Protective effects of ethyl acetate extracts of Rimulus Cinnamon on systemic inflammation and lung injury in endotoxin-poisoned mice.

Rimulus cinnamon is the dried twig of Cinnamomum cassia Presl. It is widely used in China for the treatment of inflammatory processes, amenorrhea, and other diseases. We aimed to study the protective effects of ethyl acetate extracts of R. cinnamon (EAE) on systemic inflammation and lung injury in endotoxin-poisoned mice. EAE was administered 5 d prior to lipopolysaccharide (LPS) challenge with 15 mg/kg LPS. The administration of EAE increased the levels of interferon-γ (IFN-γ) and decreased the levels of interleukin-18 (IL-18) and tumor necrosis factor-α (TNF-α) in the serum. Additionally, EAE relieved the pathological changes in the tissues of the lungs and spleen, and significantly reduced the number of neutrophils in the lung tissues. In addition, treatment with EAE decreased the mRNA expression of the NLR family, pyrin domain-containing protein 3 (NLRP3), caspase-1, and interleukin-1ß (IL-1ß) in the lungs, as well as the expression of NLRP3, caspase-1 (p20), and pro-IL-1ß proteins. These results demonstrated the promising anti-inflammatory effects of EAE in endotoxin-poisoned mice. Furthermore, EAE could alleviate the lung injury of endotoxin-poisoned mice by antagonizing the activation of the NLRP3 inflammasome.

Use of Monte Carlo simulation to evaluate the efficacy of tigecycline and minocycline for the treatment of pneumonia due to carbapenemase-producing Klebsiella pneumoniae.

BACKGROUND: Pneumonia caused by carbapenemase-producing Klebsiella pneumoniae (CP-KP) are increasingly encountered in hospitals worldwide, causing high mortality due to lack of treatment options. The goal of this study was to assess the efficacy of tigecycline and minocycline for CP-KP hospital-acquired pneumonia (HAP) by using Monte Carlo simulation. METHODS: A total of 164 non-duplicated CP-KP strains were collected from sputum or blood in patients with HAP. The MICs for antimicrobials were determined by the agar dilution method. A 10,000-patient Monte Carlo Simulation based on a PK/PD model incorporating the MICs and population pharmacokinetic parameters were conducted to calculate probability of target attainment (PTA) at each MIC value and total cumulative fraction of response (CFR). RESULTS: The susceptibility rate of tigecycline and minocycline were 79.9% and 41.5%, respectively. At recommended doses, an optimal PTA of 90% was obtained for treating HAP caused by CP-KP with MICs of tigecycline ≤0.5 mg/L or minocycline ≤4 mg/L. The CFR of tigecycline at the recommended dose and double dose (100 mg q12h) were 71.2% and 90.2%, respectively. The CFR of minocycline at recommended dose and double dose (200 mg q12h) was 53.4% and 77.2%, respectively. CONCLUSIONS: The findings of this study suggest that the recommended dose of tigecycline was not effective in HAP caused by CP-KP, and a higher CFR indicating a better clinical efficacy can be gained by doubling the dose (100 mg q12h). minocycline (200 mg q12h) might be a potential alternative of tigecycline to against strains with MICs ≤ 8 mg/L.

Essential oil of Artemisia vestita exhibits potent in vitro and in vivo antibacterial activity: Investigation of the effect of oil on biofilm formation, leakage of potassium ions and survival curve measurement.

The aim of the present study was to investigate the chemical composition of the essential oil of Artemisia vestita and to determine the antibacterial activity of the essential oil and its two major components, grandisol and 1,8­cineole, against certain respiratory infection­causing bacterial strains, in vitro and in vivo. The chemical composition of the essential oil was analyzed using gas chromatography­mass spectrometry. A micro­well dilution method was used to determine the minimum inhibition concentration (MIC) values of the essential oil and its major constituents. A model of Streptococcus pyogenes infection in mice was used to determine its in vivo activities. Lung and blood samples were obtained to assess bacterial cell counts. Toxicity evaluation of the essential oil and its components was completed by performing biochemical analysis of the serum, particularly monitoring aspartate transaminase, alanine transaminase, urea and creatinine. The essential oil exhibited potent antibacterial activity, whereas the two major constituents were less potent. The essential oil exhibited MIC values between 20 and 80 µg/ml, while the values of the two constituents were between 130 and 200 µg/ml. Scanning electron microscopy results demonstrated that the essential oil inhibited biofilm formation and altered its architecture. Survival curves indicated that the essential oil led to a reduction in the viability of different bacteria. The essential oil also induced significant leakage of potassium ions from S. pyogenes. The essential oil (100 µg/mouse) and grandisol (135 µg/mouse) significantly reduced the number of viable bacterial cells in the lungs (P<0.01). However, intake of 100 µg/mouse of essential oil or grandisol 135 µg/mouse once or twice each day for 9 days did not produce any toxic effects in the mice. In conclusion, the in vitro and in vivo results suggested that the essential oil of A. vestita and one of its major constituents, grandisol, can significantly inhibit the growth of different bacterial strains.

[Selenium metabolism in patients with severe multiple trauma].

GOAL OF THE STUDY: To define a relation between the selenium level and the risk of the development of nosocomial pneumonia in patients with severe multiple trauma depending on the trauma severity and the volume of blood loss. MATERIALS AND METHODS: We measured serum selenium concentration in 40 patients with severe multiple trauma. The ISS score was used to estimate the trauma severity. Patients were divided into 2 groups: group I--25 patients without pneumonia, group II--15 patients with pneumonia. The volume of blood loss was estimated in each group. The oxidative stress was estimated by means of the antioxidant index. RESULTS: For selected groups the significant difference (P < 0.05) in the volume of blood loss was detected. It was shown the significant decrease of selenium concentration (P < 0.05) in both groups in comparison with control for all testing time points (the 6-12 hrs, 24 hrs, 3 and 5-7 days). The mean of selenium concentration in group II was significantly lower in comparison to the group I. A significant difference of selenium concentrations (P < 0.05) between groups were detected on the 6-12 hrs and day 3 from the trauma onset. The antioxidant index was significantly lower in the group II within the 6-12 hrs, 12-24 hrs and 5-7 days (P < 0.05) in comparison to group I. CONCLUSIONS: The severe multiple trauma and severe blood loss lead to a selenium deficiency in the blood serum starting with the first hours from the trauma onset, which leads to the critical level of selenium concentration by the Ist day's end after trauma. It also leads to a pronounced oxidative stress that is reflected in the antioxidant index dynamics. Thus serum selenium concentration may be included in the set of the early prognostic detectors to detect infectious pulmonary complications development at severe multiple trauma, and it could be the basis for the decision to take early prophylaxis using selenium medications.

Vitamin D level and risk of community-acquired pneumonia and sepsis.

Previous research has reported reduced serum 25-hydroxyvitamin D (25(OH)D) levels is associated with acute infectious illness. The relationship between vitamin D status, measured prior to acute infectious illness, with risk of community-acquired pneumonia (CAP) and sepsis has not been examined. Community-living individuals hospitalized with CAP or sepsis were age-, sex-, race-, and season-matched with controls. ICD-9 codes identified CAP and sepsis; chest radiograph confirmed CAP. Serum 25(OH)D levels were measured up to 15 months prior to hospitalization. Regression models adjusted for diabetes, renal disease, and peripheral vascular disease evaluated the association of 25(OH)D levels with CAP or sepsis risk. A total of 132 CAP patients and controls were 60 ± 17 years, 71% female, and 86% Caucasian. The 25(OH)D levels <37 nmol/L (adjusted odds ratio (OR) 2.57, 95% CI 1.08-6.08) were strongly associated with increased odds of CAP hospitalization. A total of 422 sepsis patients and controls were 65 ± 14 years, 59% female, and 91% Caucasian. The 25(OH)D levels <37 nmol/L (adjusted OR 1.75, 95% CI 1.11-2.77) were associated with increased odds of sepsis hospitalization. Vitamin D status was inversely associated with risk of CAP and sepsis hospitalization in a community-living adult population. Further clinical trials are needed to evaluate whether vitamin D supplementation can reduce risk of infections, including CAP and sepsis.

The therapeutic effect of tigecycline, unlike that of Ceftazidime, is not influenced by whether the Klebsiella pneumoniae strain produces extended-spectrum ß-lactamases in experimental pneumonia in rats.

The efficacies of tigecycline and ceftazidime against fatal pneumonia in rats caused by an extended-spectrum ß-lactamase (ESBL)-positive Klebsiella pneumoniae strain or its wild-type (WT) progenitor were compared. Ceftazidime at 12.5 or 50 mg/kg of body weight twice daily (b.i.d.) was effective (50% or 100% rat survival) in pneumonia caused by the WT isolate but unsuccessful (100% rat mortality) in pneumonia caused by the ESBL-positive variant. In contrast, tigecycline at 6.25, 12.5, or 25 mg/kg b.i.d. showed dosage-dependent efficacy up to 100% rat survival irrespective of the ESBL character of the infecting organism.

[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.

[Changes in plasma hemostatic parameters under intravascular laser irradiation of blood in patients with community-acquired pneumonia].

AIM: To study the time course of changes in the activity of the protein C system and other hemostatic parameters under intravascular laser irradiation of blood (ILIB) in patients with community-acquired pneumonia (CAP). SUBJECTS AND METHODS: One hundred and forty patients aged 17 to 62 years (mean 39.5 +/- 8.4 years) with CAP were examined. A control group (n = 40) received conventional drug therapy; the study group (n = 100) had a course of ILIB in addition to conventional therapy. RESULTS: Before treatment, the patients with CAP were observed to have a lower protein C system activity and the signs of hypercoagulation that were eliminated by ILIB. CONCLUSION: ILIB is an effective method in correcting hemocoagulative disorders in patients with CAP.

Biomarkers in respiratory tract infections: diagnostic guides to antibiotic prescription, prognostic markers and mediators.

Used appropriately, biomarkers improve the assessment of respiratory tract infections and sepsis. Most prominently, circulating procalcitonin levels increase by a factor of several tens of thousands during sepsis. Using a sensitive assay, procalcitonin safely and markedly reduces antibiotic usage in respiratory tract infections and nonbacterial meningitis. Procalcitonin is the protopye of hormokine mediators. The term "hormokine" encompasses the cytokine-like behaviour of hormones during inflammation and infections. The concept is based on a ubiquitous expression of calcitonin peptides during sepsis. Adrenomedullin, another member of the calcitonin peptide superfamily, was shown to complement and improve the current prognostic assessment in lower respiratory tract infections. Other peptides share some features of hormokines, e.g. natriuretic peptide and copeptin. Hormokines are not only biomarkers of infection but are also pivotal inflammatory mediators. Like all mediators, their role during systemic infections is basically beneficial, possibly to combat invading microbes. However, at increased levels they can become harmful for their host. Multiple mechanisms of action were proposed. In several animal models the modulation and neutralisation of hormokines during infection was shown to improve survival, and thus might open new treatment options for severe infections, especially of the respiratory tract.

Zinc for severe pneumonia in very young children: double-blind placebo-controlled trial.

BACKGROUND: Pneumonia is a leading cause of morbidity and mortality in young children. Early reversal of severity signs--chest indrawing, hypoxia, and tachypnoea--improves outcome. We postulated that zinc, an acute phase reactant, would shorten duration of severe pneumonia and time in hospital. METHODS: In a double-blind placebo-controlled clinical trial in Matlab Hospital, Bangladesh, 270 children aged 2-23 months were randomised to receive elemental zinc (20 mg per day) or placebo, plus the hospital's standard antimicrobial management, until discharge. The outcomes were time to cessation of severe pneumonia (no chest indrawing, respiratory rate 50 per min or less, oxygen saturation at least 95% on room air) and discharge from hospital. Discharge was allowed when respiratory rate was 40 per minute or less for 24 consecutive hours while patients were maintained only on oral antibiotics. FINDINGS: The group receiving zinc had reduced duration of severe pneumonia (relative hazard [RH]=0.70, 95% CI 0.51-0.98), including duration of chest indrawing (0.80, 0.61-1.05), respiratory rate more than 50 per min (0.74, 0.57-0.98), and hypoxia (0.79, 0.61-1.04), and overall hospital duration (0.75, 0.57-0.99). The mean reduction is equivalent to 1 hospital day for both severe pneumonia and time in hospital. All effects were greater when children with wheezing were omitted from the analysis. INTERPRETATION: Adjuvant treatment with 20 mg zinc per day accelerates recovery from severe pneumonia in children, and could help reduce antimicrobial resistance by decreasing multiple antibiotic exposures, and lessen complications and deaths where second line drugs are unavailable.

Assessment of vitamin A status with the relative-dose-response test in Peruvian children recovering from pneumonia.

BACKGROUND: The relative-dose-response (RDR) test is used to identify subjects with marginal liver vitamin A stores, but its use has not been evaluated during episodes of infection. OBJECTIVE: The objective was to assess, with the RDR test, the vitamin A status of children recovering from pneumonia. DESIGN: As part of a double-blind, placebo-controlled clinical trial of high-dose vitamin A supplements among children hospitalized with pneumonia in Lima, Peru, we examined the association of treatment group, nutritional status, severity of disease, and induction of the acute phase response [on the basis of serum C-reactive protein (CRP)] on serum retinol and the RDR test. RESULTS: Serum retinol was low at admission and increased significantly in both the vitamin A and placebo groups during recovery. Serum CRP had a significant, inverse association with retinol at both admission and discharge. Serum retinol and CRP concentrations never differed significantly between the treatment groups. Among subjects with CRP > or =10 mg/L, 21% in the vitamin A group and 20% in the placebo groups (P = 0.83) had a positive RDR test result. Among subjects with CRP <10 mg/L, 56% in the placebo group but only 6% in the vitamin A group had positive RDR test results (P = 0.002). CONCLUSION: The RDR test was useful in assessing the vitamin A status of children recovering from pneumonia when CRP concentrations were <10 mg/L but not when CRP concentrations were higher.

[Clinical observation on dusuqing in treating senile bacterial pneumonia].

OBJECTIVE: To evaluate the clinical effect of Dusuqing (DSQ) in treating senile bacterial pneumonia and to explore its possible mechanism. METHODS: Patients were randomly divided into two groups, the treated group treated with conventional western therapy (CWT) and the combined treated group treated with CWT plus DSQ respectively. The changes of serum cytokines, interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha), before and after treatment were observed. RESULTS: In the 33 patients of the combined treated group, the total effective rate being 93.9%. While in the 31 patients of treated group, the total effective rate being 83.9%. The difference of the total effective rate between the two groups was significant (P < 0.05). The scores of principal symptoms, secondary symptoms and total scores were all obviously lowered in both groups, particularly in the combined treated group. The peripheral blood IL-2 level was lower and TNF-alpha higher in senile patients than those in healthy aged subjects respectively. All the two parameters approached normal level in the combined treated group but with insignificant change in the CWT treated group. CONCLUSION: DSQ showed obvious effect in treating senile bacterial pneumonia. The mechanism might be related with the lowering of inflammatory cytokines such as oversecreted TNF-alpha, as well as the improvement of immune function (elevation of IL-2) of organism.

Improved efficacy of ciprofloxacin administered in polyethylene glycol-coated liposomes for treatment of Klebsiella pneumoniae pneumonia in rats.

Animal and clinical data show that high ratios of the area under the concentration-time curve and the peak concentration in blood to the MIC of fluoroquinolones for a given pathogen are associated with a favorable outcome. The present study investigated whether improvement of the therapeutic potential of ciprofloxacin could be achieved by encapsulation in polyethylene glycol (PEG)-coated long-circulating sustained-release liposomes. In a rat model of unilateral Klebsiella pneumoniae pneumonia (MIC = 0.1 microg/ml), antibiotic was administered at 12- or 24-h intervals at twofold-increasing doses. A treatment period of 3 days was started 24 h after inoculation of the left lung, when the bacterial count had increased 1,000-fold and some rats had positive blood cultures. The infection was fatal within 5 days in untreated rats. Administration of ciprofloxacin in the liposomal form resulted in delayed ciprofloxacin clearance and increased and prolonged ciprofloxacin concentrations in blood and tissues. The ED(50) (dosage that results in 50% survival) of liposomal ciprofloxacin was 3.3 mg/kg of body weight/day given once daily, and that of free ciprofloxacin was 18.9 mg/kg/day once daily or 5.1 mg/kg/day twice daily. The ED(90) of liposomal ciprofloxacin was 15.0 mg/kg/day once daily compared with 36.0 mg/kg/day twice daily for free ciprofloxacin; 90% survival could not be achieved with free ciprofloxacin given once daily. In summary, the therapeutic efficacy of liposomal ciprofloxacin was superior to that of ciprofloxacin in the free form. PEG-coated liposomal ciprofloxacin was well tolerated in relatively high doses, permitting once daily administration with relatively low ciprofloxacin clearance and without compromising therapeutic efficacy.

Laboratory abnormalities in patients with bacterial pneumonia.

STUDY OBJECTIVES: This study was undertaken to evaluate the laboratory abnormalities observed in patients with bacterial pneumonia as predictors of the severity of illness. DESIGN: Retrospective analysis. SETTING: Tertiary care hospital. PATIENTS AND PARTICIPANTS: We studied 302 consecutive patients who were admitted to the Long Island Jewish Medical Center from January through December 1993 and treated for bacterial pneumonia. The patients were subdivided into two groups based on their serum phosphorus level either on hospital admission or 4 days before the onset of pneumonia, if this was acquired in-hospital. Hypophosphatemia (group 1) was defined as serum phosphorus level of < or = 2.4 mg/dL and normophosphatemia > 2.4 mg/dL (group 2). Three hundred randomly selected hospitalized patients treated for conditions other than pneumonia comprised the control group (group 3). MEASUREMENTS: Groups 1 and 2 were compared with respect to laboratory data, mortality rate, and duration of hospitalization. The laboratory data of patients in group 3 were compared with those treated for bacterial pneumonia (groups 1 and 2). Stepwise multivariate logistic regression analysis was employed to identify the variables that best predicted the onset of pneumonia. RESULTS: In groups 1 and 2, a greater (p < 0.0001) number of patients (135 of 302 patients with pneumonia, 44.7%) developed hypophosphatemia compared with patients in group 3 (31 of 300 control subjects, 10.3%). Patients with pneumonia (groups 1 and 2) had higher levels (p < 0.01) of bicarbonate compared with control subjects. Moreover, patients with pneumonia demonstrated lower levels (p < 0.01) of calcium, phosphorus, albumin, cholesterol, and alanine aminotransferase compared with control patients (group 3). Among patients with pneumonia, those with hypophosphatemia (group 1) had significantly lower levels (p < 0.05) of potassium, calcium, and albumin compared to those subjects with normophosphatemia (group 2). Furthermore, hypophosphatemic subjects manifested higher levels of glucose (p < 0.01) and creatine phosphokinase (p < 0.05) compared to their normophosphatemic counterparts. In addition, hypophosphatemic patients experienced a longer duration of hospital stay (hypophosphatemia, 24.6 +/- 2.0 days, vs normophosphatemia, 14.1 +/- 1.0, p < 0.001) and higher (p < 0.001) mortality compared to normophosphatemic subjects. The incidence of nosocomial pneumonia was higher (p < 0.0001) in hypophosphatemic patients compared to those with normophosphatemia. CONCLUSION: We conclude that hypophosphatemia, hypocalcemia, hypokalemia, and hypoalbuminemia may be predictors of the severity of illness in patients admitted to the hospital with bacterial pneumonia.