These data strongly suggest that colistin may be an important option for combination therapy against critical MDRP infections. For pneumonia especially, intranasal colistin with rifampicin may be beneficial not only for synergistic antibacterial activity, but also for blocking LPS.
Legionella pneumophila is an intracellular organism and the major aetiological agent of Legionnaires' disease. Although recent progress has identified Toll-like receptors (TLRs) as receptors for recognition of pathogen-associated molecular patterns in a variety of microorganisms, understanding the contribution of TLRs to the host response in L. pneumophila infection is still limited. This study examined the roles of TLR2 and TLR4 in murine L. pneumophila pneumonia and an in vitro infection model using bone-marrow-derived macrophages. TLR2-deficient mice, but not TLR4-deficient mice, demonstrated higher lethal sensitivity to pulmonary challenge with L. pneumophila than wild-type mice (P<0.05). Although no differences in pulmonary bacterial burden were observed among the mouse strains examined, lower values of macrophage inflammatory protein-2 (MIP-2), keratinocyte-derived cytokine and interleukin (IL)-6 and higher IL-12 levels were noted in lung homogenates of TLR2-deficient mice compared with the wild-type control and TLR4-deficient mice. Recruitment of inflammatory cells, particularly neutrophils, was severely disturbed in the lungs of TLR2-deficient mice. Reduced MIP-2 production was demonstrated in bone-marrow-derived macrophages from TLR2-deficient mice in response to live L. pneumophila and purified LPS of this strain, but not Escherichia coli LPS. These data highlight the involvement and importance of TLR2 in the pathogenesis of L. pneumophila pneumonia in mice. The results showed that TLR2-mediated recognition of Legionella LPS and subsequent chemokine-dependent cellular recruitment may be a crucial host innate response in L. pneumophila pneumonia.
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...
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