Pharmacokinetics and pharmacodynamics of linezolid in obese patients with cellulitis

BACKGROUND: Linezolid is an oxazolidinone antimicrobial with excellent oral bioavailability and tissue penetration and is active against multidrug-resistant skin/soft tissue pathogens. OBJECTIVE: To study the pharmacokinetics and antibacterial activity of linezolid against selective skin/soft tissue pathogens in obese patients. METHODS: We obtained multiple serum samples from 7 obese patients (>50% over their calculated ideal body weight) receiving oral linezolid 600 mg every 12 hours for treatment of cellulitis. Following a minimum of 3 doses, serum concentrations of linezolid were measured in each subject prior to (trough) and 1 and 6 hours after a dose. These samples were then tested against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) (linezolid minimum inhibitory concentrations [MICs] 1.0, 2.0, 4.0 microg/mL) and one strain each of vancomycin-resistant Enterococcus faecium (VRE) (MIC 2.0 microg/mL), Bacteroides fragilis (MIC 2.0 microg/mL), and Peptostreptococcus magnus (MIC 1.0 microg/mL). Serum inhibitory titers (SITs) and bactericidal titers (SBTs) were measured at each time point, and the median activity for these 7 patients was calculated. RESULTS: Mean linezolid serum concentrations were 4.2, 12.3, and 7.2 microg/mL at these respective time points. Median SITs for 12 hours (100% of the dosing interval) were observed against each organism with the exception of the least susceptible strain of MRSA (MIC 4.0 microg/mL); serum inhibitory activity was observed only at the one-hour time point against this isolate. Furthermore, prolonged (> or =6 h) median SBTs were observed against one isolate of MRSA (MIC 1.0 microg/mL) as well as the strain of VRE and P. magnus. CONCLUSIONS: Serum concentrations of oral linezolid in this patient population were diminished compared with those of healthy volunteers, but still provided prolonged serum inhibitory activity against common pathogens associated with skin/soft tissue infections. One treatment concern would be an obese patient receiving oral linezolid who was infected with a less susceptible (MIC > or =4.0 microg/mL) strain of S. aureus. Bactericidal activity was also observed against selective pathogens.     

Novel functional role of heat shock protein 90 in ATP-sensitive K+ channel-mediated hypoxic preconditioning

AIMS: ATP-sensitive K+ (K ATP) channels are implicated in the protective effect of ischaemic preconditioning (IPC). Kir6.2 has been shown to be involved in the cardioprotection of IPC. However, the mechanism by which Kir6.2-containing K ATP channels protect the heart is still largely unknown. The present study was designed to explore the potential mechanism involved in K ATP channel-mediated cardioprotection. METHODS AND RESULTS: Cellular models of hypoxic preconditioning (HP) from rat heart-derived H9c2 cells and adult rat cardiomyocytes were employed. Dominant negative and small interfering RNA (siRNA) technology were utilized in combination with biochemical, immunofluorescent, and cell viability assays. The cell viability study revealed that HP significantly increased the viable cells after prolonged hypoxia and reoxygenation. This protective effect was prevented by expression of dominant negative Kir6.2AAA, siRNA targeting Kir6.2, or the K ATP channel inhibitor 5-hydroxydecanoate. Further, our data showed that inhibiting heat shock protein 90 (HSP90) function with the HSP90 inhibitor geldanamycin or HSP90 expression with siRNA completely inhibited the protection of HP. We found that HSP90 was associated with Kir6.2 and its activity was linked to mitochondrial targeting of Kir6.2. CONCLUSION: We demonstrate that Kir6.2 is critical in HP of cardiomyocytes. Importantly, we show that HSP90 is involved in K ATP-mediated cytoprotection, possibly by promoting mitochondrial targeting of Kir6.2.     

The impact of respiration on left atrial and pulmonary venous anatomy: Implications for image-guided intervention

BACKGROUND: Image-guided intervention using pre-acquired CT/MR 3-dimensional images is an emerging strategy for atrial fibrillation (AF) ablation but may be limited by its use of static images to depict dynamic physiology. The effect of biologic factors such as respiration on the left atrial-pulmonary venous (LA-PV) anatomy is not well understood but is likely to have important implications. Conventional CT/MR imaging is performed during an inspiratory breath-hold, while electroanatomical mapping (EAM) during "quiet" breathing approximates an expiratory breath-hold. This study examined the effects of respiration on LA-PV anatomy and the error introduced by respiration on the integration of EAM with 3D MR imaging. METHODS: Pre-procedural MRI angiography was performed at both end-expiration (EXP) and end-inspiration (INSP) in 20 patients undergoing AF catheter ablation. 3D INSP and EXP surface reconstructions of the LA-PVs were compared. In selected pts, EAM data acquired during the ablation procedure (n=7) were integrated with the 3D MRI datasets. RESULTS: Qualitative assessment of the INSP and EXP 3D images revealed splaying of the PVs and reduction in PV caliber of the right-sided PVs during held inspiration. After aligning these two datasets, the average surface-to-surface distance calculated by region ranged from 1.99mm (right middle PV) to 3.79mm (left superior PV). Registration of the EAM to the MRI models was better for the EXP dataset (2.30+/-0.73mm) than the INSP dataset (3.03+/-0.57mm; p=0.004). CONCLUSION: There are significant changes in LA-PV anatomy with respiration. MR images acquired during standard held inspiration may introduce unnecessary errors in registration during image-guided intervention.     

Donor management in cardiac transplantation

The most important limitation in organ transplantation is donor availability. Canada is facing a serious situation with respect to organ donation rates and transplantation. The number of patients listed for heart transplant continues to increase while the number of available donors has plateaued. Several steps can be taken to address this growing mismatch. The proper identification and assessment of potential donors together with improvements in medical management may increase the donor pool. Additionally, the use of marginal donors and the development of new organ preservation techniques may lead to an increase in the number of potential heart transplants in Canada. This paper summarizes the identification, evaluation and management of heart transplant donors, and defines strategies to improve procurement activity in heart transplantation.     

Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature

POEMS syndrome is characterized by peripheral neuropathy (PN), a clonal plasma cell disorder (PCD), organomegaly, endocrinopathy, skin changes, edema, sclerotic bone lesions, and thrombocytosis. Based on the improved response rates observed with peripheral blood stem cell transplantation (PBSCT) in patients with other PCDs, autologous PBSCT may be an attractive treatment option for this syndrome. Sixteen patients with POEMS syndrome have undergone PBSCT at Mayo. Of these patients, 15 had a severe rapidly progressive sensorimotor PN (9 were wheelchair dependent) and 14 were male. Median age was 51 years (range, 19-62 years). The median number of prior therapies was 3 (range, 0-7). From first symptoms and from diagnosis of POEMS the times to transplantation were 42 months and 5 months (ranges, 8-185 months and 2-149 months), respectively. There were 15 patients who had significantly abnormal pretransplant pulmonary function tests. There was one transplant-related death. During the peritransplant period, 5 patients required intubation for respiratory compromise, including one who required intubation during his stem cell mobilization period. Another patient required noninvasive biphasic positive airway pressure throughout his course. Of the 14 evaluable patients, all have had neurologic improvement or stabilization. Other features have improved substantially. PBSCT for POEMS syndrome is effective therapy but may also be associated with significant morbidity.