The holy basil administration diminishes the NF-kB expression and protects alveolar epithelial cells from pneumonia infection through interferon gamma.

Bacterial pneumonia is one of the most important causes of mortality in the United States. The bacteria Klebsiella pneumoniae (KP) accounts for a significant proportion of community and hospital-acquired infections. Here, we determine that the holy basil (Ocimum sanctum) extract improves cell viability and dampens the proinflammatory cytokine response in an in vitro model of pneumonia. For this, A549, a human alveolar basal epithelial cell line, was subjected to a lethal KP model following a 24-hr pretreatment with basil extract. Bacteremia, cell viability, apoptosis, MTT assay, phagocytic capacity, cytokines, and Khe gene expression were assessed in these cells following pneumonia. Cell morphology analysis showed that holy basil protected A549 cells from KP infection-mediated effects by inhibiting cell death due to apoptosis. Additionally, in the presence of basil, A549 cells demonstrated significantly higher bactericidal capacity and phagocytosis. Administration of holy basil led to reduced expression of hypoxia-inducible factor-1/2a, nuclear factor kappa B, and Khe in the KP-infected cells while increasing interferon (IFN)-γ expression. Our results suggest that basil significantly reduced cell death in the setting of KP infection, likely via attenuation of cytokine and IFN-γ mediated signaling pathways. Holy basil is a promising therapeutic agent for managing and treating bacterial pneumonia based on its potency.

Pistacia weinmannifolia ameliorates cigarette smoke and lipopolysaccharide­induced pulmonary inflammation by inhibiting interleukin­8 production and NF­κB activation.

Pistacia weinmannifolia (PW) has been used in traditional Chinese medicine to treat headaches, dysentery, enteritis and influenza. However, PW has not been known for treating respiratory inflammatory diseases, including chronic obstructive pulmonary disease (COPD). The present in vitro analysis confirmed that PW root extract (PWRE) exerts anti­inflammatory effects in phorbol myristate acetate­ or tumor necrosis factor α (TNF­α)­stimulated human lung epithelial NCI­H292 cells by attenuating the expression of interleukin (IL)­8, IL­6 and Mucin A5 (MUC5AC), which are closely associated with the pulmonary inflammatory response in the pathogenesis of COPD. Thus, the aim of the present study was to evaluate the protective effect of PWRE on pulmonary inflammation induced by cigarette smoke (CS) and lipopolysaccharide (LPS). Treatment with PWRE significantly reduced the quantity of neutrophils and the levels of inflammatory molecules and toxic molecules, including tumor TNF­α, IL­6, IL­8, monocyte chemoattractant protein­1, neutrophil elastase and reactive oxygen species, in the bronchoalveolar lavage fluid of mice with CS­ and LPS­induced pulmonary inflammation. PWRE also attenuated the influx of inflammatory cells in the lung tissues. Furthermore, PWRE downregulated the activation of nuclear factor­κB and the expression of phosphodiesterase 4 in the lung tissues. Therefore, these findings suggest that PWRE may be a valuable adjuvant treatment for COPD.

Efficacy and Safety of Intravenous-to-oral Lefamulin, a Pleuromutilin Antibiotic, for the Treatment of Community-acquired Bacterial Pneumonia: The Phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) Trial.

BACKGROUND: Lefamulin, a pleuromutilin antibiotic, is active against pathogens commonly causing community-acquired bacterial pneumonia (CABP). The Lefamulin Evaluation Against Pneumonia (LEAP 1) study was a global noninferiority trial to evaluate the efficacy and safety of lefamulin for the treatment of CABP. METHODS: In this double-blind study, adults with CABP of Pneumonia Outcomes Research Team risk class ≥III were randomized 1:1 to receive lefamulin at 150 mg intravenously (IV) every 12 hours or moxifloxacin at 400 mg IV every 24 hours. After 6 doses, patients could be switched to an oral study drug if prespecified improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, either linezolid or placebo was added to moxifloxacin or lefamulin, respectively. The US Food and Drug Administration primary endpoint was an early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug in the intent-to-treat (ITT) population (noninferiority margin, 12.5%). The European Medicines Agency co-primary endpoints were an investigator assessment of clinical response (IACR) 5-10 days after the last dose of the study drug in the modified ITT (mITT) and clinically evaluable (CE) populations (noninferiority margin, 10%). RESULTS: There were 551 patients randomized (n = 276 lefamulin; n = 275 moxifloxacin). Lefamulin was noninferior to moxifloxacin for ECR (87.3% vs 90.2%, respectively; difference -2.9%, 95% confidence interval [CI] g -8.5 to 2.8) and IACR (mITT, 81.7% vs 84.2%, respectively; difference -2.6%, 95% CI -8.9 to 3.9; CE, 86.9% vs 89.4%, respectively; difference -2.5%, 95% CI -8.4 to 3.4). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin. CONCLUSIONS: Lefamulin was noninferior to moxifloxacin for the primary efficacy endpoints and was generally safe and well tolerated. CLINICAL TRIALS REGISTRATION: NCT02559310.

Solithromycin: A novel ketolide antibiotic.

PURPOSE: The pharmacology, pharmacokinetics, pharmacodynamics, antimicrobial activity, clinical safety, and current regulatory status of solithromycin are reviewed. SUMMARY: Solithromycin is a novel ketolide antibiotic developed for the treatment of community-acquired bacterial pneumonia (CABP). Its pharmacologic, pharmacokinetic, and pharmacodynamic properties provide activity against a broad range of intracellular organisms, including retained activity against pathogens displaying various mechanisms of macrolide resistance. Phase III clinical trials of solithromycin demonstrated noninferiority of both oral and i.v.-to-oral regimens of 5-7 days' duration compared with moxifloxacin for patients with moderately severe CABP. Nearly one third of patients receiving i.v. solithromycin experienced infusion-site reactions. Although no liver-related adverse events were reported in patients receiving oral solithromycin, more patients receiving i.v.-to-oral solithromycin experienced asymptomatic, transient transaminitis, with alanine transaminase levels of >3 to >5 times the upper limit, compared with those treated with moxifloxacin. These results led the Food and Drug Administration to conclude that the solithromycin new drug application was not approvable as filed, adding that the risk of hepatotoxicity had not yet been adequately characterized. The agency further recommended a comparative study of patients with CABP to include approximately 9,000 patients exposed to solithromycin in order to exclude drug-induced liver injury events occurring at a rate of 1 in 3,000 with 95% probability. CONCLUSION: Solithromycin is a novel ketolide antibiotic with activity against a broad spectrum of intracellular organisms, including those displaying macrolide resistance. While demonstrating noninferiority to a current first-line agent in the treatment of CABP, concerns for drug-induced liver injury and infusion-site reactions have placed its regulatory future in doubt.

Dusuqing granules (DSQ) suppress inflammation in Klebsiella pneumonia rat via NF-κB/MAPK signaling.

BACKGROUND: Dusuqing granules (DSQ) have been used in the treatment of bacterial pneumonia clinically, with remarkable benefits. This study was initiated to explore the effects of DSQ on pulmonary inflammation by regulating nuclear factor (NF)-κB/mitogen-activated protein kinase (MAPK) signaling in bacterial pneumonia rats. METHODS: Rat model was duplicated with Klebsiella pneumonia by a one-time intratracheal injection. Rats were randomized into control, model, DSQ and levofloxacin (LVX) groups. After administrated with appropriate medicines for 7 days, lung tissues were harvested and prepared for pathological analysis, and interleukin (IL)-1, IL-6, monocyte chemotactic protein (MCP)-1and macrophage inflammatory protein (MIP)-2 detections. NF-κB mRNA was measured by real-time qPCR, and the phosphorylation and total proteins of P38MAPK, JNK46/54, ERK42/44 were determined by Western blotting. RESULTS: Marked pathological impairments were observed in model rats, whereas were improved in DSQ group. The cytokines levels, NF-κB mRNA expression and the phosphorylation of P38MAPK, JNK46/54 and ERK42/44 proteins were significantly higher in model group, and were significantly depressed in DSQ group. CONCLUSION: The protective effects of DSQ on Klebsiella pneumonia might be attributed to its inactivative effects of NF-κB/ MAPK pathway.

Evaluation of combination therapy for Burkholderia cenocepacia lung infection in different in vitro and in vivo models.

Burkholderia cenocepacia is an opportunistic pathogen responsible for life-threatening infections in cystic fibrosis patients. B. cenocepacia is extremely resistant towards antibiotics and therapy is complicated by its ability to form biofilms. We investigated the efficacy of an alternative antimicrobial strategy for B. cenocepacia lung infections using in vitro and in vivo models. A screening of the NIH Clinical Collection 1&2 was performed against B. cenocepacia biofilms formed in 96-well microtiter plates in the presence of tobramycin to identify repurposing candidates with potentiator activity. The efficacy of selected hits was evaluated in a three-dimensional (3D) organotypic human lung epithelial cell culture model. The in vivo effect was evaluated in the invertebrate Galleria mellonella and in a murine B. cenocepacia lung infection model. The screening resulted in 60 hits that potentiated the activity of tobramycin against B. cenocepacia biofilms, including four imidazoles of which econazole and miconazole were selected for further investigation. However, a potentiator effect was not observed in the 3D organotypic human lung epithelial cell culture model. Combination treatment was also not able to increase survival of infected G. mellonella. Also in mice, there was no added value for the combination treatment. Although potentiators of tobramycin with activity against biofilms of B. cenocepacia were identified in a repurposing screen, the in vitro activity could not be confirmed nor in a more sophisticated in vitro model, neither in vivo. This stresses the importance of validating hits resulting from in vitro studies in physiologically relevant model systems.

Role for phospholipid acyl chains and cholesterol in pulmonary infections and inflammation.

Bacterial and viral respiratory tract infections result in millions of deaths worldwide and are currently the leading cause of death from infection. Acute inflammation is an essential element of host defense against infection, but can be damaging to the host when left unchecked. Effective host defense requires multiple lipid mediators, which collectively have proinflammatory and/or proresolving effects on the lung. During pulmonary infections, phospholipid acyl chains and cholesterol can be chemically and enzymatically oxidized, as well as truncated and modified, producing complex mixtures of bioactive lipids. We review recent evidence that phospholipids and cholesterol and their derivatives regulate pulmonary innate and adaptive immunity during infection. We first highlight data that oxidized phospholipids generated in the lung during infection stimulate pattern recognition receptors, such as TLRs and scavenger receptors, thereby amplifying the pulmonary inflammatory response. Next, we discuss evidence that oxidation of endogenous pools of cholesterol during pulmonary infections produces oxysterols that also modify the function of both innate and adaptive immune cells. Last, we conclude with data that n-3 polyunsaturated fatty acids, both in the form of phospholipid acyl chains and through enzymatic processing into endogenous proresolving lipid mediators, aid in the resolution of lung inflammation through distinct mechanisms. Unraveling the complex mechanisms of induction and function of distinct classes of bioactive lipids, both native and modified, may hold promise for developing new therapeutic strategies for improving pulmonary outcomes in response to infection.

Pseudomonas aeruginosa: breaking down barriers.

Many bacterial pathogens have evolved ingenious ways to escape from the lung during pneumonia to cause bacteremia. Unfortunately, the clinical consequences of this spread to the bloodstream are frequently dire. It is therefore important to understand the molecular mechanisms used by pathogens to breach the lung barrier. We have recently shown that Pseudomonas aeruginosa, one of the leading causes of hospital-acquired pneumonia, utilizes the type III secretion system effector ExoS to intoxicate pulmonary epithelial cells. Injection of these cells leads to localized disruption of the pulmonary-vascular barrier and dissemination of P. aeruginosa to the bloodstream. We put these data in the context of previous studies to provide a holistic model of P. aeruginosa dissemination from the lung. Finally, we compare P. aeruginosa dissemination to that of other bacteria to highlight the complexity of bacterial pneumonia. Although respiratory pathogens use distinct and intricate strategies to escape from the lungs, a thorough understanding of these processes can lay the foundation for new therapeutic approaches for bacterial pneumonia.

Evaluation of in vitro and in vivo anti-inflammatory activity of biologically active phospholipids with anti-neoplastic potential in porcine model.

BACKGROUND: This study aims to investigate the anti-inflammatory effect of biologically active phospholipids (BAP) used in preparations for clinical practice in humans. Until date, except anti-neoplastic ability, little is known about anti-inflammatory property of the phospholipids. METHODS: While the course of bacterially induced acute pneumonia and markers of inflammation were studied in in vivo system in pigs orally supplemented with BAP, the pro- and anti-inflammatory response of lipopolysaccharide-stimulated porcine monocyte-derived macrophages to 24 h- and 48 h-treatment by BAP was investigated in in vitro system. In vivo, the animal health status was monitored and pro-inflammatory IL-1ß and IL-8 in sera were detected by ELISA during the experiment, while bronchoalveolar lavage fluids (BALF) and the lungs were examined post-mortem. Total and differential counts of white blood cell (WBC) were determined in blood and BALF. In vitro, mRNA expression of pro-inflammatory (TNF-α, IL-1ß, CXCL10) and anti-inflammatory (IL-10 and Arg1) cytokines, and level of activated caspase 1 and phosphorylated protein kinase C epsilon (pPKCϵ), were studied using qRT-PCR and Western blot, respectively. For the purposes of both systems, 6 animals were used in each of the BAP-supplemented and the control groups. RESULTS: In vivo, BAP had a positive influence on the course of the disease. The immunomodulatory effects of BAP were confirmed by lower levels of IL-1ß, IL-8, and a lower WBC count in the supplemented group in comparison with the control group. A lower percentage of lung parenchyma was affected in the supplemented group comparing to the control group (on average, 4% and 34% of tissue, respectively). In vitro, BAP suppressed mRNA expression of mRNA for IL-10 and all pro-inflammatory cytokines tested. This down-regulation was dose- and time-dependent. Arg1 mRNA expression remained unaffected. Further dose- and time-dependent suppression of the activated caspase 1 and pPKCϵ was detected in macrophages when treated with BAP. CONCLUSIONS: Our results demonstrate that BAP has anti-inflammatory and immunomodulatory properties, thus emphasizing the potential of this compound as a natural healing agent.

The efficacy, safety, and pharmacokinetics of biapenem administered thrice daily for the treatment of pneumonia in the elderly.

Biapenem has been widely used to treat bacterial pneumonia; however, there is little information concerning its efficacy and safety in elderly patients. Based on pharmacokinetic-pharmacodynamic theory, administration of biapenem thrice rather than twice daily would be expected to be more effective because of longer time above the minimum inhibitory concentration. In this study, we aimed to evaluate the efficacy, safety, and pharmacokinetics of biapenem (300 mg) administered thrice daily in pneumonic patients aged 65 years or older. Biapenem was effective in 22 of 25 patients, as assessed by the improvement in clinical symptoms and/or the eradication of the causative organisms, and caused no serious adverse events. The pharmacokinetic profile was established based on simulations using a modeling program. Among 17 patients whose causative organisms were detected, time above the minimum inhibitory concentration was estimated to be 100% in 16 patients, all of whom showed clinical improvement. The results of this study confirmed the efficacy and safety of 300 mg of biapenem administered thrice daily for the treatment of pneumonia in elderly patients.

[Protection and mechanism of Fagopyrum cymosum on lung injury in rats with Klebsiella pneumonia].

OBJECTIVE: To study the mechanism of protective effect of Fagopyrum cymosum on lung injury induced by Klebsiella pneumonia in rats. METHODS: The model of rats with Klebsiella pneumonia was established. The male SD rats were randomly divided into control group, model group, Fagopyrum cymosum (6, 3, 1.5 g/kg) three groups, levofloxacin (25 mg/kg) group. The pathological change of lung was observed. The content of IL-1beta, IL-6, IL-8, TNF-alpha, ICAM-1, INF-gamma in serum were measured by radioimmunoassay and Elisa. TNF-alpha, ICAM-1, NF-kappaB p65 protein expressions were measured by immunohistochemistry. MIP-2mRNA expression was detected by in situ hybridization. RESULTS: The rats of model group had obvious lung injury, but those of Fagopyrum cymosum and levofloxacin groups had less injury. The contents of IL-1beta, IL-6, IL-,8, TNF-alpha, ICAM-1 and INF-gamma in serum and the expressions of TNF-a, ICAM-1, NF-kappaB p65 and MIP--2mRNA of model group were significantly higher than those of the control group (P < 0.05 or P < 0.01), while the indexes of Fagopyrum cymosum and levofloxacin groups were significantly lower than those of model group (P < 0.05 or P < 0.01). CONCLUSION: The lung injury induced by Klebsiella pneumonia is related to TNF-alpha, ICAM-1, NF-kappaB p65 and MIP-2mRNA. To decrease the excessive expression of TNF-alpha, ICAM-1, NF-kappaB p65 and MIP-2mRNA might be the main mechanism of protective effect of Fagopyrum cymosum on lung injury.

Efficacy and safety of moxifloxacin for community-acquired bacterial pneumonia based on pharmacokinetic analysis.

Moxifloxacin is a respiratory quinolone that is expected to be useful for treating community-acquired bacterial pneumonia, but few clinical studies and not a detailed evaluation of its pharmacokinetics have been conducted in Japan in patients with pneumonia. We assessed the efficacy and safety of moxifloxacin in 18 patients with community-acquired bacterial pneumonia using pharmacokinetic-pharmacodynamic analysis. There was significant improvement in body temperature, white blood cell count, C-reactive protein, and chest X-ray score on day 3 of moxifloxacin treatment, which persisted until the completion of treatment (all p < 0.05). Nine strains, including Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, and Enterobacter cloacae, were isolated from sputum cultures of nine patients. The isolated strains were eradicated by moxifloxacin. The mean area under the concentration-time curve from 0 to 24 hours [AUC(0-24 h) (AUC(0-24 h,ss))], maximum plasma concentration (C(max)), and trough plasma level (C(trough)) of moxifloxacin at steady state was 52.0 µg h/ml, 4.5, and 0.9 µg/ml, respectively. Mean AUC(0-24 h,ss)/mimimum inhibitory concentration (MIC), and C(max)/MIC ratios for patients in whom MICs of moxifloxacin were determined for pathogenic bacteria were 723 and 62, respectively. The median AUC(0-24 h,ss)/MIC and C(max)/MIC ratios (based on Monte Carlo simulation employing MICs for 257 strains of S. pneumoniae collected during a respiratory infection survey by the Japanese Society of Chemotherapy in 2007) were 209.56 and 17.88, respectively. Thus, when the target for the AUC/MIC ratio was set at ≥30 and that for the C(max)/MIC ratio at ≥5, the achievement rate for these two parameters was 97.36% and 96.71%, respectively. Two patients (11%) experienced three adverse effects [one nausea, another increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], but the events were not serious. Based on these results, moxifloxacin (400 mg once daily) was considered useful for treating community-acquired bacterial pneumonia and is expected to show excellent efficacy and safety as well as suppressing the emergence of resistance.

[Effects of Chinese herbal medicine Dusuqing Granule on toll-like receptor 4 signaling in multiple organ injury induced by bacterial pneumonia in aged rats].

OBJECTIVE: To study the protective mechanism of Dusuqing Granule, a compound Chinese herbal medicine, on the senile multiple organ injury caused by bacterial pneumonia by observing the expression changes of molecules related to toll-like receptor 4 (TLR4) signaling. METHODS: A total of 55 male Sprague-Dawley aged rats were divided into control group, untreated group, Dusuqing group and lomefloxacin group. There were 25 rats in the untreated group and 10 rats in each of the other three groups. Multiple organ injury in a rat model of pneumonia was induced by injection of Klebsiella pneumoniae through tracheal intubation. By means of immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR), examinations were made on mRNA expressions of lipopolysaccharide-binding protein (LBP), CD14, TLR4 and interleukin-1 receptor-associated kinase-1 (IRAK-1) in the tissues of the lung, heart and small intestine, and also on the protein expressions of TLR4, tumor necrosis factor receptor-associated factor 6 (TRAF6) and nuclear factor-κB (NF-κB). RESULTS: Expressions of LBP, CD14, TLR4 and IRAK-1 mRNAs in the tissues of the lung, heart and small intestine in the untreated group were stronger than those in the control group (P<0.01 or Plt;0.05). The protein expressions of TLR4, TRAF6 and NF-κB were increased dramatically in the untreated group as compared with the control group (Plt;0.01 or Plt;0.05). Compared with the untreated group, the expressions of LBP, CD14, TLR4 and IRAK-1 mRNAs in the tissues of the lung, heart and small intestine in the Dusuqing group were weakened significantly (Plt;0.01 or Plt;0.05). Meanwhile, the protein expressions of TLR4, TRAF6 and NF-κB were decreased markedly in the Dusuqing group (Plt;0.01 or Plt;0.05). CONCLUSION: Dusuqing Granule is effective in suppressing toll-like receptor signal transduction activation and reducing the secretion of cytokines and inflammatory mediators, which can further reduce the organ tissue injury. Dusuqing Granule can decrease the levels of TLR signal transduction activation including the targets LBP, CD-14, TLR4, IRAK-1, TRAF6 and NF-κB, which is different from the special inhibitor that acts only on some segments.

Dietary (n-3) polyunsaturated fatty acids affect the kinetics of pro- and antiinflammatory responses in mice with Pseudomonas aeruginosa lung infection.

The underlying mechanisms by which eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) affect host resistance to Pseudomonas aeruginosa are unclear. The aim of this study was to determine their role on the kinetic of pro- and antiinflammatory response in lung infection. Mice fed either a control diet or a diet enriched with EPA and DHA were infected intratracheally and we studied lung expression of proinflammatory markers [CXCL1, interleukin (IL)-6, tumor necrosis factor-alpha], antiinflammatory markers (IL-10, A20, and IkappaB alpha), and PPARalpha and PPARgamma. The inflammatory response was assessed using recruitment of neutrophils and macrophages into bronchoalveolar lavage fluid, bacterial clearance from the lung, pulmonary injury, and 7-d survival rate. Compared with the control group, EPA and DHA delayed the expression of proinflammatory markers during the first 2 h (P < 0.05), upregulated proinflammatory marker expression (P < 0.05), and induced overexpression of antiinflammatory markers at 8 h (P < 0.05), enhanced recruitment of neutrophils at 16 h (P < 0.05), and induced PPARalpha and PPARgamma overexpression at 4 and 8 h (P < 0.01), respectively. Pulmonary bacterial load decreased and pulmonary injury and mortality were reduced during the first 24 h (P < 0.05). In conclusion, EPA and DHA modulate the balance between pro- and antiinflammatory cytokines, alter the early response of the host to P. aeruginosa infection, and affect the early outcome of infection.

Infectious etiology modifies the treatment effect of zinc in severe pneumonia.

BACKGROUND: Zinc is undergoing evaluation as an inexpensive therapeutic adjuvant for severe pediatric pneumonia. OBJECTIVE: We explored the effect of etiology on the treatment effect of zinc in young children hospitalized for severe pneumonia. DESIGN: We analyzed data from a randomized, double-blind, placebo-controlled clinical trial conducted at the Christian Medical College Hospital, a teaching hospital in Tamilnadu, India. Children aged 2-23 mo (n = 299) were randomly assigned to receive a 10-mg tablet of zinc sulfate or placebo twice a day during hospitalization. The primary outcomes were length of hospitalization and time to resolution of severe pneumonia stratified by etiologic classification on the basis of serum C-reactive protein (CRP) concentrations at admission. RESULTS: CRP concentrations were available for 295 (98.7%) of the enrolled cases. Of these 295 cases, 223 (75.6%) were classified as suspected nonbacterial pneumonias (CRP concentrations 40 mg/L), the median length of hospitalization was approximately 20 h longer in the zinc-supplemented group than in the placebo group (87.3 and 68.3 h, respectively; HR: 0.56; 95% CI: 0.34, 0.93; P = 0.025). The treatment effect was not modified in the suspected nonbacterial cases of pneumonia. CONCLUSIONS: Our results suggest that the treatment effect of zinc for severe pediatric pneumonia may be modified by bacterial infection. Further studies are required to develop appropriate recommendations for the use of zinc in the treatment of severe pneumonia. This trial was registered at clinicaltrials.gov as NCT00198666.

The effect of Bach's magnificat on emotions, immune, and endocrine parameters during physiotherapy treatment of patients with infectious lung conditions.

The purpose of this study was to determine the effect of Bach's Magnificat on emotions, immune, and endocrine parameters in patients of specific infectious lung conditions. Participants (N = 40; 9 men & 31 women) ranging in age from 40 to 75 participated in the study. Patients were randomly allocated to an experimental and control group. During a 3-day period the experimental group received physiotherapy with the selected music, while the control group only received physiotherapy. ANOVA statistics indicate significant changes in the following parameters: POMS-scale, CD4+:CD8+ ratio, cortisol, and cortisol:DHEA ratio. The intervention of music demonstrates communication between the mind and body.

The effects of granulocyte colony-stimulating factor in preclinical models of infection and acute inflammation.

The cytokine granulocyte colony-stimulating factor (G-CSF) is a potent endogenous trigger for the release of neutrophils from bone marrow stores and for their activation for enhanced antimicrobial activity. G-CSF has been widely evaluated in preclinical models of acute illness, with generally promising though divergent results. A recombinant G-CSF molecule has recently undergone clinical trials to assess its efficacy as an adjuvant therapy in community-acquired and nosocomial pneumonia, however, these studies failed to provide convincing evidence of benefit. We undertook a systematic review of the published literature reporting the effects of modulation of G-CSF in preclinical in vivo models to determine whether evidence of differential efficacy might explain the disappointing results of human studies and point to disease states that might be more likely to benefit from G-CSF therapy. G-CSF has been evaluated in 86 such studies involving a variety of different models. The strongest evidence of benefit was seen in studies involving intraperitoneal challenge with live organisms; benefit was evident whether the agent was given before or after challenge. G-CSF demonstrates anti-inflammatory activity in models of systemic challenge with viable organisms or endotoxin, but only when the agent is given before challenge; evidence of benefit after challenge was minimal. Preclinical models of intrapulmonary challenge only show efficacy when the cytokine is administered before the infectious challenge, and suggested harm in gram-negative pneumonia resulting from challenge with Escherichia coli or Klebsiella. There is little evidence for therapeutic efficacy in noninfectious models of acute illness. We conclude that the most promising populations for evaluation of G-CSF are neutropenic patients with invasive infection and patients with intra-abdominal infection, particularly those with the syndrome of tertiary, or recurrent, peritonitis. Significant variability in the design and reporting of studies of preclinical models of acute illness precludes more sophisticated data synthesis.

Pharmacokinetic/pharmacodynamic assessment of the in-vivo efficacy of imipenem alone or in combination with amikacin for the treatment of experimental multiresistant Acinetobacter baumannii pneumonia.

A guinea-pig pneumonia model involving imipenem-susceptible and imipenem-resistant strains of Acinetobacter baumannii was developed to assess the in-vitro and in-vivo activities of imipenem, alone or in combination with amikacin, and the pharmacokinetic and pharmacodynamic parameters. Serum levels were measured by bioassay (imipenem) or immunoassay (amikacin), followed by calculation of pharmacokinetic and pharmacodynamic parameters (Cmax, AUC, t1/2, Cmax/MIC, AUC/MIC, and Deltat/MIC). In-vivo efficacy was evaluated by comparing bacterial counts in the lungs of treatment groups with end-of-therapy controls by anova and post-hoc tests. Decreases in the Cmax (13.4%), AUC (13%), t1/2 (25%) and Deltat/MIC (11.8-32.2%) of imipenem were observed when it was administered with amikacin, compared with administration of imipenem alone. Similarly, decreases in the Cmax (34.5%), AUC (11.6%), Cmax/MIC (34.5%) and AUC/MIC (11.7%) of amikacin were observed when it was administered with imipenem. Bacterial counts in lungs were reduced by imipenem (p 0.004) with the imipenem-susceptible strain, and by amikacin (p 0.001) with the imipenem-resistant strain. The combination of imipenem plus amikacin was inferior to imipenem alone with the imipenem-susceptible strain (p 0.01), despite their in-vitro synergy, and was inferior to amikacin alone with the imipenem-resistant strain (p < 0.0001). In summary, combined use of imipenem with amikacin was less efficacious than monotherapy, probably because of a drug-drug interaction that resulted in decreased pharmacokinetic and pharmacodynamic parameters for both antimicrobial agents.

[Stakes, treatment strategies and progression of MRSA nosocomial pneumonia, especially pneumonia due to mechanical ventilation]. / Enjeux, stratégies de traitement et évolution des pneumonies nosocomiales à SARM, notamment les pneumonies acquises sous ventilation mécanique.

THE IMPORTANCE OF THE INITIAL TREATMENT: Many studies have shown excess mortality during acquired pneumonia with mechanical ventilation when the initial antibiotic treatment is inappropriate, even following subsequent adaptation of the latter. EFFICACY OF TREATMENT: From a clinical point of view, since the regression of the various signs appears after varying time lapses, it is not easy to judge within the first three days the efficacy of an antibiotic. From a microbiological point of view, the bacterial concentrations observed at the time of diagnosis decrease within the first two days, when the response to treatment is favorable. PROBLEMS WITH VANCOMYCIN: Treatment of reference in the case of gram+ germ infections, vancomycin currently fails in 40% of MRSA pneumonias acquired under mechanical ventilation. The probable reason for such failure is an insufficient local concentration, which does not exceed the minimal inhibiting concentration (MIC) of the germ. BETWEEN EFFICACY AND TOLERANCE: The increase in the MIC of vancomycin in the serum and the lungs during acute MRSA acquired under mechanical ventilation may provoke problems in tolerance, notably renal.

Evaluation of trovafloxacin in the treatment of Klebsiella pneumoniae lung infection in tumour-bearing mice.

Trovafloxacin, a new trifluoroquinolone, was evaluated for its therapeutic efficacy against Klebsiella pneumoniae lung infection in tumour (P388 murine leukaemia cells)-bearing mice, treated with or without a chemotherapeutic agent, daunorubicin (DNR) and in mice without tumour. Its activity was compared with ciprofloxacin and cephazolin. The effect on therapeutic efficacy of the addition of recombinant granulocyte colony stimulating factor (rGCSF) was also examined. Our study showed that both quinolones successfully cured pneumonia owing to infection with K. pneumoniae in mice without tumours but that all antibiotics failed in tumour-bearing mice if DNR was withheld. Substantial differences were noted in DNR-treated tumour-bearing mice with infection-the cure rate with trovafloxacin was 91% whereas the cure rate with ciprofloxacin or cephazolin was 57%. Addition of rGCSF to ciprofloxacin did not substantially improve its efficacy (when assessed by protection against death owing to infection; the survival rate was 41%). Trovafloxacin cure rates ranged from 80 to 90% whether or not rGCSF was added to the treatment regimen. Our results suggest that prior cancer chemotherapy had no adverse effect on the therapeutic efficacy of trovafloxacin, and that trovafloxacin may be a promising therapeutic agent for treatment of bacterial infections in the presence of leucopenia.