Heme oxygenase-1 inhibits DENV-induced endothelial hyperpermeability and serves as a potential target against dengue hemorrhagic fever.

Dengue virus (DENV) is a cause of vascular endothelial dysfunction and vascular leakage, which are characterized as hallmarks of dengue hemorrhagic fever or dengue shock syndrome, which become a severe global health emergency with substantial morbidity and mortality. Currently, there are still no promising therapeutics to alleviate the dengue-associated vascular hemorrhage in a clinical setting. In the present study, we first observed that heme oxygenase-1 (HO-1) expression level was highly suppressed in severe DENV-infected patients. In contrast, the overexpression of HO-1 could attenuate DENV-induced pathogenesis, including plasma leakage and thrombocytopenia, in an AG129 mouse model. Our data indicate that overexpression of HO-1 or its metabolite biliverdin can maintain endothelial integrity upon DENV infection in vitro and in vivo. We further characterized the positive regulatory effect of HO-1 on the endothelial adhesion factor vascular endothelial-cadherin to decrease DENV-induced endothelial hyperpermeability. Subsequently, we confirmed that two medicinal plant-derived compounds, andrographolide, and celastrol, widely used as a nutritional or medicinal supplement are useful to attenuate DENV-induced plasma leakage through induction of the HO-1 expression in DENV-infected AG129 mice. In conclusion, our findings reveal that induction of the HO-1 signal pathway is a promising option for the treatment of DENV-induced vascular pathologies.

Impact of Nutritional Assessment on the Clinical Outcomes of Patients with Non-albicans Candidemia: A Multicenter Study.

Several studies have demonstrated that malnutrition is a negative prognostic factor for clinical outcomes. However, there is limited evidence for the effect of malnutrition on clinical outcomes in patients with candidemia. We investigated the relationship between malnutrition and all-cause 28-day mortality among patients with non-albicans candidemia. Between July 2011 and June 2014, all adult patients with non-albicans candidemia, including C. tropicalis, C. glabrata, C. parapsilosis and so on, were enrolled. The Malnutrition Universal Screening Tool (MUST) scores were used to determine the patients' nutritional status before the onset of candidemia. A total of 378 patients were enrolled; 43.4% developed septic shock and 57.1% had a high risk of malnutrition (MUST ≥ 2). The all-cause 28-day mortality rate was 40.7%. The Cox proportional hazards model revealed that C. tropicalis (HR, 2.01; 95% CI, 1.24-3.26; p = 0.005), Charlson comorbidity index (HR, 1.10; 95% CI, 1.03-1.18; p = 0.007), Foley catheter use (HR, 1.68; 95% CI, 1.21-1.35; p = 0.002), concomitant bacterial infections (HR, 1.55; 95% CI, 1.11-2.17; p = 0.010), low platelet count (HR, 3.81; 95% CI, 2.45-5.91; p < 0.001), not receiving antifungals initially (HR, 4.73; 95% CI, 3.07-7.29; p < 0.001), and MUST ≥ 2 (HR, 1.54; 95% CI, 1.09-2.17; p = 0.014) were independently associated with all-cause 28-day mortality. A simple screening tool for nutritional assessment should be used for patients with non-albicans candidemia to detect early clinical deterioration, and a tailored nutritional care plan should be established for malnourished individuals, to improve their clinical outcomes.

Association of vitamin D levels and risk of latent tuberculosis in the hemodialysis population.

BACKGROUND: Vitamin D is essential in the host defense against tuberculosis (TB). Suboptimal vitamin D status is common in the hemodialysis population. Hemodialysis patients have an increased risk compared to the general population latent tuberculosis infection (LTBI). However, the association between vitamin D deficiency and LTBI in this population remains unclear. MATERIALS AND METHODS: We conducted a cross-sectional study between March and May 2017. Interferon-gamma release assay (IGRA) through QuantiFERON-TB Gold In-Tube was used to assess LTBI. Plasma 25-hydroxycholecalciferol (25-OHD) levels were measured by Elecsys Vitamin D Total assay. Suboptimal vitamin D levels included vitamin D insufficiency 20-29 ng/mg and vitamin D deficiency <20 ng/mL. Predictors for LTBI were analyzed. RESULTS: A total of 287 participants were enrolled. The suboptimal vitamin D level was 31.4% (90/287), which including the vitamin D deficiency was 13.9% (40/287). A total of 49.1% (141/287) people received nutritional vitamin D supplementation. The prevalence of IGRA positivity in this study was 25.1% (72/287). There was no significant difference in vitamin D concentrations or the proportion of vitamin D supplementation among the IGRA-positive and IGRA-negative groups (p = 0.789 and 0.496, respectively). In multivariate analysis, age >65 years old (odds ratio (OR), 1.89; 95% CI, 1.08-3.31; p = 0.026) and TB history (OR, 3.51; 95% CI, 1.38-8.91; p = 0.008) were independent predictors of IGRA positivity. CONCLUSION: This is the first study to report that vitamin D deficiency was not associated with IGRA positivity in a hemodialysis population. Aging and TB history were both independent predictors for LTBI.

Clinical characteristics of Candida tropicalis fungaemia with reduced triazole susceptibility in Taiwan: a multicentre study.

Candida tropicalis is the second most common Candida species causing fungaemia in Taiwan, and decreased susceptibility to fluconazole has been reported. This study analysed the clinical characteristics of adult patients with C. tropicalis fungaemia and the antifungal susceptibilities of isolates at five tertiary hospitals in Taiwan (1 July 2011 to 30 June 2014). A standardised case record form was used retrospectively to collect demographic, clinical and microbiological characteristics, antifungal treatment and outcomes. MICs of non-duplicate isolates were determined using SensititreTM YeastOneTM and were interpreted using cut-off values recommended by the CLSI. A total 248 patients were diagnosed over the study period; 30-day crude mortality was 52.0%. Multivariate analysis showed that high Charlson comorbidity index ≥4 (OR = 2.09, 95% CI 1.22-3.59; P = 0.008), neutropenia (OR = 4.61, 95% CI 1.42-15.00; P = 0.011) and treatment with an azole-based regimen (OR = 0.39, 95% CI 0.17-0.90; P = 0.028) were significantly associated with 30-day mortality. A total of 33.9% of isolates were non-susceptible to fluconazole (MIC50, 2 mg/L; MIC90, 16 mg/L; MIC range, 0.25 to >256 mg/L), whilst 56.9% to voriconazole (MIC50, 0.25 mg/L; MIC90, 1 mg/L; MIC range, 0.015 to >8 mg/L) according to CLSI clinical breakpoints. There was no significant correlation between overall mortality and MICs of fluconazole or voriconazole. This study showed high mortality in patients with C. tropicalis fungaemia, and azole-based antifungal treatment could improve outcomes regardless of fluconazole MICs of infecting isolates compared with patients without any treatment within 48 h.

Association of bacterial genotypes and epidemiological features with treatment failure in hemodialysis patients with methicillin-resistant Staphylococcus aureus bacteremia.

OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) infections in the hemodialysis (HD) population are epidemiologically classified as healthcare-associated infections. The data about the clinical impact and bacterial characteristics of hospital-onset (HO)- and community-onset (CO)-MRSA in HD patients are scarce. The current study analyzed the difference in the clinical and molecular characteristics of HO-MRSA and CO-MRSA. METHODS: We performed a retrospective review and molecular analysis of clinical isolates from 106 HD patients with MRSA bacteremia from 2009 to 2014. CA genotypes were defined as isolates carrying the SCCmec type IV or V, and HA genotypes were defined as isolates harboring SCCmec type I, II, or III. RESULTS: CO-MRSA infections occurred in 76 patients, and 30 patients had HO-MRSA infections. There was no significant difference in the treatment failure rates between patients with CO-MRSA infections and those with HO-MRSA infections. CA genotypes were associated with less treatment failure (odds ratio [OR]: 0.18; 95% confidence interval [95% CI], 0.07-0.49; p = 0.001). For isolates with a vancomycin minimum inhibitory concentration (MIC) < 1.5 mg/L, the multivariate analysis revealed that HA genotypes and cuffed tunneled catheter use were associated with treatment failure. For isolates with a vancomycin MIC ≥1.5 mg/L, the only risk factor for treatment failure was a higher Pitt score (OR: 1.76; 95% CI, 1.02-3.05; p = 0.043). CONCLUSION: CA genotypes, but not the epidemiological classification of CO-MRSA, impacted the clinical outcome of MRSA bacteremia in the HD population.

Resistance to first- and second-line antituberculosis drugs in Southern Taiwan: Implications for empirical treatment.

BACKGROUND: Multidrug-resistant and extensively drug-resistant tuberculosis infections cause public health concerns worldwide. Local epidemiologic data about the drug resistance of Mycobacterium tuberculosis isolate (Mtb) is critical to guide appropriate empirical therapy to cure patients and restrain the spread of tuberculosis. METHODS: Antituberculosis susceptibility testing was performed for 287 Mtbs, including 63 MDR-Mtbs collected in southern Taiwan from 2011 to 2015. Tuberculosis patients were classified into newly diagnosed cases and previously treated cases based on patients' medical history. RESULTS: Almost no resistance was found to the tested second-line antituberculosis drugs in non-MDR-Mtbs. Higher resistance rates to ethambutol, ofloxacin, and streptomycin were observed in MDR-Mtbs compared to non-MDR-Mtbs. Among 63 MDR-Mtbs, 61.9% of patients were newly diagnosed and 38.1% were previously treated cases. For MDR-Mtb, the drug-resistance rates in previously treated cases were significantly higher for ethambutol, pyrazinamide, ofloxacin, moxifloxacin, streptomycin, and p-aminosalicylic acid. When MDR-Mtbs are identified in previously treated cases, empirical administration of ethambutol, pyrazinamide, ofloxacin, or moxifloxacin may not provide effective treatment. The resistance rates to these drugs were all more than 50%. Furthermore, 25% of MDR-Mtbs from previously treated patients were resistant to p-aminosalicylic acid. CONCLUSION: We observed almost no resistance to the tested second-line antituberculosis drugs among non-MDR-Mtbs. Anti-tuberculosis regimen with pyrazinamide, ethambutol, fluoroquinolone, kanamycin, cycloserine and p-aminosalicylic acid can be empirically used for newly diagnosed MDR-TB cases. For previously treated MDR-TB patients, empirical ethambutol, pyrazinamide, ofloxacin, or moxifloxacin may not provide effective treatment because the resistance rates to these drugs were all >50%.

The effect of Helicobacter pylori eradication on the levels of essential trace elements.

OBJECTIVE: This study was designed to compare the effect of Helicobacter pylori (H. pylori) infection treatment on serum zinc, copper, and selenium levels. PATIENTS AND METHODS: We measured the serum zinc, copper, and selenium levels in H. pylori-positive and H. pylori-negative patients. We also evaluated the serum levels of these trace elements after H. pylori eradication. These serum copper, zinc, and selenium levels were determined by inductively coupled plasma mass spectrometry. RESULTS: Sixty-three H. pylori-positive patients and thirty H. pylori-negative patients were studied. Serum copper, zinc, and selenium levels had no significant difference between H. pylori-positive and H. pylori-negative groups. There were 49 patients with successful H. pylori eradication. The serum selenium levels were lower after successful H. pylori eradication, but not significantly (P = 0.06). There were 14 patients with failed H. pylori eradication. In this failed group, the serum selenium level after H. pylori eradication therapy was significantly lower than that before H. pylori eradication therapy (P < 0.05). The serum zinc and copper levels had no significant difference between before and after H. pylori eradication therapies. CONCLUSION: H pylori eradication regimen appears to influence the serum selenium concentration (IRB number: KMUH-IRB-20120327).

Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum ß-lactamase-producing Proteus mirabilis.

This study was intended to delineate the role of carbapenems and piperacillin/tazobactam in treating bacteremia caused by extended-spectrum ß-lactamase (ESBL)-producing Proteus mirabilis. We performed a multicenter and retrospective study of the patients with ESBL-producing P. mirabilis bacteremia. The outcomes of the patients treated by piperacillin/tazobactam or a carbapenem for at least 48 hours and the MICs of the prescribed drugs for these isolates were analyzed. Forty-seven patients with available clinical data were included. The overall 30-day mortality rate was 29.8%. All available isolates (n = 44) were susceptible to ertapenem, meropenem, and doripenem, and 95.6% were susceptible to piperacillin/tazobactam; however, only 11.4% of the isolates were susceptible to imipenem. Among the 3 patients infected with isolates exhibiting non-susceptibility to imipenem (MIC ≥2 mg/L) who were treated with imipenem, none died within 28 days. The 30-day (14.3% versus 23.1%, P = 0.65) or in-hospital (19.1% versus 30.8%, P = 0.68) mortality rate of 21 patients treated by a carbapenem was lower than that of 13 treated by piperacillin/tazobactam. However, among those treated by piperacillin/tazobactam, the mortality rate of those infected by the isolates with lower piperacillin/tazobactam MICs (≤0.5/4 mg/L) was lower than that of the isolates with MICs of ≥1/4 mg/L (0%, 0/7 versus 60%, 3/5; P = 0.045). ESBL-producing P. mirabilis bacteremia is associated with significant mortality, and carbapenem therapy could be regarded as the drugs of choice. The role of piperacillin/tazobactam, especially for the infections due to the isolates with an MIC ≤0.5/4 mg/L, warrants more clinical studies.

Nemonoxacin (TG-873870) for treatment of community-acquired pneumonia.

With a broad-spectrum of activity, fluoroquinolones have been widely and successfully used for decades for the treatment of and prophylaxis against various bacterial infections, including community-acquired pneumonia (CAP). However, the use of fluoroquinolones has been compromised by the emergence and spreading of bacterial resistance and the potential for adverse effects. Therefore, there is an unmet need for newer compounds that have a broader spectrum of activity to overcome existing bacterial resistance as well as the potential to minimize the risk of adverse effects. Nemonoxacin (TG-873870), a newly developed quinolone, has demonstrated broad-spectrum activity against Gram-positive, Gram-negative and atypical pathogens, including drug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. Results from Phases I and II studies of treatment of CAP are encouraging. This article reviews the updated data on nemonoxacin, including the bacterial susceptibility, the pharmacologic characteristics, and toxicities, and clinical trials using nemonoxacin for treatment of CAP.

Emerging resistance problems and future perspectives in pharmacotherapy for complicated urinary tract infections.

INTRODUCTION: Urinary tract infections (UTIs) are among the most common infectious diseases and contribute to high financial burden worldwide. Administration of appropriate antibiotic therapy is the key to achieving good therapeutic outcomes. The authors review the current status of global or regional epidemiology, especially on the antimicrobial resistance and several potential agents against complicated UTIs by multidrug-resistant (MDR) pathogens. AREAS COVERED: The authors summarized the susceptibility status on several major surveillance programs on uropathogens, focusing on Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci. Besides, the current perspectives of several potential antimicrobials against MDR uropathogens available for UTIs were also reviewed. EXPERT OPINION: High resistance to broad-spectrum antibiotics, especially to extended-spectrum ß-lactams, carbapenems, and fluoroquinolones among uropathogens emerges as a critical problem in many countries. Appropriate antimicrobial stewardship and continuous surveillance are necessary to monitor the trends of susceptibility for main pathogens. For these MDR uropathogens, polymyxin, fosfomycin, tigecycline, nitrofurantoin, linezolid, and daptomycin might be potential treatments for patients with uncomplicated and complicated UTIs in some countries, although they might not be approved by their regulation. However, more clinical evidence and more extensive meta-analyses are needed to evaluate and confirm the effectiveness of their usage in countries with a high prevalence of multidrug resistance.

Exendin-4 protected against cognitive dysfunction in hyperglycemic mice receiving an intrahippocampal lipopolysaccharide injection.

BACKGROUND: Chronic hyperglycemia-associated inflammation plays critical roles in disease initiation and the progression of diabetic complications, including Alzheimer's disease (AD). However, the association of chronic hyperglycemia with acute inflammation of the central nervous system in the progression of AD still needs to be elucidated. In addition, recent evidence suggests that Glucagon-like peptide-1 receptor (GLP-1R) protects against neuronal damage in the brain. Therefore, the neuroprotective effects of the GLP-1R agonist exendin-4 (EX-4) against hyperglycemia/lipopolysaccharides (LPS) damage were also evaluated in this study. METHODOLOGY/PRINCIPAL FINDINGS: Ten days after streptozotocin (STZ) or vehicle (sodium citrate) treatment in mice, EX-4 treatment (10 µg/kg/day) was applied to the mice before intrahippocampal CA1 injection of LPS or vehicle (saline) and continued for 28 days. This study examined the molecular alterations in these mice after LPS and EX4 application, respectively. The mouse cognitive function was evaluated during the last 6 days of EX-4 treatment. The results showed that the activation of NF-κB-related inflammatory responses induced cognitive dysfunction in both the hyperglycemic mice and the mice that received acute intrahippocampal LPS injection. Furthermore, acute intrahippocampal LPS injection exacerbated the impairment of spatial learning and memory through a strong decrease in monoaminergic neurons and increases in astrocytes activation and apoptosis in the hyperglycemic mice. However, EX-4 treatment protected against the cognitive dysfunction resulting from hyperglycemia or/and intrahippocampal LPS injection. CONCLUSIONS/SIGNIFICANCE: These findings reveal that both hyperglycemia and intrahippocampal LPS injection induced cognitive dysfunction via activation of NF-κB-related inflammatory responses. However, acute intrahippocampal LPS injection exacerbated the progression of cognitive dysfunction in the hyperglycemic mice via a large increase in astrocytes activation-related responses. Furthermore, EX-4 might be considered as a potential adjuvant entity to protect against neurodegenerative diseases.

Correlation between carbapenem consumption and resistance to carbapenems among Enterobacteriaceae isolates collected from patients with intra-abdominal infections at five medical centers in Taiwan, 2006-2010.

We investigated the trend in resistance to carbapenems among isolates of Enterobacteriaceae that had been collected from patients with intra-abdominal infections at five medical centers in Taiwan from 2006 to 2010 and evaluated the correlation between resistance to carbapenems and consumption of said agents as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART). During the study period, the usage of ertapenem and that of total carbapenems (ertapenem, imipenem, and meropenem) increased significantly from 6.13 to 13.38 defined daily doses per 1000 patient-days for ertapenem and from 20.43 to 34.25 defined daily doses per 1000 patient-days for total carbapenems. The most common species were Escherichia coli (n = 1095), Klebsiella spp. (n = 663), and Enterobacter spp. (n = 202). The susceptibility of all isolates to ertapenem and to imipenem varied during the study period. For ertapenem, the rates of nonsusceptibility ranged from 3.5% to 10.3% and those for imipenem ranged from 3.5% to 10.7%. Although the use of carbapenems increased during the study period, there was no marked increase in resistance to carbapenems. Continuous monitoring of resistance trends is necessary so that antimicrobial prescription policies can be adjusted and infection control intervention programs can be implemented.

Fusidic acid for the treatment of bone and joint infections caused by meticillin-resistant Staphylococcus aureus.

There is a lack of surveillance data on resistance to fusidic acid (FA) in Asia, and no reviews of FA usage for the treatment of orthopaedic infections have been conducted since the year 2000. In this study, we present a systemic literature review of FA resistance in Asia and the clinical use of FA for the treatment of bone and joint infections (BJIs). The in vitro activity of FA against meticillin-resistant Staphylococcus aureus (MRSA) isolates remains good, with low (<10%) resistance rates in most Asian countries. FA in Asia appears to be a better oral anti-MRSA agent than trimethoprim/sulfamethoxazole and clindamycin. More than 80 cases of FA use for BJI have been reported since 2000 and the recurrence or failure rate is <10%. There is much evidence supporting the use of FA in combination with other antibiotics (e.g. rifampicin) as an oral treatment following intravenous glycopeptide treatment for BJIs.

Functional role of wogonin in anti-angiogenesis.

Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway occurs commonly in cancer cells and endothelial cells, and contributes to angiogenesis. Wogonin is a compound with many biologically relevant properties. We previously reported that wogonin blocked IL-6-induced angiogenesis through suppression of VEGF expression, an important regulator of angiogenesis. However, the pathway involved in the suppressive effect of wogonin on IL-6-induced VEGF has not been completely clarified. This study aimed to investigate the molecular mechanisms participating in the suppression of wogonin on IL-6-induced VEGF in vitro, focusing on IL-6R/JAK1/STAT3/VEGF pathway. Both STAT3 siRNA and wogonin treatment resulted in an abolition of the expression of VEGF. Moreover, our data revealed that wogonin treatment after STAT3 knock-down did not further suppress VEGF expression. The addition of IL-6R siRNA or wogonin resulted in a decrease in the expression level of the phosphorylated JAK1 protein. Furthermore, wogonin significantly decreased the amount of phosphorylated STAT3. Finally, by EMSA, wogonin suppressed IL-6-induced STAT3 binding activity in a concentration-dependent manner. Taken together, our results show that wogonin suppresses IL-6-induced VEGF by modulating the IL-6R/JAK1/STAT3 signaling pathway. Based on this study, we suggest that wogonin may provide a new potential therapeutic option for treatment of IL-6-related pathological angiogenesis.

Role of moxifloxacin for the treatment of community-acquired [corrected] complicated intra-abdominal infections in Taiwan.

Complicated intra-abdominal infections (cIAIs) are common yet serious infections that can potentially lead to substantial morbidity and morbidity. As an essential adjunct to source control, the goals of antimicrobial therapy are to promote patient recovery, reduce recurrence risk, and prevent antimicrobial resistance. The current international guidelines on the empirical treatment of community-acquired complicated IAIs were published by the Infectious Diseases Society of America (IDSA) and Surgical Infections Society (SIS) in 2010. These guidelines all recommend the use of a fluoroquinolone (ciprofloxacin or levofloxacin) plus metronidazole for mild-to-moderate- and high-severity cases. Moxifloxacin monotherapy is recommended by the current IDSA/SIS guidelines for the treatment of mild-to-moderate complicated IAIs. Moxifloxacin has demonstrated a broad spectrum coverage of both aerobic and anaerobic pathogens, good tissue penetration into the gastrointestinal tract, and a good tolerability profile. Clinical data have demonstrated that moxifloxacin is at least as effective as other standard therapeutic regimens recommended by current clinical guidelines. Due to the high rates of extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae and fluoroquinolone-resistant Enterobacteriaceae among isolates causing community-acquired IAIs in Asia, any fluoroquinolones (including moxifloxacin) are not recommended as drugs of choice for the empirical treatment of community-acquired IAIs, particularly in countries (China, India, Thailand, and Vietnam) with fluoroquinolone resistance rates among Escherichia coli isolates of >20%. Given the low rates of fluoroquinolone-resistant (<20%) and extended-spectrum ß-lactamase (ESBL)-producing (<10%) Enterobacteriaceae isolates associated community-acquired IAIs in Taiwan, it appears that moxifloxacin is considered an appropriate first-line therapy for patients with community-acquired complicated IAIs in this country.

Zingiber officinale (ginger) compounds have tetracycline-resistance modifying effects against clinical extensively drug-resistant Acinetobacter baumannii.

Extensively drug-resistant Acinetobacter baumannii (XDRAB) is a growing and serious nosocomial infection worldwide, such that developing new agents against it is critical. The antimicrobial activities of the rhizomes from Zingiber officinale, known as ginger, have not been proven in clinical bacterial isolates with extensive drug-resistance. This study aimed to investigate the effects of four known components of ginger, [6]-dehydrogingerdione, [10]-gingerol, [6]-shogaol and [6]-gingerol, against clinical XDRAB. All these compounds showed antibacterial effects against XDRAB. Combined with tetracycline, they showed good resistance modifying effects to modulate tetracycline resistance. Using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method, these four ginger compounds demonstrated antioxidant properties, which were inhibited by MnO2, an oxidant without antibacterial effects. After the antioxidant property was blocked, their antimicrobial effects were abolished significantly. These results indicate that ginger compounds have antioxidant effects that partially contribute to their antimicrobial activity and are candidates for use in the treatment of infections with XDRAB.