Aims
To characterize the demographic and pharmacogenetic factors that influence interpatient variability in the plasma concentrations of the HIV non‐nucleoside reverse transcriptase inhibitor efavirenz.
Methods
Data from all samples analyzed for efavirenz in our TDM service in 2002 and 2003 were reviewed. Information on gender, age, body weight, height, race, hormonal contraceptive use (in a subset of patients), and time between sampling and last intake was recorded. PCR‐restriction fragment length polymorphism analysis was performed to detect the cytochrome P450 2B6 (CYP2B6) C1459T variant (present in CYP2B6*6 and CYP2B6*7) which is associated with low CYP2B6 activity.
Results
A total of 255 patients were included in this analysis. The median plasma efavirenz concentration was 2.50 (interquartile range: 1.85–3.55) mg l−1. Eight patients (3.1%) were considered to have a subtherapeutic plasma concentration (<1.0 mg l−1) and 48 (18.9%) a toxic efavirenz concentration (>4.0 mg l−1). Gender, time after last intake, and race were the only factors that were significantly related to plasma efavirenz concentration in a multivariate analysis. No influence was observed for body weight, hormonal contraceptive use, and the presence of the CYP2B6 C1459T polymorphism.
Conclusions
Gender and race are important factors in determining interpatient variability in plasma efavirenz concentrations which were unaffected by the presence of the CYP2B6 C1459T polymorphism. Physicians should be particularly alert for signs of efavirenz‐induced toxicity in females and non‐Caucasian patients.
Antibiotics with different mechanisms of action may vary with respect to their effects on the release and immunostimulatory activities of cell wall fragments from gram-positive bacteria. Therefore, after Staphylococcus aureus was cultured for 4 h in the absence of antibiotics (control) and in the presence of β-lactam antibiotics (imipenem, flucloxacillin, or cefamandole) and protein synthesis-inhibiting antibiotics (erythromycin, clindamycin, or gentamicin), the lipoteichoic acid (LTA) and peptidoglycan (PG) levels in the bacterial supernatants were measured. β-Lactam antibiotics greatly enhanced the release of LTA and PG (4- to 9-fold and 60- to 85-fold, respectively), whereas protein synthesis inhibitors did not affect PG release and even inhibited the release of LTA compared to the amount of LTA released in control cultures. The capacity of β-lactam supernatants to stimulate the production of tumor necrosis factor alpha and interleukin-10 in human whole blood was significantly higher than that of protein synthesis inhibitor or control supernatants; the amounts of these cytokines released were directly proportional to the concentrations of PG and LTA in the supernatants. Enzymatic degradation of PG in the supernatants indicated that PG was mainly responsible for the observed biological reactivity.
Two patients, returning to the Netherlands from pilgrimage in Medina and Mecca, Kingdom of Saudi Arabia, were diagnosed with Middle East respiratory syndrome coronavirus (MERS-CoV) infection in May 2014. The source and mode of transmission have not yet been determined. Hospital-acquired infection and community-acquired infection are both possible.
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