Ana Maria Sandri's research while affiliated with Pontifícia Universidade Católica do Rio Grande do Sul and other places

Objectives: To develop a population pharmacokinetic (PK) model with data from the largest polymyxin B-treated patient population studied to date to optimise its dosing in hospitalised patients. Methods: Hospitalised patients receiving intravenous polymyxin B for ≥48h were enrolled. Blood samples were collected at steady-state and drug concentrations were analysed by LC-MS/MS. Population PK analysis and Monte Carlo simulations were performed to determine the probability of target attainment (PTA). Results: One hundred and forty-two patients received intravenous polymyxin B (1.33-6 mg/kg/day), providing 681 plasma samples. Twenty-four patients were on renal replacement therapy (RRT), including 13 on continuous veno-venous hemodiafiltration (CVVHDF). A two-compartment model adequately described the PK with body weight as a covariate on volume of distribution that affected Cmax, but it did not impact clearance or exposure. Creatinine clearance (CrCL) was a statistically significant covariate on clearance, although clinically relevant variations of dose-normalized drug exposure were not observed across a wide CrCL range. The model described higher clearance in CVVHDF patients than in non-CVVHDF patients. Maintenance doses of ≥2.5 mg/kg/day or ≥150 mg/day had a PTA≥90% (for non-pulmonary infections target) at steady state for MICs≤2mg/L. The PTA at steady state for CVVHDF patients was lower. Conclusions: Fixed loading and maintenance doses of polymyxin B seemed to be more appropriate than weight-based dosing regimens in patients weighing 45-90kg. Higher doses may be needed in patients on CVVHDF. Substantial variability in polymyxin B clearance and volume of distribution was found, suggesting that therapeutic drug monitoring may be indicated.

Polymyxin B (PMB) has reemerged as a last‐line therapy for infections caused by multidrug‐resistant gram‐negative pathogens, but dosing is challenging because of its narrow therapeutic window and pharmacokinetic (PK) variability. Population PK (POPPK) models based on suitably powered clinical studies with appropriate sampling strategies that take variability into consideration can inform PMB dosing to maximize efficacy and minimize toxicity and resistance. Here we reviewed published PMB POPPK models and evaluated them using an external validation data set (EVD) of patients who are critically ill and enrolled in an ongoing clinical study to assess their utility. Seven published POPPK models were employed using the reported model equations, parameter values, covariate relationships, interpatient variability, parameter covariance, and unexplained residual variability in NONMEM (Version 7.4.3). The predictive ability of the models was assessed using prediction‐based and simulation‐based diagnostics. Patient characteristics and treatment information were comparable across studies and with the EVD (n = 40), but the sampling strategy was a main source of PK variability across studies. All models visually and statistically underpredicted EVD plasma concentrations, but the two‐compartment models more accurately described the external data set. As current POPPK models were inadequately predictive of the EVD, creation of a new POPPK model based on an appropriately powered clinical study with an informed PK sampling strategy would be expected to improve characterization of PMB PK and identify covariates to explain interpatient variability. Such a model would support model‐informed precision dosing frameworks, which are urgently needed to improve PMB treatment efficacy, limit resistance, and reduce toxicity in patients who are critically ill.

Introduction: Infection with vancomycin-resistant Enterococcus spp (VRE) has been a worldwide problem since mid 1980's and, in Brazil, since 1996. This study was conducted to evaluate the experience with VRE in our institution. Methods: A prospective cohort study from 2000 to 2009 was conducted at Hospital São Lucas da PUCRS. All hospitalized patients with VRE positive culture were included and followed from their diagnosis until they were negative for VRE or their discharge. Only the first admission for each VRE positive patient was included. Pulsed field gel electrophoresis (PFGE) was performed to determine how VRE had spread. Results: A total of 315 cases of VRE were identified, 224 of which were isolated from rectal swabs. Vancomycin-resistant/ampicilin susceptible Enterococcus faecalis were identified in 312 isolates. PFGE was performed in 47 VRE isolates that presented an indistinguishable migratory profile. The median length of hospital stay and length of stay before VRE isolation were 46 days and 21 days, respectively; 52% of the patients were aged 60 and above. The annual distribution of the new VRE cases showed a clear decrease from 2000 to 2009. Discussion: This study shows a substantial VRE colonization (71%) with a homogenous pattern that emphasizes its transversal spread. Predominance of E. faecalis differs from the literature which largely describes a higher prevalence of vancomycin-resistant Enterococcus faecium . The follow up of VRE during 9 years in our institution highlighted the importance of continuous surveillance to prevent outbreaks in our hospital.

Background: Polymyxin B is a last-line therapy for multidrug-resistant gram-negative bacteria. There is a dearth of pharmacokinetic data to guide dosing in critically ill patients. Methods: Twenty-four critically ill patients were enrolled and blood/urine samples were collected over a dosing interval at steady state. Polymyxin B concentrations were measured by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic analysis and Monte Carlo simulations were conducted. Results: Twenty-four patients aged 21-87 years received intravenous polymyxin B (0.45-3.38 mg/kg/day). Two patients were on continuous hemodialysis, and creatinine clearance in the other patients was 10-143 mL/min. Even with very diverse demographics, the total body clearance of polymyxin B when scaled by total body weight (population mean, 0.0276 L/hour/kg) showed remarkably low interindividual variability (32.4% coefficient of variation). Polymyxin B was predominantly nonrenally cleared with median urinary recovery of 4.04%. Polymyxin B total body clearance did not show any relationship with creatinine clearance (r(2) = 0.008), APACHE II score, or age. Median unbound fraction in plasma was 0.42. Monte Carlo simulations revealed the importance of initiating therapeutic regimens with a loading dose. Conclusions: Our study showed that doses of intravenous polymyxin B are best scaled by total body weight. Importantly, dosage selection of this drug should not be based on renal function.

Objectives: To evaluate the pharmacokinetics of polymyxin B in patients on continuous venovenous haemodialysis (CVVHD) after intravenous administration of unadjusted dosage regimens. Patients and methods: Two critically ill patients had eight blood samples collected during a 12 h interval on days 8 and 10 of polymyxin B therapy. Dialysate was collected every hour during the 12 h dosing interval. Polymyxin B binding in plasma was determined by rapid equilibrium dialysis. Concentrations of polymyxin B in plasma and dialysate samples were quantified using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay. Results: Respective maximum plasma concentrations in patients 1 and 2 were 8.62 and 4.38 mg/L; total body clearances (scaled linearly by body weight) were 0.043 and 0.027 L/h/kg, respectively, of which 12.2% and 5.62% were dialysis clearance, respectively. The corresponding volumes of distribution of polymyxin B at steady state were 0.50 and 0.34 L/kg, respectively, and protein binding in pooled plasma samples was 74.1% and 48.8%, respectively. Conclusions: Our findings indicate that the recommended polymyxin B doses should not be reduced for patients on CVVHD.

Outbreaks by carbapenem-resistant Providencia stuartii (CRPS) are rarely described. Clinical characteristics of patients with CRPS in an intensive care unit and resistance mechanisms were investigated. Carbapenemase production and/or outer membrane alterations were not detected; only CTX-M-2 and AmpC hyperproduction were noted. The outbreak was ultimately controlled in a 3-month period.

After the introduction of routine treatment for every nasal carrier of methicillin-resistant Staphylococcus aureus, active follow-up surveillance for nosocomial methicillin-resistant S. aureus infection was conducted for 5 years in an intensive care unit of a tertiary-care teaching hospital. There was a significant decrease in the incidence of nosocomial methicillin-resistant S. aureus infection during the later years of follow-up. Decolonization of nasal carriers of methicillin-resistant S. aureus is probably associated with such findings.