PK/PD modeling of daptomycin against MRSA and MRSE and Monte Carlo simulation for bacteremia treatment

Objectives The aim of this study was to investigate the effect of daptomycin against methicillin-resistant staphylococci (MRSA and MRSE) bacteremia using computer modeling. Methods A pharmacokinetic/pharmacodynamic (PK/PD) modeling strategy to explain the data from an in vitro dynamic model employing time-kill curves for MRSA and MRSE was proposed. Bacterial killing was followed over time by determining viable counts and the resulting time-kill data was analyzed. Monte Carlo simulations were performed using pharmacokinetic parameters and pharmacodynamic data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (MIC) targets of daptomycin. Simulations were conducted to assess the reduction in the number of colony-forming units (CFU)/mL for 18 days of treatment with daptomycin at doses of 6, 8, and 10 mg/kg/24 h or 48 h with variations in creatinine clearance ( CLCR): 15–29 mL/ min/1.73 m2, 30–49 mL/min/1.73 m2, 50–100 mL/min/1.73 m2, as well as for defining the probability of reaching the target fAUC/MIC = 80 in the same dose and clearance range. A PK/PD model with saturation in the number of bacteria in vitro, growth delay, and bacterial death, as well as Hill’s factor, was used to describe the data for both MRSA and MRSE. Results Monte Carlo simulations showed that for MRSA there was a reduction > 2 log CFU/mL with doses ≥ 6 mg/kg/day in 75th percentile of the simulated population after 18 days of treatment with daptomycin, whereas for MRSE this reduction was observed in 95th percentile of the population. Conclusions The presented in vitro PK/PD model and associated modeling approach were able to characterize the timekill kinetics of MRSA and MRSE. Our study based on PTAs suggests that doses ≥ 6 mg/kg/day of daptomycin should be used to treat bacteremia caused by MRSA and MRSE in patients with CLCR of 15–29 mL/min/1.73 m2. For patients with CLCR ≥ 50 mL/min/1.73 m2, it would be necessary to employ a dose of 10 mg/kg/day to treat complicated bacteremias

Time-kill curves of daptomycin and Monte Carlo simulation for the treatment of bacteraemia caused by Enterococcus faecium

Objectives The aim of this study was to investigate the effect of daptomycin against vancomycin-resistant Enterococcus faecium bacteraemia using computer modelling. Methods Data obtained in vitro from time-kill curves were evaluated by PK/PD modelling and Monte Carlo simulations to determine the logarithmic reduction in the number of colony-forming units (CFU)/mL over 18 days of daptomycin treatment at 6, 8, and 10 mg/kg doses every 24 or 48 h and with variations in creatinine clearance (CLCR) of 15–29, 30–49, and 50–100 mL/min/1.73 m2. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) for an area under the unbound drug concentration-time curve/minimum inhibitory concentration (fAUC/MIC) > 36 at the same doses and CLCR. Results Static time-kill model was employed to investigate the antibacterial efficacy of constant daptomycin concentrations. The time-kill curve analysis was performed using mathematical modelling based on a Hill coefficient factor. There was an expressive reduction (> 2 Log CFU/mL) over 18 days of daptomycin treatment in 75th percentile of individuals with CLCR of 15–100 mL/min/1.73 m2) with daptomycin 6–10 mg/kg/day, except for daptomycin every 48 h. Using fAUC/MIC > 36, PTA was > 90% at MICs ≤ 2 μg/mL. Conclusions Higher daptomycin doses were associated with higher mortality in time-kill curves. The simulations indicated that independent of the CLCR the therapeutic responses of VRE occur with doses of daptomycin ≥ 6 mg/kg/day and daptomycin every 48 h is insufficient to treat enterococcal bacteraemia

MIELITE TRANSVERSA POR HERPES VÍRUS: RELATO DE CASO

Introdução: A mielite transversa é um distúrbio neuroimune da medula espinhal, caracterizada por paresia, parestesia, disfunção intestinal ou urinária. O relato de novos casos ganha importância à medida em que a mielite transversa é uma afecção extremamente rara, com prevalência subestimada entre um a oito novos casos por milhão de pessoas por ano. A despeito disso, a necessidade de um rápido diagnóstico é crucial para evitar paraplegia e morte. Relato de caso: Paciente masculino de 24 anos, previamente hígido, descreve sinais e sintomas inespecíficos de febre, mialgia e surgimento de exantema maculopapular em membros superiores e dorso, evoluindo com dificuldade de micção e evacuação, sendo, por diversas vezes, realizado sondagem vesical de alívio e tratado, empiricamente, para infecção urinária. Após uma semana, já em atendimento hospitalar, associa ao quadro clínico lombalgia, paresia e parestesia em membros com dificuldade para deambular. A punção lombar evidenciou líquor com padrão viral e PCR positivo para Herpes Vírus I e II. A ressonância magnética de neuroeixo comprovou lesão medular extensa. Foi realizado pulsoterapia com metilprednisolona, aciclovir intravenoso por 21 dias e profilaxia para estrongiloidíase. Após 2 meses, já com recuperação significativa de marcha e controle esfincteriano, repetiu-se nova ressonância, que evidenciou ausência de lesões medulares. Comentários: As mielites possuem etiologias autoimunes, neoplásicas, vasculares ou infecciosas. No entanto, 64% dos casos são idiopáticos, dada a grande dificuldade de se estabelecer a natureza causal da infecção. Após ter sido descartada compressão medular por ressonância magnética, a história clínica típica associada com achados sugestivos de infecção no líquido cefalorraquidiano (LCR) nos aproximam do diagnóstico de mielopatia infecciosa. A mielite por Herpes Vírus pode apresentar padrão ascendente ou não ascendente e lesões cutâneas herpéticas não são prevalentes nesses casos ao contrário do quadro descrito pelo paciente