Ana Maria Sandri

Population Pharmacokinetics of Intravenous Polymyxin B in Critically Ill Patients: Implications for Selection of Dosage Regimens

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.

Reduction in incidence of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection in an intensive care unit: role of treatment with mupirocin ointment and chlorhexidine baths for nasal carriers of MRSA.

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.

Pharmacokinetics of polymyxin B in patients on continuous venovenous haemodialysis

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.

Treatment of hepatitis B virus-associated nephropathy.

Epidemiological studies have shown a relationship between hepatitis B virus (HBV) infection and development of proteinuria in some patients (most commonly children), with a predominance for male gender and histological findings of membranous nephropathy on renal biopsy. The presence of immune complexes in the kidney suggests an immune complex basis for the disease, but a direct relation between HBV and membranous nephropathy (or other types of glomerular diseases) remains to be proven. Clearance of HBV antigens, either spontaneous or following antiviral treatments results in improvement in proteinuria. Thus, prompt recognition and specific antiviral treatment are critical in managing patients with HBV and renal involvement. The present review focuses on treatment of HBV with special emphasis given to antiviral therapies, its complications, and dosing in patients with HBV-associated kidney disease.

Detection of blaKPC-2 in a carbapenem-resistant Kluyvera georgiana

Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Unidade de Microbiologia e Biologia Molecular, Servico de Patologia Clinica, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil; Infectious Diseases Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil; Infection Control Service, Hospital Sao Lucas da Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil; Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Sao Paulo, Brazil; Microbiologia—Fleury Medicina e Saude, Sao Paulo, Brazil

Outbreak of Carbapenem-Resistant Providencia stuartii in an Intensive Care Unit

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.

Treatment of HIV-Associated Nephropathies

In patients with HIV, the use of highly active antiretroviral therapy has improved life expectancy. At the same time, this increase in life expectancy has been associated with a higher frequency of chronic kidney disease due to factors other than HIV infection. Besides HIV-associated nephropathy, a number of different types of immune complex and non-immune complex-mediated processes have been identified on kidney biopsies, including vascular disease (nephrosclerosis), diabetes, and drug-related renal injury. In this setting, renal biopsy needs to be considered in order to obtain the correct diagnosis in individual patients with HIV and kidney impairment. Many issues regarding the optimal treatment of the different pathological processes affecting the kidneys of these patients have remained unresolved. Further research is needed in order to optimize treatment and renal outcomes in patients with HIV and kidney disease.

Treatment of hepatitis C-mediated glomerular disease

Chronic kidney disease (CKD) is becoming a major public health issue worldwide, mainly due to the increasing prevalence of hypertension, diabetes and aging population. Chronic hepatitis C virus (HCV) infection commonly involves the kidneys, can be a cause of CKD, and significantly impacts morbidity and mortality in these patients. Prompt recognition and knowledge of how to best manage these patients are essential in order to have a successful renal outcome. Patients with HCV and kidney involvement can often be managed with a specific combination of antiviral drugs, immunosuppressants, plasmapheresis, and newer monoclonal antibodies. However, no large randomized controlled trials have been conducted in this patient population, optimal management of HCV-mediated kidney diseases is not well defined, and treatment itself can be associated with significant toxicity in patients with CKD. This article reviews the recent literature, discusses the limitations of current therapies, as well as toxicity associated with treatment, and suggests future areas for research.

Reply to Pai

TO THE EDITOR—We thank Dr Pai for highlighting the importance of optimal dosing of polymyxins [1]. As described in our original paper [2], a number of commonly used approaches to account for body size were extensively evaluated via population modeling and covariate analysis. These body size models included allometric and linear scaling by both total body weight (TBW) and lean body weight (LBW), the latter requiring calculations using TBW, height, and sex [3]. All of these 4 body size models resulted in unbiased and adequately precise population-predicted polymyxin B concentrations, in contrast to the base model without scaling. As mentioned in our paper, utilizing allometric or linear scaling by LBW did not provide a benefit in reducing the unexplained (ie, random) between-subject variability (BSV) in clearance and volume of distribution compared to allometric or linear scaling by TBW. As also reported in our paper, allometric scaling by TBW (ie, [TBW/70 kg]) provided only a marginal reduction in the BSV of clearance compared to linear scaling by TBW. Dosing via an allometric approach is substantially more complex than dosing by milligrams per kilogram TBW, and this additional complexity did not appear to be justified by the marginal reduction in BSV. For this reason, Monte Carlo simulations were based on linear scaling by TBW [2]. Dr Pai focused on 2 potential “outlier” patients [1]. It should be noted that any patient population, particularly the critically ill, may contain patients with extreme body size–adjusted clearance values. If each patient was dosed based on individual body size to achieve a specific polymyxin target area under the curve (AUC), the 41-kg patient would be underdosed by 48%–56% with any of the 4 scaling approaches, including scaling by LBW. The 250-kg patient would be overdosed by 27% based on linear scaling with TBW, but would be underdosed by 26%–39% based on linear or allometric scaling by LBW and by 66% without any scaling. Therefore, dose-adjusting for body size by any method would allow more accurate dosing of the 250-kg patient compared to no scaling. It is critical to suggest an optimized dosing approach based on the entire available patient population; considering all 24 patients [2], the accuracy of dosing by different scaling methods was very similar. Therefore, we reported the most clinician-friendly scaling approach (ie, dosing as milligrams per kilogram TBW). Although our comprehensive covariate analysis identified body size as the only patient covariate influencing polymyxin B clearance in our population, clearly other as yet unidentified factors may exist. As stated in the conclusions [2], further clinical studies on polymyxin B pharmacokinetics and pharmacodynamics are urgently needed. This certainly includes future studies on polymyxin B pharmacokinetics in obese patients, which will enable researchers to make specific dosage recommendations for this patient population.

Vancomycin resistant enterococcus spp (VRE): follow up during 9 years in a tertiary teaching hospital in southern Brazil

Introduction: Infection with vancomycin-resistant Enterococcus spp (VRE) has been a worldwide problem since mid 1980s 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 Sao 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.