Sera from patients with active systemic lupus erythematosus patients enhance the toll-like receptor 4 response in monocyte subsets.

BACKGROUND: Systemic Lupus Erythematosus (SLE) is an auto-immune disease whose complex pathogenesis remains unraveled. Here we aim to explore the inflammatory ability of SLE patients' sera upon peripheral blood (PB) monocyte subsets and myeloid dendritic cells (mDCs) obtained from healthy donors. METHODS: In this study we included 11 SLE patients with active disease (ASLE), 11 with inactive disease (ISLE) and 10 healthy controls (HC). PB from healthy donors was stimulated with patients' sera, toll-like receptor (TLR) 4 ligand - lipopolysaccharide or both. The intracellular production of TNF-α was evaluated in classical, non-classical monocytes and mDCs, using flow cytometry. TNF-α mRNA expression was assessed in all these purified cells, after sera treatment. RESULTS: We found that sera of SLE patients did not change spontaneous TNF-α production by monocytes or dendritic cells. However, upon stimulation of TLR4, the presence of sera from ASLE patients, but not ISLE, significantly increased the intracellular expression of TNF-α in classical and non-classical monocytes. This ability was related to titers anti-double stranded DNA antibodies in the serum. High levels of anti-TNF-α in the patients' sera were associated with increased TNF-α expression by co-cultured mDCs. No relationship was found with the levels of a wide variety of other pro-inflammatory cytokines. A slight increase of TNF-α mRNA expression was observed in these purified cells when they were cultured only in the presence of SLE serum. CONCLUSIONS: Our data suggest that SLE sera induce an abnormal in vitro TLR4 response in classical and non-classical monocytes, reflected by a higher TNF-α intracellular expression. These effects may be operative in the pathogenesis of SLE.

Clinical implications of vancomycin heteroresistant and intermediately susceptible Staphylococcus aureus.

Staphylococcus aureus (S. aureus) has proven to be a major pathogen with the emergence of methicillin-resistant S. aureus (MRSA) infections and recently with heteroresistant vancomycin-intermediate S. aureus (hVISA) and vancomycin-intermediate S. aureus (VISA) infections. Although vancomycin is traditionally a first-line and relatively effective antibiotic, its continued use is under question because reports of heteroresistance in S. aureus isolates are increasing. Both hVISA and VISA infections are associated with complicated clinical courses and treatment failures. The prevalence, mechanism of resistance, clinical significance, and laboratory detection of hVISA and VISA infections are not conclusive, making it difficult to apply research findings to clinical situations. We provide an evidence-based review of S. aureus isolates expressing heterogenic and reduced susceptibility to vancomycin.

Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime.

STUDY OBJECTIVE: To evaluate the observed incidence of acute kidney injury (AKI) in adult patients receiving either piperacillin-tazobactam and vancomycin or cefepime-vancomycin for more than 48 hours. DESIGN: Retrospective matched cohort. SETTING: Large academic medical center. PATIENTS: Adult patients without preexisting renal dysfunction admitted over an 8-month time period who received either the combination of piperacillin-tazobactam and vancomycin or cefepime-vancomycin for more than 48 hours were evaluated for AKI, defined by the Acute Kidney Injury Network criteria. MEASUREMENTS AND MAIN RESULTS: A total of 224 patients receiving either antimicrobial combination were evaluated for AKI. The incidence of AKI was significantly higher in the piperacillin-tazobactam and vancomycin group (34.8%) compared with the cefepime-vancomycin group (12.5%) in the unmatched analysis (p<0.0001). After adjusting for potential sources of bias through propensity score matched pairs and conditional logistic regression, piperacillin-tazobactam and vancomycin combination therapy (p=0.003) was an independent predictor of AKI. There were no significant differences in time to AKI or hospital length of stay between groups. CONCLUSIONS: The results of this study suggest that there may be an association between piperacillin-tazobactam and vancomycin combination therapy and increased incidence of AKI.