Background. Efavirenz (EFV) is metabolized primarily by cytochrome P450 2B6 (CYP2B6), and high plasma concentrations of the drug are associated with a GrT polymorphism at position 516 (516GrT) of CYP2B6 and frequent central nervous system (CNS)-related side effects. Here, we tested the feasibility of genotype-based dose reduction of EFV.Methods. CYP2B6 genotypes were determined in 456 human immunodeficiency virus type 1 (HIV-1)-infected patients who were receiving EFV treatment or were scheduled to receive EFV-containing treatment. EFV dose was reduced in CYP2B6 516GrT carriers who had high plasma EFV concentrations while receiving the standard dosage (600 mg). EFV-naive homozygous CYP2B6 516GrT carriers were treated with low-dose EFV. In both groups, the dose was further reduced when plasma EFV concentration remained high.

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Aspiration pneumonia is thought to be associated with a poor outcome in patients with community acquired pneumonia (CAP). However, there has been no systematic review regarding the impact of aspiration pneumonia on the outcomes in patients with CAP. This review was conducted using the MOOSE guidelines: Patients: patients defined CAP. Exposure: aspiration pneumonia defined as pneumonia in patients who have aspiration risk. Comparison: confirmed pneumonia in patients who were not considered to be at high risk for oral aspiration. Outcomes: mortality, hospital readmission or recurrent pneumonia. Three investigators independently identified published cohort studies from PubMed, CENTRAL database, and EMBASE. Nineteen studies were included for this systematic review. Aspiration pneumonia increased in-hospital mortality (relative risk, 3.62; 95% CI, 2.65–4.96; P < 0.001, seven studies) and 30-day mortality (3.57; 2.18–5.86; P < 0.001, five studies). In contrast, aspiration pneumonia was associated with decreased ICU mortality (relative risk, 0.40; 95% CI, 0.26–0.60; P < 0.00001, four studies). Although there are insufficient data to perform a meta-analysis on long-term mortality, recurrent pneumonia, and hospital readmission, the few reported studies suggest that aspiration pneumonia is also associated with these poor outcomes. In conclusion, aspiration pneumonia was associated with both higher in-hospital and 30-day mortality in patients with CAP outside ICU settings.

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In this study, we have evaluated the efficacy of calcium-EDTA (Ca-EDTA) as an inhibitor of bacterial metalloenzymes, such as metallo-␤-lactamase (MBL) and other proteases, in a mouse model of Pseudomonas aeruginosa pneumonia. The simultaneous presence of Ca-EDTA (32 g/ml) reduced the MICs of imipenem (IPM) in all MBL-producing P. aeruginosa isolates (IMP-1, -2, -7, and -10 and VIM-2) but not non-MBLproducing strains. In the pneumonia model, mice were intranasally infected with MBL-producing P. aeruginosa and then kept under conditions of hyperoxia to mimic ventilator-associated pneumonia. With both intranasal and subcutaneous administrations, Ca-EDTA significantly potentiated survival benefits of IPM compared to those of IPM alone. Ca-EDTA combination therapy induced a significant reduction of the bacterial burden in the lungs (P < 0.05). Furthermore, the inhibition activity of Ca-EDTA against MBL activity was confirmed by using the purified IMP-1 enzyme, which was characterized by a 50% inhibitory concentration (IC 50 ) of 55 ؎ 8.2 M. Finally, the protective effects of Ca-EDTA were demonstrated by culture supernatant-induced epithelial cell damage and acute lung injury in mice. These data suggest the therapeutic potential of Ca-EDTA not only by the blocking of MBLs but also by neutralizing tissue-damaging metalloproteases in P. aeruginosa infections.Pseudomonas aeruginosa is an opportunistic pathogen that causes a wide range of acute and chronic infections. In particular, this organism is a major cause of respiratory damage and death in patients with several types of pulmonary diseases. Recent epidemiological data demonstrated that P. aeruginosa is a leading cause of ventilator-associated pneumonia (VAP) and is associated with high mortality rates (1,8,33,36). The estimated prevalence of VAP in intensive care unit (ICU) setting ranges from 5 to 67%, and the mortality rates are 24 to 76%, according to population studies (1,8,11,18,34,35,37). It is also well known that P. aeruginosa is intrinsically resistant to a variety of antibiotics and tends to acquire resistance during and after antimicrobial treatment (24, 45). Of several resistant mechanisms, metallo-␤-lactamase (MBL)-producing P. aeruginosa is becoming a serious global concern (15, 46). MBLs confer resistance to essentially all ␤-lactams, including carbapenems, and their catalytic activities are generally not neutralized by commercially available ␤-lactamase inhibitors such as clavulanic acid and tazobactam (41). The presence of zinc in the active site of the enzymes is a characteristic feature of MBLs, which enable this group of enzymes to hydrolyze a broad range of ␤-lactams, even newly developed carbapenem antibiotics (26).EDTA is a metallo-chelator and is known to have intrinsic antimicrobial activity. Such activities include direct antimicrobial effects, potentiating the activity of other classes of antibiotics, detoxication, and neutralization of bacterial toxins/enzymes. One of the recognized modes of action of EDTA is to potentiate other antibiot...