A pharmacokinetic/pharmacodynamic analysis of ceftaroline prophylaxis in patients with external ventricular drains.

BACKGROUND: Ceftaroline is a broad-spectrum cephalosporin antibiotic with activity against drug-resistant bacteria, including strains of methicillin-resistant Staphylococcus aureus (MRSA), and may be useful to prevent and treat ventriculostomy-related infections (VRIs). The purpose of this study was to analyze the pharmacokinetics and pharmacodynamics of prophylactic ceftaroline in neurosurgical patients with an external ventricular drain (EVD). METHODS: Adult patients in the neurosurgical intensive care unit with an EVD were given prolonged prophylaxis with ceftaroline. Serum and cerebral spinal fluid (CSF) were obtained simultaneously at 2, 6, and 12 h after initiation of the fourth dose of ceftaroline and concentrations were measured by a liquid chromatography tandem mass spectrometry assay. Time-kill curves against isolates of coagulase-negative S. aureus, methicillin-sensitive S. aureus, MRSA, and Streptococcus pneumoniae were determined in serum and CSF at each collection time point. RESULTS: A total of five patients with a mean age of 63 y and mean weight of 83 kg were enrolled. The mean CSF:serum penetration ratios of ceftaroline were 0.005 (0.5%), 0.021 (2.1%), and 0.043 (4.3%) at 2, 6, and 12 h, respectively. The mean ceftaroline exposure ratio area under the curve (AUC)csf/AUCserum) was 0.011 (1.1%). Bactericidal activity at each collection time point was observed against each strain of staphylococci from serum samples and a penicillin-sensitive strain of S. pneumoniae from CSF samples. CONCLUSION: This investigation suggests that ceftaroline could have clinical utility for the prevention of VRIs in patients with EVDs.

Chemical venous thromboembolic prophylaxis is safe and effective for patients with traumatic brain injury when started 24 hours after the absence of hemorrhage progression on head CT.

BACKGROUND: Venous thromboembolism (VTE) continues to be an important complication for patients with trauma, including patients with intracranial hemorrhage. We implemented a protocol starting chemical prophylaxis 24 hours after the absence of progression of hemorrhage on computed tomography (CT) to increase consistency with the use of chemical venous thromboembolic prophylaxis in this population. The objective of this study was to review the protocol of VTE prophylaxis for patients with traumatic brain injury at our institution to determine whether it has been effective and safe in preventing VTE without increasing intracranial hemorrhage. METHODS: A retrospective case series was conducted to study 205 patients with intracranial hemorrhage admitted to a Level I trauma center during a 24-month period. These patients were reviewed with respect to type of intracranial injury, need for surgery, injury severity, time to initiation of chemical prophylaxis, and progression of injury on brain CT. Patients with a hospital length of stay less than 3 days or nonstable CT were excluded in the analysis of administration of chemical prophylaxis. Time to chemical prophylaxis in relation to absence of progression on brain CT was examined as well as the subsequent risk of progression of hemorrhage and risk of VTE events. The overall rate of venous thromboembolism was compared with that of matched historical controls. RESULTS: All patients received mechanical prophylaxis in the form of sequential compression devices. One hundred sixty-two intracranial hemorrhages were identified in 122 patients who met the study's inclusion criteria. Of this group of patients who did not have progression of hemorrhage on follow-up CT, 76.2% received chemical prophylaxis during their hospitalization.No patients had progression of intracranial hemorrhage after initiation of chemical VTE prophylaxis, and no patients developed VTE. This represents a decrease of VTE from previous years. No other complications related to chemical VTE prophylaxis were identified. CONCLUSION: A protocol based on an early use of chemical venous thromboembolic prophylaxis after the absence of progression of tramatic intracranial hemorrhage does not result in increased progression of intracranial hemorrhage and reduced the rate of venous thromboembolic events at our institution.

CCR7/CCL19 controls expression of EDG-1 in T cells.

T lymphocytes circulate between the blood, tissues, and lymph. These T cells carry out immune functions, using the C-C chemokine receptor 7 (CCR7) and its cognate ligands, CCL19 and CCL21, to enter and travel through the lymph nodes. Distinct roles for each ligand in regulating T lymphocyte trafficking have remained elusive. We report that in the human T cell line HuT78 and in primary murine T lymphocytes, signaling from CCR7/CCL19 leads to increased expression and phosphorylation of extracellular signal-regulated kinase 5 (ERK5) within eight hours of stimulation. Within 48-72 h we observed peak levels of endothelial differentiation gene 1 (EDG-1), which mediates the egress of T lymphocytes from lymph nodes. The increased expression of EDG-1 was preceded by up-regulation of its transcription factor, Krüppel-like factor 2 (KLF-2). To determine the cellular effect of disrupting ERK5 signaling from CCR7, we examined the migration of ERK5(flox/flox)/Lck-Cre murine T cells to EDG-1 ligands. While CCL19-stimulated ERK5(flox/flox) naïve T cells showed increased migration to EDG-1 ligands at 48 h, the migration of ERK5(flox/flox)/Lck-Cre T cells remained at a basal level. Accordingly, we define a novel signaling pathway that controls EDG-1 up-regulation following stimulation of T cells by CCR7/CCL19. This is the first report to link the two signaling events that control migration through the lymph nodes: CCR7 mediates entry into the lymph nodes and EDG-1 signaling controls their subsequent exit.