanos , Tratamento de Substituição de Opiáceos , Plasma/química , Infecções dos Tecidos Moles/complicações , Infecções Cutâneas Estafilocócicas/complicações , Staphylococcus aureus/isolamento & purificação , Abuso de Substâncias por Via Intravenosa/complicações , Adulto JovemRESUMO
BACKGROUND: Individualization of mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) therapeutic drug monitoring may minimize the risk of organ transplant rejection. The MPA area under the 12-hour concentration-time curve (MPA-AUC(0-12h)) is a more powerful predictor of rejection than are MPA trough levels. Measurement of MPA-AUC(0-12h,) however, is difficult and clinically impractical. The limited sampling strategy (LLS) has been proposed to overcome this problem. OBJECTIVE: To validate the predictive performance of MPA LSS algorithms previously published for heart transplant (HTx) recipients (initial group) when applied to a new independent group of 29 HTx recipients (validation group) during the first year after transplantation. PATIENTS AND METHODS: In a previous study, we established 2 algorithms using a LSS in HTx recipients: (1) 5.568 + 0.902 x C(1.25) + 2.022 x C(2) + 4.594 x C(6) and (2) 3.8 + 1.025 . C(1.25) + 1.819 x C(2) + 1.566 x C(4) + 3.479 x C(6). Agreement between abbreviated AUC and the full AUC(0-12h) was tested using the Bland-Altman method. The validation group was used to test and assess bias and precision. RESULTS: The 2 LSS algorithms used predicted the corresponding MPA-AUC(0-12h) with a mean bias of -4.85% and -3.6% and mean precision of 15.9% and 14%, respectively. CONCLUSIONS: The MPA-AUC(0-12h) obtained using the LSS may be useful to guide clinical management and dosing. This study prospectively validates 2 algorithms for calculation of MPA-AUC(0-12h) using an LSS calculated in HTx recipients. Bias and precision values suggest that our algorithms could be used for MPA therapeutic drug monitoring predictions in HTx recipients who share the same characteristics.