Flavonoids from Gynostemma pentaphyllum exhibit differential induction of cell cycle arrest in H460 and A549 cancer cells.

Flavonoids, containing mainly kaempferol rhamnohexoside derivatives, were extracted from Gynostemma pentaphyllum (G. pentaphyllum) and their potential growth inhibition effects against H460 non-small cell lung cancer cells was explored and compared to that on A549 cells. The extracted flavonoids were found to exhibit antiproliferation effects against H460 cells (IC50 = 50.2 µg/mL), although the IC50 of H460 is 2.5-fold that of A549 cells (IC50 = 19.8 µg/mL). Further investigation revealed that H460 cells are more susceptible to kaempferol than A549, whereas A549 cell growth is better inhibited by kaempferol rhamnohexoside derivatives as compared with H460. In addition, flavonoids from G. pentaphyllum induced cell cycle arrest at both S and G2/M phases with concurrent modulated expression of the cellular proteins cyclin A, B, p53 and p21 in A549 cells, but not H460. On the contrary, apoptosis and concomitant alteration in balance of BCL-2 and BAX expression as well as activation of caspase-3 were equally affected between both cells by flavonoid treatment. These observations strongly suggest the growth inhibition discrepancy between H460 and A549 following flavonoid treatment can be attributed to the lack of cell cycle arrest in H460 cells and the differences between H460 and A549 cells may serve as contrasting models for further mechanistic investigations.

Cefepime therapy for monomicrobial bacteremia caused by cefepime-susceptible extended-spectrum beta-lactamase-producing Enterobacteriaceae: MIC matters.

BACKGROUND: Extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae isolates are important clinical pathogens. In addition, the efficacy of cefepime for such infections is controversial. METHODS: We performed a retrospective study of monomicrobial bacteremia caused by ESBL producers at 2 medical centers between May 2002 and August 2007. The patients definitively treated with in vitro active cefepime (cases) were compared with those treated with a carbapenem (controls) in a propensity score-matched analysis to assess therapeutic effectiveness. The 30-day crude mortality is the primary endpoint. RESULTS: A total of 178 patients were eligible for the study. Patients who received cefepime (n = 17) as definitive therapy were more likely to have a clinical failure (odds ratio [OR] 6.2; 95% confidence interval [CI], 1.7-22.5; P = .002), microbiological failure (OR 5.5; 95% CI, 1.3-25.6; P = .04), and 30-day mortality (OR 7.1; 95% CI, 2.5-20.3; P < .001) than those who received carbapenem therapy (n = 161). Multivariate regression revealed that a critical illness with a Pitt bacteremia score ≥ 4 points (OR 5.4; 95% CI, 1.4-20.9; P = .016), a rapidly fatal underlying disease (OR 4.4; 95% CI, 1.5-12.6; P = .006), and definitive cefepime therapy (OR 9.9; 95% CI, 2.8-31.9; P < .001) were independently associated with 30-day crude mortality. There were 17 case-control pairs in the propensity scores matched analysis. The survival analysis consistently found that individuals who received cefepime therapy had a lower survival rate (log-rank test, P = .016). CONCLUSIONS: Based on the current Clinical and Laboratory Standards Institute susceptible breakpoint of cefepime (minimum inhibitory concentration ≤ 8 µg/mL), cefepime definitive therapy is inferior to carbapenem therapy in treating patients with so-called cefepime-susceptible ESBL-producer bacteremia.

Carbapenem therapy for bacteremia due to extended-spectrum-ß-lactamase-producing Escherichia coli or Klebsiella pneumoniae: implications of ertapenem susceptibility.

A retrospective study was conducted at two medical centers in Taiwan to evaluate the clinical characteristics, outcomes, and risk factors for mortality among patients treated with a carbapenem for bacteremia caused by extended-spectrum-beta-lactamase (ESBL)-producing organisms. A total of 251 patients with bacteremia caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates treated by a carbapenem were identified. Among these ESBL-producing isolates, rates of susceptibility to ertapenem (MICs ≤ 0.25 µg/ml) were 83.8% and 76.4%, respectively; those to meropenem were 100% and 99.3%, respectively; and those to imipenem were 100% and 97.9%, respectively. There were no significant differences in the critical illness rate (P = 0.1) or sepsis-related mortality rate (P = 0.2) for patients with bacteremia caused by ESBL-producing K. pneumoniae (140 isolates, 55.8%) and E. coli (111 isolates, 44.2%). Multivariate analysis of variables related to sepsis-related mortality revealed that the presence of severe sepsis (odds ratio [OR], 15.9; 95% confidence interval [CI], 5.84 to 43.34; P < 0.001), hospital-onset bacteremia (OR, 4.65; 95% CI, 1.42 to 15.24; P = 0.01), and ertapenem-nonsusceptible isolates (OR, 5.12; 95% CI, 2.04 to 12.88; P = 0.001) were independent risk factors. The patients receiving inappropriate therapy had a higher sepsis-related mortality than those with appropriate therapy (P = 0.002), irrespective of ertapenem, imipenem, or meropenem therapy. Infections due to the ertapenem-susceptible isolates (MICs ≤ 0.25 µg/ml) were associated with a more favorable outcome than those due to ertapenem-nonsusceptible isolates (MICs > 0.25 µg/ml), if treated by a carbapenem. However, the mortality for patients with bacteremic episodes due to isolates with MICs of ≤ 0.5 µg/ml was similar to the mortality for those whose isolates had MICs of >0.5 µg/ml (P = 0.8). Such a finding supports the rationale of the current CLSI 2011 criteria for carbapenems for Enterobacteriaceae.

Lactobacillus rhamnosus GG as dietary supplement improved survival from lipopolysaccharides-induced sepsis in mice.

Sepsis is a state of host immune response triggered by virus or bacterial infection, in which the extent of regional and systemic inflammation and companion counter-inflammatory reactions determines disease outcomes. Probiotics are known for the immunomodulatory effect on allergic disorders, but it is not clear whether the beneficiary effect extends to sepsis and increases survival. In this mouse model, we injected intraperitoneally lipopolysaccharides (LPS) to induce sepsis, and investigated whether the pretreatment of Lactobacillus rhamnosus GG (LGG) contributed to host survival and examined the alteration of the gut microbiota and blood cytokines/chemokines profile before sepsis induction. Four-week-old male BALB/c mice were divided into two groups: one group were fed daily with LGG as a dietary supplement for fourteen days, whereas the other group with sterile water. Before sepsis induction, some mice from each group were killed to collect stool in the intestine and blood for microbial metagenomic and cytokine/chemokine analyses, respectively, and the rest were monitored afterward for mortality. The relative abundance of several families in the gut microbiota after LGG treatment was altered as well as the ratio of Firmicutes/Bacteroidetes. In addition, several pro-inflammatory cytokines such as G-CSF, IL7, IL15, and MCP1 were lower in the LGG group than in the control group. The survival rate following LPS-induced sepsis improved with LGG treatment. Our results indicated that dietary supplement of probiotic LGG improved survival from LPS-induced sepsis, most likely through pre-septic changes in the gut microbial constituents by LGG with reciprocal alteration of host immune system to a less reactive state to incoming pathogens.

Bactericidal activity of soymilk fermentation broth by in vitro and animal models.

Soybean fermentation broth (SFB) exhibits potent antibacterial activity against different species of bacteria in in vitro assays and animal models. Four isoflavone compounds-daidzin, genistin, genistein, and daidzein-of SFB were analyzed and quantified by high-performance liquid chromatography. In the in vitro test, daidzin and daidzein had more potent antibacterial activity than genistin. The minimum inhibition concentration values for these bacteria of SFB ranged from 1.25% to 5%, and the minimum bactericidal concentration values of strains ranged from 2.5% to 10%, depending on the species or strain. Vancomycin-resistant Entercoccus faecalis (VRE) strains were also tested for susceptibility to SFB in two species of animal model: the Sprague-Dawley rat and the BALB/c mouse. SFB-fed Sprague-Dawley rats showed excellent elimination efficiency against VRE, close to 99% compared with the phosphate-buffered saline-fed control group. In the BALB/c mouse model, SFB antibacterial activity was 65-80% against VRE compared with the control. In conclusion, SFB contains natural antibacterial substances such as daidzin, genistin, and daidzein that inhibit bacterial growth.

Clinical characteristics of urosepsis caused by extended-spectrum beta-lactamase-producing Escherichia coli or Klebsiella pneumonia and their emergence in the community.

BACKGROUND: The purpose of this study is to delineate clinical characteristics of urosepsis caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae (ESBL-EK) in different clinical settings, with an emphasis on community-acquired infections. METHODS: A retrospective study was conducted at two medical centers in Taiwan. From May 2002 to August 2007, clinical data of adults with urosepsis caused by ESBL-EK were collected. Patients were categorized into three groups according to the place of acquisition. Baseline characteristics, microbiological data and clinical outcomes were compared. RESULTS: Ninety-three cases of ESBL-EK urosepsis were included. Their mean age was 69.4 years, and 48.4% were men. Eleven (11.8%), 41 (44.1%), and 41 (44.1%) patients were categorized as having community-acquired, healthcare-associated, and hospital-acquired infections, respectively. Cases of ESBL-EK urosepsis from different settings shared similar characteristics in terms of age, gender, comorbidity and resistance profiles of bacterial strains. Of the bacterial isolates, 75% and 38.7% were resistant to fluoroquinolones and aminoglycosides, respectively. Cases of community-acquired urosepsis had a lower disease severity than those acquired in healthcare facilities or hospitals. Of note, there was no case fatality in 11 cases of community-acquired urosepsis and, in contrast, a crude mortality rate of 41.5% was found among adults with hospital-acquired urosepsis (p < 0.001). CONCLUSION: A limited number of adults with community-acquired urosepsis caused by ESBL-EK in the present study had a favorable outcome. Nonetheless, clinicians should be cautious of the emergence of urinary tract infections caused by ESBL-producers in the community setting.

Carbapenem therapy for bacteremia due to extended-spectrum ß-lactamase-producing Escherichia coli or Klebsiella pneumoniae.

For 244 patients with bacteremia due to extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli or Klebsiella pneumoniae treated by ertapenem (73, 29.9%) or either imipenem or meropenem (171, 70.1%), the therapeutic efficacy was evaluated. Ertapenem therapy was effective for patients with ESBL-producing E. coli or K. pneumoniae bacteremia in terms of mortality and microbiological responses, as compared with imipenem or meropenem.

Clinical manifestations and prognostic factors in cancer patients with bacteremia due to extended-spectrum ß-lactamase-producing Escherichia coli or Klebsiella pneumoniae.

BACKGROUND: Clinical information about bacteremia due to extended-spectrum ß-lactamase (ESBL)-producing pathogens in cancer patients was limited. The study was aimed to identify the clinical manifestations and risk factors for mortality in ESBL-producer bacteremia in cancer patients. METHODS: A retrospective study of bacteremia caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae in adults with cancer in National Cheng Kung University Hospital and National Taiwan University Hospital from July 2002 to August 2007 was conducted. Clinical characteristics, initial manifestations, and antimicrobial therapy were analyzed for their association with crude mortality at 14 days after bacteremia onset. RESULTS: A total 113 episodes of bacteremia caused by E coli (59.3%), K pneumoniae (39.8%) or both (0.9%) were included. Patients with hematological malignancy were younger (55 ± 22 vs. 69 ± 14 years, p < 0.003) and had less co-morbidity, but were more likely to have neutropenia (73.1% vs. 4.6%, p < 0.001) than those with solid tumor. By the univariate analysis in 113 episodes of ESBL-producer bacteremia, several risk factors, including pneumonia or soft-tissue infection as the bacteremia source, initial manifestations with high Pitt bacteremia scores, shock, respiratory failure or severe sepsis, and inappropriate definitive therapy were associated with 14-day crude mortality. By multivariate analysis, only pneumonia [adjusted odds ratio (AOR), 5.2; 95% confident interval (CI), 1.3-21.0; p = 0.021], severe sepsis (AOR, 24.3; 95% CI, 5.6-105.0; p < 0.001), and inappropriate definitive therapy (AOR, 11.3; 95% CI, 1.7-72.8; p = 0.011) were independently associated with a fatal outcome. CONCLUSION: The presence of neutropenia or underlying hematological malignancy in cancer patients with ESBL-producer bacteremia was not associated with an increase in the mortality rate. Appropriate definitive antimicrobial therapy will be beneficial in improving clinical outcome.