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Objective: Fluoroquinolones and 3rd-generation cephalosporins that are prescribed for pneumonia may be avoided and replaced by a penicillin in some cases. We aimed to determine if the proportion of patients treated for pneumonia with a cephalosporin, a fluoroquinolone or both varies among Emergency Departments (EDs), and to estimate the proportion of avoidable prescriptions. Methods: This was a retrospective study of patients treated for pneumonia in eight French EDs, and subsequently hospitalized in non-ICU wards. Third-generation cephalosporins or respiratory fluoroquinolones were presumed unavoidable if they met both criteria: (1) age ≥65 years or comorbid condition; and (2) allergy or intolerance to penicillin, or failure of penicillin, or previous treatment with penicillin, or for fluoroquinolones only, suspected legionellosis. Results: We included 832 patients. Thirty-four percent (95 % CI, 31-38 %) of patients were treated with a cephalosporin, a respiratory fluoroquinolone or both (range among EDs 19-44 %). Four EDs were independent risk factors for prescription of a cephalosporin, a fluoroquinolone or both [adjusted OR, 2.27 (1.64-3.15)], as were immune compromise [aOR 2.54 (1.56-4.14)], antibacterial therapy started before arrival in the ED [aOR 3.32 (2.30-4.81)], REA-ICU class III or IV [aOR 1.93 (1.15-3.23)], PSI class V [aOR 1.49 (1.00-2.20)], fluid ressuscitation [aOR 3.98 (2.49-6.43)] and non-invasive ventilation in the ED [aOR, 7.18 (1.7-50.1)]. Treatment with a cephalosporin, a fluoroquinolone or both was avoidable in 67 % (62-73 %) of patients. Conclusion: Cephalosporins and fluoroquinolones use in pneumonia is highly variable among EDs. The majority of these prescriptions are avoidable. Antibiotic stewardship programs should be implemented to restrict their use in EDs. [ABSTRACT FROM AUTHOR]

Background. Linezolid is considered as a therapeutic alternative to the use of glycopeptides for the treatment of pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA). Clinical studies reported a potent survival advantage conferred by the oxazolidinone and called into question the use of glycopeptides as first-line therapy.Methods. In a mouse model of MRSA-induced pneumonia, quantitative bacteriology, proinflammatory cytokine concentrations in lung, myeloperoxidase activity, Ly6G immunohistochemistry, and endothelial permeability were assessed to compare therapeutic efficacy and immunomodulative properties of linezolid and vancomycin administered subcutaneously every 12 hours.Results. Significant antibacterial activity was achieved after 48 hours of treatment for linezolid and vancomycin. Levels of interleukin 1β, a major proinflammatory cytokine, and macrophage inflammatory protein 2, a chemokine involved in the recruitment of neutrophils, were decreased by both antimicrobials. Only linezolid was able to dramatically reduce the production of tumor necrosis factor α. Analysis of myeloperoxidase activity and Ly6G immunostaining showed a dramatic decrease of neutrophil infiltration in infected lung tissues for linezolid-treated animals. A time-dependent increase of endothelial permeability was observed for the control and vancomycin regimens. Of interest, in the linezolid group, decreased endothelial permeability was detected 48 hours after infection.Conclusions. Our results indicate that linezolid could be superior to vancomycin for the management of MRSA pneumonia by attenuating an excessive inflammatory reaction and protecting the lung from pathogen-associated damages. [ABSTRACT FROM AUTHOR]

Objectives To assess the activity of ceftolozane, a novel oxyimino-cephalosporin, in comparison with ceftazidime and piperacillin/tazobactam against a multidrug-resistant Pseudomonas aeruginosa strain using a murine model of pneumonia. Methods Quantitative bacteriology, survival, histological examination, myeloperoxidase activity, proinflammatory cytokine levels in lungs and endothelial permeability were evaluated to determine the effects of ceftolozane and comparators on P. aeruginosa-induced pneumonia. Results After 48 h of treatment, ceftolozane reduced the bacterial load by 3–4 log10 cfu/g of lung. Systemic dissemination of the pulmonary infection and development of lung damage were inhibited in all β-lactam-treated animals. P. aeruginosa-induced pneumonia led to elevated concentrations of tumour necrosis factor-α, interleukin (IL)-1β and macrophage inflammatory protein (MIP)-2 in the lungs. While the levels of proinflammatory cytokines decreased following ceftazidime and piperacillin/tazobactam therapy, ceftolozane exhibited increased concentrations of IL-1β and MIP-2 after 24 h of infection, resulted in significantly increased levels of recruited neutrophils within the infected lung without increasing lung endothelial permeability. Conclusions These data strongly support ceftolozane as an effective option for the treatment of severe P. aeruginosa respiratory infections by improving the early pulmonary inflammatory response without impairing 48 h post-infection homeostasis. [ABSTRACT FROM PUBLISHER]

Objectives The aim of this study was to compare the in vivo activities of the new antistaphylococcal drugs ceftaroline fosamil, daptomycin and tigecycline at projected human therapeutic doses against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) strains in a rabbit model of endocarditis. Methods The efficacy of therapeutic regimens in our model was evaluated following 4 days of treatment by determining colony counts of infected vegetations. Emergence of resistant variants during therapy was assessed. Results Using this model of infective endocarditis, ceftaroline fosamil and daptomycin demonstrated high bactericidal in vivo activity (reduction of >5 log10 cfu/g of vegetation) after a 4 day treatment against MSSA, MRSA and GISA strains. Both drugs were more efficacious than tigecycline, which showed moderate activity but failed to exhibit a bactericidal effect. Ceftaroline was superior to daptomycin in terms of sterilization of the vegetations. Emergence of resistant variants during daptomycin therapy was observed in two animals (one in the MSSA group and one in the MRSA group) but was not observed in ceftaroline- or tigecycline-treated animals. Conclusions The novel β-lactam agent ceftaroline fosamil was the most active bactericidal drug in this model and is a promising therapeutic option for the treatment of severe S. aureus infections, including those caused by MRSA and GISA strains. [ABSTRACT FROM PUBLISHER]

Infections are the most frequent cause of complications in trauma patients. Post-traumatic immune suppression (IS) exposes patients to pneumonia (PN). The main pathogen involved in PN is Methicillin Susceptible Staphylococcus aureus (MSSA). Dendritic cells () may be centrally involved in the IS. We assessed the consequences of hemorrhage on pneumonia outcomes and investigated its consequences on DCs functions. A murine model of hemorrhagic shock with a subsequent MSSA pneumonia was used. Hemorrhage decreased the survival rate of infected mice, increased systemic dissemination of sepsis and worsened inflammatory lung lesions. The mRNA expression of Tumor Necrosis Factor-alpha (TNF-α), Interferonbeta (IFN-β) and Interleukin (IL)-12p40 were mitigated for hemorrhaged-mice. The effects of hemorrhage on subsequent PN were apparent on the pDCs phenotype (reduced MHC class II, CD80, and CD86 molecule membrane expression). In addition, hemorrhage dramatically decreased CD8+ cDCs- and CD8- cDCs-induced allogeneic T-cell proliferation during PN compared with mice that did not undergo hemorrhage. In conclusion, hemorrhage increased morbidity and mortality associated with PN; induced severe phenotypic disturbances of the pDCs subset and functional alterations of the cDCs subset. After hemorrhage, a preventive treatment with CpG-ODN or Monophosphoryl Lipid A increased transcriptional activity in DCs (TNF-α, IFN-β and IL-12p40) and decreased mortality of post-hemorrhage MSSA pneumonia. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the activity of a new cephalosporin, ceftaroline, in comparison with other antistaphylococcal drugs (linezolid and vancomycin) at projected human therapeutic doses against methicillin-resistant Staphylococcus aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) strains. [ABSTRACT FROM PUBLISHER]

Ceftazidime and amikacin were administered in a Pseudomonas aeruginosa rabbit endocarditis model using computer-controlled intravenous (iv) infusion pumps to simulate human serum concentrations for the following regimens: continuous (constant rate) infusion of 4, 6 or 8 g of ceftazidime over 24 h or intermittent dosing of 2 g every 8 h either alone or in combination with amikacin (15 mg/kg once daily). The in vivo activities of these regimens were tested on four Pseudomonas aeruginosa strains. Animals were killed 24 h after the beginning of treatment. Efficacy was assessed by comparing the effects of the different groups on bacterial counts in vegetations for each strain tested. For a susceptible reference strain (ATCC 27853; MICs of ceftazidime and amikacin 1 and 2 mg/L, respectively), continuous infusion of 4 g alone or with amikacin was as effective as intermittent dosing with amikacin. For a clinical isolate producing an oxacillinase (MICs of ceftazidime and amikacin 8 and 32 mg/L, respectively), continuous infusion of 6 g was equivalent to intermittent dosing. For a clinical isolate producing a TEM-2 penicillinase (MIC of ceftazidime and amikacin 4 mg/L), continuous infusion of 6 g, but not intermittent dosing, had a significant in vivo effect. For a clinical isolate producing an inducible, chromosomally encoded cephalosporinase (MIC of ceftazidime and amikacin 8 and 4 mg/L, respectively), neither continuous infusion nor intermittent dosing proved effective. Determination of ceftazidime concentrations in vegetations showed that continuous infusion produced tissue concentrations at the infection site far greater than the MIC throughout the treatment. It is concluded that continuous infusion of the same total daily dose provides significant activity as compared with fractionated infusion. This study confirms that a concentration of 4-5 x MIC is a reasonable therapeutic target in most clinical settings of severe P. aeruginosa infection. [ABSTRACT FROM AUTHOR]

Two children with severe pneumonia, purulent pleural effusions, and abscess formation unresponsive to appropriate antibiotic therapy recovered promptly after the introduction of linezolid and imipenem association. Linezolid is a new antibiotic with high bioavailability and an outstanding safety profile, synergistic with imipenem, which may deserve a place in the armamentarium for severe pneumonia in children [ABSTRACT FROM AUTHOR]

The article discusses a study on the in vivo efficacy of ceftaroline fosamil against a methicillin-resistant Staphylococcus aureus (MRSA) strain in a rabbit endocarditis model. It explains that ceftaroline fosamil is a form of broad-spectrum cephalosporin demonstrating bactericidal capability against MRSA . Applied on a rabbit endocarditis model, and analyzed through GraphPad Prism and Bonferroni test, the study showed that bactericidal activity against MRSA at 20 and 40mg/kg twice-daily doses.

The aim of this study was to compare ceftolozane with ceftazidime, piperacillin/tazobactam (TZP) and imipenem in an experimental rabbit model of Pseudomonas aeruginosa pneumonia. Efficacy was assessed following 2 days of treatment by total colony counts in different tissues (lung, spleen and blood culture). Mean ± standard deviation pulmonary bacterial loads were 4.9 ± 0.3, 3.6 ± 0.3, 4.8 ± 0.2, 5.5 ± 0.8 and 3.9 ± 0.3 log10 CFU/g of lung for ceftolozane (1 g), ceftolozane (2 g), ceftazidime, TZP and imipenem, respectively, compared with 6.3 ± 0.9 log10 CFU/g of lung for control animals. The higher ceftolozane dose [2 g three times daily (t.i.d.)] showed significantly better efficacy than the lower dose (1 g t.i.d.). In conclusion, in this rabbit model of P. aeruginosa pneumonia, ceftolozane had an efficacy equivalent to that of comparator agents at a dose of 1 g t.i.d. and had better efficacy at a higher dose (2 g t.i.d.). [ABSTRACT FROM AUTHOR]

Abstract: In this study, the in vivo impact of the MexAB-OprM efflux system on antipseudomonal β-lactam efficacy was investigated. The respective activities of human simulated regimens of ticarcillin (TIC), piperacillin/tazobactam (PIP/TAZ) and ceftazidime (CFZ) on two isogenic mutants of Pseudomonas aeruginosa PAO1, namely PAO4098E overexpressing MexAB-OprM and PAO4098ET which is OprM-depleted, were evaluated in an experimental rabbit endocarditis model. The following human daily doses by intermittent administration or continuous infusion were simulated: 15g and 18g for TIC; 12g and 16g for PIP/TAZ; and 3g and 6g for CFZ. TIC, PIP/TAZ and CFZ exhibited minimum inhibitory concentrations of 64, 8 and 2μg/mL, respectively, against PAO4098E and 0.5, 0.5 and 1μg/mL against PAO4098ET. Against PAO4098E, only the high-dose regimens of CFZ were effective, with the most significant effect being achieved by continuous infusion. In contrast, all the tested regimens were effective against PAO4098ET. In the most difficult-to-treat infections due to P. aeruginosa exhibiting the efflux system MexAB-OprM, CFZ at high doses and by continuous infusion should be preferred to TIC and PIP/TAZ. [Copyright &y& Elsevier]