Identification of risk factors for nephrotoxicity in patients receiving extended-duration, high-trough vancomycin therapy.

BACKGROUND: In the past, impurities in vancomycin formulations were thought to contribute to nephrotoxicity. In contrast, when current, purer formulations are dosed at conventional trough levels (i.e., 5-15 mg/L), the incidence of nephrotoxicity is relatively low. Recent guidelines have recommended targeting higher vancomycin trough levels in treatment of complicated methicillin-resistant Staphylococcus aureus infections. Dosing based on these higher trough levels may be associated with nephrotoxicity, so the potential risk factors for vancomycin-associated nephrotoxicity require clearer definition. OBJECTIVES: To determine the occurrence of nephrotoxicity in patients receiving more than 7 days of vancomycin therapy with high trough levels (15-20 mg/L) and to identify and evaluate specific risk factors related to development of vancomycin-associated nephrotoxicity (i.e., serum creatinine ≥ 44.2 µmol/L or increase ≥ 50% [i.e., ≥ 26.2 µmol/L] from baseline on 2 consecutive days). METHODS: Health care records were reviewed for patients seen at 2 major teaching hospitals between January 2008 and March 2011. Patients who had attained high trough levels of vancomycin were screened for eligibility. Patients with unstable renal function, those undergoing hemodialysis, and those for whom dosage and/or sampling times were unclear were excluded. Univariate and multivariate analyses were performed to identify risk factors associated with nephrotoxicity. Univariate variables with p < 0.1 were included in the logistic regression model. RESULTS: Of the 176 patients with high trough levels included in the analysis, 24 (14%) experienced nephrotoxicity. In univariate analysis, admission to a general medicine unit (the setting of care for 16 [67%] of the 24 patients with nephrotoxicity) and extended duration of vancomycin treatment were identified as risk factors for nephrotoxicity (p < 0.1). Other risk factors included gastrointestinal comorbidity (p = 0.056), malignancy (p = 0.044), and febrile neutropenia (p = 0.032). Multivariate analysis identified treatment on general medicine units and treatment courses longer than 7 days as independent predictors of vancomycin-associated nephrotoxicity. CONCLUSION: Patients being treated on general medicine units and those receiving vancomycin for more than 7 days had an increased likelihood of experiencing nephrotoxicity. The increased risk for patients on general medicine units is likely multifactorial. The relationship between treatment duration and risk of nephrotoxicity appeared to be linear. When using extended-duration, high-trough vancomycin therapy, clinicians should be vigilant in monitoring for nephrotoxicity.

CONTEXTE: On croyait autrefois que les impuretés contenues dans les préparations de vancomycine pouvaient contribuer à causer une néphrotoxicité. D'un autre côté, lorsque les préparations actuelles plus pures sont dosées selon les concentrations minimales classiques (c.-à-d., 5­15 mg/L), les cas de néphrotoxicité sont relativement peu nombreux. Des lignes directrices récentes recommandaient de viser des concentrations minimales plus élevées de vancomycine pour traiter les infections compliquées à Staphylococcus aureus résistant à la méthicilline. Comme ces concentrations minimales plus élevées peuvent être associées à la néphrotoxicité, il est nécessaire de mieux définir les facteurs de risque potentiels de néphrotoxicité associée à l'administration de vancomycine. OBJECTIFS: Déterminer le nombre de cas de néphrotoxicité chez les patients recevant un traitement de vancomycine de plus de sept jours avec des concentrations minimales élevées (15­20 mg/L), ainsi que cerner et évaluer les facteurs de risque précis associés à une néphrotoxicité causée par la vancomycine (c.-à-d., une créatinine sérique de ≥ 44,2 µmol/L ou une augmentation de ≥ 50 % [c.-à-d., ≥ 26,2 µmol/L] par rapport aux valeurs de base pendant deux jours consécutifs). MÉTHODES: Les dossiers médicaux des patients rencontrés entre janvier 2008 et mars 2011 dans deux importants hôpitaux universitaires ont été examinés. Les patients chez qui les concentrations minimales de vancomycine avaient atteint des valeurs élevées ont été évalués afin de juger s'ils étaient admissibles. Les patients dont la fonction rénale était instable, ceux qui subissaient une hémodialyse et ceux pour qui la posologie ou le temps d'échantillonnage n'étaient pas clairs ont été exclus. Des analyses univariée et multivariée ont été effectuées pour cerner les facteurs de risque associés à une néphrotoxicité. Les variables univariées dont le p était inférieur à 0,1 ont été incorporées dans le modèle de régression logistique. RÉSULTATS: Parmi les 176 patients avec des concentrations minimales élevées, 24 (14 %) ont souffert de néphrotoxicité. Lors de l'analyse univariée, l'hospitalisation dans un service de médecine générale (unité où les soins étaient prodigués pour 16 [67 %] des 24 patients souffrant de néphrotoxicité) ainsi que la prolongation du traitement avec la vancomycine ont été reconnues comme des facteurs de risque de néphrotoxicité (p < 0,1). La comorbidité gastro-intestinale (p = 0,056), le cancer (p = 0,044) et la neutropénie fébrile (p = 0,032) représentaient aussi des facteurs de risque. L'analyse multivariée a déterminé que le traitement dans un service de médecine générale et les traitements de plus de sept jours étaient des indicateurs indépendants de risque de néphrotoxicité associée à la prise de vancomycine. CONCLUSION: Les patients ayant été traités dans un service de médecine générale et ceux ayant reçu un traitement de vancomycine de plus de sept jours présentaient un plus grand risque de néphrotoxicité. Le risque accru pour les patients séjournant dans un service de médecine générale est probablement multifactoriel. Le lien entre la durée du traitement et le risque de néphrotoxicité semble linéaire. Lorsqu'ils font appel à un traitement de vancomycine à concentration minimale élevée, les cliniciens doivent procéder à un suivi attentif pour déceler tout signe de néphrotoxicité. [Traduction par l'éditeur].

Mode of action, in vitro activity, and in vivo efficacy of AFN-1252, a selective antistaphylococcal FabI inhibitor.

The mechanism of action of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), which is involved in fatty acid biosynthesis, was confirmed by using biochemistry, macromolecular synthesis, genetics, and cocrystallization of an AFN-1252-FabI complex. AFN-1252 demonstrated a low propensity for spontaneous resistance development and a time-dependent reduction of the viability of both methicillin-susceptible and methicillin-resistant S. aureus, achieving a ≥2-log(10) reduction in S. aureus counts over 24 h, and was extremely potent against clinical isolates of S. aureus (MIC(90), 0.015 µg/ml) and coagulase-negative staphylococci (MIC(90), 0.12 µg/ml), regardless of their drug resistance, hospital- or community-associated origin, or other clinical subgroup. AFN-1252 was orally available in mouse pharmacokinetic studies, and a single oral dose of 1 mg/kg AFN-1252 was efficacious in a mouse model of septicemia, providing 100% protection from an otherwise lethal peritoneal infection of S. aureus Smith. A median effective dose of 0.15 mg/kg indicated that AFN-1252 was 12 to 24 times more potent than linezolid in the model. These studies, demonstrating a selective mode of action, potent in vitro activity, and in vivo efficacy, support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections.

Development and validation of a novel vancomycin dosing nomogram for achieving high-target trough levels at 2 canadian teaching hospitals.

BACKGROUND: Recent guidelines recommend a vancomycin trough (predose) level between 15 and 20 mg/L in the treatment of invasive gram-positive infections, but most initial dosing nomograms are designed to achieve lower targets (5-15 mg/L). Clinicians need guidance about appropriate initial dosing to achieve the higher target. OBJECTIVE: To develop and validate a high-target vancomycin dosing nomogram to achieve trough levels of 15-20 mg/L. METHODS: A retrospective study was conducted at 2 teaching hospitals, St Paul's Hospital and Vancouver General Hospital in Vancouver, British Columbia. Patients who were treated with vancomycin between January 2008 and June 2010 and who had achieved a trough level of 14.5-20.5 mg/L were identified. Demographic and clinical data were collected. Multiple linear regression was used to develop a vancomycin dosing nomogram for each hospital site. An integrated nomogram was constructed by merging the data from the 2 hospitals. A unique set of patients at each institution was used for validating their respective nomograms and a pooled group of patients for validating the integrated nomogram. Predictive success was evaluated, and a nomogram was deemed significantly different from another nomogram if p < 0.05 via "χ(2) testing. RESULTS: Data from 78 patients at one hospital and 91 patients at the other were used in developing the respective institutional nomograms. For each hospital's data set, both age and initial serum creatinine were significantly associated with the predicted dosing interval (p < 0.001). Validation in a total of 105 test patients showed that the integrated nomogram had a predictive success rate of 56%. CONCLUSIONS: A novel vancomycin dosing nomogram was developed and validated at 2 Canadian teaching hospitals. This integrated nomogram is a tool that clinicians can use in selecting appropriate initial vancomycin regimens on the basis of age and serum creatinine, to achieve high-target levels of 15-20 mg/L. The nomogram should not replace clinical judgment for patients with unstable and/or reduced renal function.

Expression profiling of herpesvirus and vaccinia virus proteins using a high-throughput baculovirus screening system.

We have developed a high-throughput system for generating baculoviruses and testing the expression, solubility, and affinity column purification of encoded proteins. We have used this system to generate baculoviruses for and analyze the expression of 337 proteins from three different herpesviruses (HSV-1, EBV, and CMV) and vaccinia virus. Subsets of these proteins were also tested for expression and solubility in E. coli. Comparisons of the results in the two systems are presented for each virus.