A 20-Year Study of Capsular Polysaccharide Seroepidemiology, Susceptibility Profiles, and Virulence Determinants of Klebsiella pneumoniae from Bacteremia Patients in Taiwan.

In this study, we selected bacteremic Klebsiella pneumoniae isolates from the Taiwan Surveillance of Antimicrobial Resistance program. A total of 521 isolates were collected over a period of 2 decades, including 121 from 1998, 197 from 2008, and 203 from 2018. Seroepidemiology showed that the top five capsular polysaccharide types were serotypes K1, K2, K20, K54, and K62, constituting 48.5% of the total isolates, and the respective ratios at each time point have remained similar over the past 2 decades. The antibacterial susceptibility tests showed that K1, K2, K20, and K54 were susceptible to most antibiotics, while K62 was relatively resistant compared to other typeable and nontypeable strains. In addition, six virulence-associated genes, clbA, entB, iroN, rmpA, iutA, and iucA, were predominant in K1 and K2 isolates of K. pneumoniae. In conclusion, serotypes K1, K2, K20, K54, and K62 of K. pneumoniae are the most prevalent serotypes and carry more virulence determinants in bacteremia patients, which may indicate their invasiveness. If further serotype-specific vaccine development is performed, these five serotypes should be included. Since the antibiotic susceptibility profiles were stable over a long duration, empirical treatment may be predicted according to serotype if rapid diagnosis from direct clinical specimens is available, such as PCR or antigen serotyping for serotype K1 and K2. IMPORTANCE This is the first nationwide study to examine the seroepidemiology of Klebsiella pneumoniae using blood culture isolates collected over a period of 20 years. The study found that the prevalence of serotypes remained consistent over the 20-year period, with high-prevalence serotypes associated with invasive types. Nontypeable isolates had fewer virulence determinants than other serotypes. With the exception of serotype K62, the other high-prevalence serotypes were highly susceptible to antibiotics. If rapid diagnosis using direct clinical specimens, such as PCR or antigen serotyping, is available, empirical treatment can be predicted based on serotype, particularly for K1 and K2. The results of this seroepidemiology study could also help the development of future capsule polysaccharide vaccines.

Cross-protection induced by highly conserved outer membrane proteins (Omps) in mice immunized with OmpC of Salmonella Typhi or OmpK36 of Klebsiella pneumoniae.

BACKGROUND/PURPOSE: Outer membrane proteins (Omps) are a family of proteins that are highly conserved throughout the evolution of Enterobacteriaceae. Previous studies using sequence comparisons have found a high degree of sequence homology between OmpK36 of Klebsiella pneumoniae and OmpC of Salmonella enterica serovar Typhi. Whether highly conserved OmpC can be directly extrapolated as a common vaccine candidate against K. pneumoniae or other Enterobacteriaceae remains to be verified. METHODS: OmpK36 and OmpC were purified and used to immunize BALB/c mice. After immunization, five mice from each group were injected intraperitoneally with a cell suspension of K. pneumoniae or S. Typhi, and the mice were monitored daily for 14 days to measure the severity of illness and assess their survival. RESULTS: Cross-reacting OmpK36 and OmpC antibodies were identified in the mice immunized with OmpK36 or OmpC. No cross-protection was observed in the mice immunized with OmpC in the presence of K. pneumoniae infection. CONCLUSION: Although a high degree of similarity was observed for the amino acid sequences between OmpK36 and OmpC, our results suggested that no cross-protection occurred in the mice challenged with other species.

Virulence among different types of hypervirulent Klebsiella pneumoniae with multi-locus sequence type (MLST)-11, Serotype K1 or K2 strains.

BACKGROUND: Two different types of hypervirulent K. pneumoniae (HvKp), the MLST-11 and serotype K1/K2 strains, have been frequently described in recent studies. Although these two types of strains were described to be HvKp, their virulence was not compared. In this study, in vitro and in vivo approaches were used to assess differences in virulence. MATERIALS AND METHODS: A total of twenty-nine isolates, including 6 strains of each of serotype K1 and K2 isolates and 17 strains of ST11 isolates, were selected for this study. Phenotypic tests of virulence were performed by the string test and analysis of the virulent associated genes was detected by PCR. In vitro models of serum resistance and phagocytosis were used as the parameters to assess the virulence. In-frame deletion of virulence-associated genes was performed to study their contributions to virulence. The median lethal dose, i.e., the LD50, in mice was determined following IP injection. RESULTS: Although serotype K1 and K2 strains and ST11 isolates had similar virulence gene profiles, the ST11 isolates showed less serum and phagocytic resistance than the serotype K1/K2 isolates. The mouse lethality test revealed that all ST11 isolates were unable to cause lethality, even at > 107 CFU, while serotypes K1 and K2 showed an LD50 at ≤ 103 CFU. Aerobactin or capsule knockout mutants exhibited a lower LD50 than the parental strain, while capsule mutants showed a more significant decrease in LD50. CONCLUSION: Since there was a significant difference in virulence levels between the two types of HvKp when assessed in in vitro and in vivo models, it may be better to use the designation "HvKp" for some strains based on animal studies to avoid confusion. Virulence and non-virulence could be analysed in a relative manner, especially in comparison studies.

Does Antimicrobial Therapy Affect Mortality of Patients with Carbapenem-Resistant Klebsiella pneumoniae Bacteriuria? A Nationwide Multicenter Study in Taiwan.

Few clinical studies have previously discussed patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bacteriuria. This study aimed to assess the effect of antimicrobial therapy on the mortality of patients with CRKP bacteriuria. Hospitalized adults with CRKP bacteriuria were enrolled retrospectively from 16 hospitals in Taiwan during 2013 and 2014. Critically ill patients were defined as those with an Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥ 20. Multivariate Cox regression analysis was used to determine independent risk factors for 14- and 28-day mortality. Of 107 patients with CRKP bacteriuria, the 14-day and 28-day mortality was 14.0% and 25.2%, respectively. Thirty-three patients received appropriate antimicrobial therapy. In the multivariate Cox regression analysis, the APACHE II score ≥ 20 was the only independent risk factor for 14-day mortality (hazard ratio [HR]: 6.15, p = 0.024). APACHE II score ≥ 20 (HR: 3.05, p = 0.018) and male sex (HR: 2.57, p = 0.037) were associated with 28-day mortality. Among critically ill patients with CRKP bacteriuria, appropriate antimicrobial therapy was not associated with 14-day or 28-day survival. In conclusion, in patients with CRKP bacteriuria, the use of appropriate antimicrobial therapy was not an independent factor associated with reduced mortality. Our findings may inform future antibiotic stewardship interventions for bacteriuria caused by multidrug resistant pathogens.

Truncated Pneumolysin from Streptococcus pneumoniae as a TLR4-Antagonizing New Drug for Chronic Inflammatory Conditions.

Microbial proteins have recently been found to have more benefits in clinical disease treatment because of their better-developed strategy and properties than traditional medicine. In this study, we investigated the effectiveness of a truncated peptide synthesized from the C-terminal sequence of pneumolysin, i.e., C70PLY4, in Streptococcus pneumoniae, in treating chronic inflammatory conditions. It has been shown that C70PLY4 significantly blocks the transendothelial migration of neutrophils and attenuates the formation of atherosclerotic plaque and the secretion of soluble forms of the intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule 1 (VCAM-1), and E-selectin in high-fat-diet/streptozotocin-induced inflammatory rats. The mechanism and the docking simulation analysis further indicated that C70PLY4 might serve as a Toll-like receptor 4 (TLR4) antagonist by competing for the binding site of MD2, an indispensable protein for lipopolysaccharide (LPS)-TLR4 interaction signaling, on the TLR4 structure. Moreover, compared to the full-length PLY, C70PLY4 seems to have no cytotoxicity in human vascular endothelial cells. Our study elucidated a possible therapeutic efficacy of C70PLY4 in reducing chronic inflammatory conditions and clarified the underlying mechanism. Thus, our findings identify a new drug candidate that, by blocking TLR4 activity, could be an effective treatment for patients with chronic inflammatory diseases.

Effects of different resistance mechanisms on antimicrobial resistance in Acinetobacter baumannii: a strategic system for screening and activity testing of new antibiotics.

A total of 50 engineered strains with various antimicrobial resistance mechanisms were constructed by in-frame deletion, site-directed mutagenesis and plasmid transformation from two fully-susceptible strains (Acinetobacter baumannii KAB1544 and ATCC 17978), including 31 strains with chromosomally-mediated resistance and 19 with plasmid-mediated resistance. Each of the 50 resistance mechanisms showed similar effects on the minimum inhibitory concentrations (MICs) of KAB1544 and ATCC 17978. Compared with the parental strains, the engineered strains related to some efflux pumps showed a significant (≥4-fold) difference in the MICs of ß-lactams, quinolones, aminoglycosides, tetracyclines, folate pathway inhibitors and/or phenicols, whereas no significant effects on the MICs were found for the engineered strains lacking OmpA, CarO, Omp25, Omp33, OmpW or OprD. Mechanisms due to GyrA/ParC mutations, ß-lactamases, aminoglycoside-modifying enzymes, 16S rRNA methylases and tet resistance genes contributed their corresponding resistance, as previously published. In conclusion, strains constructed in this study have clear resistance mechanisms and can be used to screen and assess compounds against specific resistance mechanisms for treating Acinetobacter. In addition to our previously published system for Enterobacteriaceae, the combination of these two systems could increase the coverage of bacterial types for drug assessment and facilitate the selection process of new candidates in drug development against drug-resistant superbugs.

Appropriate Treatment for Bloodstream Infections Due to Carbapenem-Resistant Klebsiella pneumoniae and Escherichia coli: A Nationwide Multicenter Study in Taiwan.

BACKGROUND: In a multicenter study from Taiwan, we aimed to investigate the outcome of patients who received different antimicrobial therapy in carbapenem-resistant Enterobacteriaceae bloodstream infections and proposed a new definition for tigecycline use. METHODS: Patients from 16 hospitals in Taiwan who received appropriate therapy for bloodstream infections due to carbapenem-resistant Klebsiella pneumoniae and Escherichia coli were enrolled in the study between January 2012 and June 2015. We used a cox proportional regression model for multivariate analysis to identify independent risk factors of 14-day mortality. Tigecycline was defined as appropriate when the isolates had a minimum inhibitory concentration (MIC) ≤0.5 mg/L, and we investigated whether tigecycline was associated with mortality among patients with monotherapy. RESULTS: Sixty-four cases with carbapenem-resistant K pneumoniae (n = 50) and E coli (n = 14) bloodstream infections were analyzed. Of the 64 isolates, 17 (26.6%) had genes that encoded carbapenemases. The 14-day mortality of these cases was 31.3%. In the multivariate analysis, Charlson Comorbidity Index (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.42; P = .022) and colistin monotherapy (HR, 5.57; 95% CI, 2.13-14.61; P < .001) were independently associated with 14-day mortality. Among the 55 patients with monotherapy, the 14-day mortality was 30.9% (n = 17). Tigecycline use was not associated with mortality in the multivariate analysis. CONCLUSIONS: Tigecycline monotherapy was a choice if the strains exhibited MIC ≤0.5 mg/L, and colistin monotherapy was not suitable. Our findings can initiate additional clinical studies regarding the efficacy of tigecycline in carbapenem-resistant Enterobacteriaceae infections.

Systemic proinflammation after Mycobacterium tuberculosis infection was correlated to the gut microbiome in HIV-uninfected humans.

BACKGROUND: The dysbiosis of gut microbiome and interaction with host immunity after Mycobacterium tuberculosis (MTB) infection are under investigation. We had found fatigue symptom concurrent with dysbiosis by decreasing the ratio of Firmicutes to Bacteroidetes (F/B ratio) in active tuberculosis (TB). The study aims to assess the inflammatory biomarkers and their interaction with gut microbiome in active TB and latent TB infection before starting anti-TB regimens. MATERIALS AND METHOD: Interleukin-1 beta (IL-1B), IL-4, IL-6, IL-10, CD3+, CD4+, CD8+ T cells and interferon-gamma (IFN-γ) releasing assay (IGRA) were measured in 25 active TB patients, 32 LTBI subjects and 23 healthy controls (HC). Gut microbiome profiles were obtained using 16S rRNA MiSeq sequencing method. RESULTS: The leucocytosis (7032 ± 387 cell/cum, P < 0.05), increase in IL-6 (229.7 ± 104 µg/dL, P < 0.05), and decrease in IL-4 (0.27 µg/dL ± 0.1, P < 0.05) were presented in active TB. The proportion of polymorphic neutrophil (PMN) in peripheral blood was positively related to the relative abundance of Bacteroidetes in LTBI and active TB (R2  = 0.23, P < 0.05). The F/B ratio was positively related to the detectable IL-1B in TB (R2  = 0.97, P < 0.01) and to the IL-4 in LTBI (R2  = 0.27, P < 0.05). In LTBI, the relative abundances of Coriobacteriaceae were positively related to the secretion of IFN-gamma against MTB-antigens more likely associated with of CD4+ T cell (R2  = 0.42, P < 0.05). CONCLUSION: In active TB, dysbiosis with higher relative abundances of Bacteroidetes in stool and low F/B ratio was related to systemic proinflammation. In LTBI, dose-response relationship between peripheral PMN and relative abundances of Bacteroidetes was remained but not leads to systemic inflammation.

Carbapenem Nonsusceptible Klebsiella pneumoniae in Taiwan: Dissemination and Increasing Resistance of Carbapenemase Producers During 2012-2015.

Before 2011, the prevalence rates of carbapenemase-producing Klebsiella pneumoniae (CPKP) among carbapenem nonsusceptible K. pneumoniae (CnSKP) isolates were below 10% in Taiwan. The study presents the dissemination and increased antimicrobial resistance of CPKP from January 2012 to August 2015, as shown by Taiwanese multicenter surveillance. Isolates with minimum inhibitory concentrations (MICs) of >1 µg/mL for imipenem or meropenem were collected, screened for various carbapenemase genes by PCR, and tested for antimicrobial susceptibility. Among 1,457 CnSKP isolates, 1,250 were collected from medical centers. The CnSKP prevalence in medical centers increased by 1.7-fold during the study. Among all CnSKP isolates, 457 were CPKP. The CPKP rate among CnSKP increased by 1.5-fold and reached 36.8% in 2015. The CPKP nonsusceptibility rate to aztreonam, fluoroquinolones, and aminoglycosides increased yearly. Six CPKP isolates carried dual carbapenemase genes. Three Ambler classes were identified in 451 isolates with a single carbapenemase: classes A (315 blaKPC-2, 2 blaKPC-3, 28 blaKPC-17, 2 blaKPC-34), B (26 blaIMP-8, 2 blaNDM-1, 36 blaVIM-1), and D (40 blaOXA-48). The blaOXA-48 rate among CPKP increased by 6-fold over three years. Most KPC and OXA-48 producers were ST11. CnSKP was increasingly prevalent, owing to CPKP dissemination. Additionally, CPKP became more resistant during the study period.

Is fluoroquinolone monotherapy a useful alternative treatment for Pseudomonas aeruginosa bacteraemia?

PURPOSE: Pseudomonas aeruginosa bacteraemia is associated with high mortality, and most monotherapies are beta-lactam-based. We aimed to investigate clinical outcomes of definitive fluoroquinolone monotherapy versus beta-lactam monotherapy for P. aeruginosa bacteraemia. METHODS: This retrospective study enrolled adult patients receiving definitive monotherapy with beta-lactam or fluoroquinolone between November 2013 and November 2014 at Taipei Veterans General Hospital. The independent risk factors for 28-day mortality were analyzed by logistic regression and propensity score-adjusted analysis. RESULTS: Among the 105 patients enrolled, 78 patients received beta-lactams and 27 received fluoroquinolones (20 with ciprofloxacin and 7 with levofloxacin). Primary bacteraemia (39.0%) and urinary tract infections (37.1%) were the most common sources of bacteraemia. The 28-day mortality rate was 11.1% for those receiving fluoroquinolones and 32.1% for those receiving beta-lactams (P = 0.062). The 28-day mortality rate between the two groups stratified by APACHE II and Pitt bacteraemia scores showed no significant differences in each category. Propensity score-adjusted multivariate analysis revealed that definitive therapy with a fluoroquinolone was not associated with 28-day mortality (OR 0.42; 95% CI 0.08-2.23; P = 0.305). CONCLUSIONS: Fluoroquinolone might be an alternative to beta-lactam as a definitive monotherapy for P. aeruginosa bacteraemia provided they are active in vitro. Our results could be a basis for further studies and provide a possible target for antibiotic stewardship interventions in P. aeruginosa bacteraemia.

Treatment outcome of non-carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae infections: a multicenter study in Taiwan.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are associated with high mortality, and experiences with its treatment are usually based on carbapenemase-producing strains. Non-carbapenemase-producing CRKP is of clinical significance, but relevant studies are lacking. This nationwide study aimed to evaluate the outcome of antimicrobial therapy in patients with non-carbapenemase-producing CRKP infections. Patients with non-carbapenemase-producing CRKP infections were enrolled from 16 hospitals during January 2013 to December 2014 in Taiwan. Carbapenem resistance was defined as reduced susceptibility with a minimum inhibitory concentration of ≥2 mg/L for imipenem or meropenem. The resistance mechanisms of CRKP isolates were analyzed, and the clinical data of these patients were collected retrospectively. Independent risk factors of 14-day morality were determined by Cox regression analysis. A total of 99 patients with non-carbapenemase-producing CRKP infections were enrolled, and 14-day mortality was 27.3%. Among 67 patients treated with appropriate antimicrobial therapy, most (n = 61) patients received monotherapy. The 14-day mortality was lower in patients treated with appropriate monotherapy (21.3%) than in those with inappropriate therapy (37.5%). The multivariate regression model identified monotherapy (hazard ratio [HR], 0.30; 95% confidence interval [CI], 0.13-0.71; P = 0.005) as protective factor, and APACHE II scores (HR, 1.09; 95% CI, 1.01-1.18; P = 0.022) as risk factor associated with 14-day mortality. Tigecycline, colistin, and carbapenem were the most commonly used drugs in monotherapy. This study provides evidence supporting the efficacy of monotherapy in the treatment of non-carbapenemase-producing CRKP infections, and provides a future target for antibiotics stewardship for CRKP infection.

Efficacy of isoniazid salvage therapy for latent tuberculosis infection in patients with immune-mediated inflammatory disorders - A retrospective cohort study in Taiwan.

BACKGROUND: Active tuberculosis (TB) in patients with latent tuberculosis infection (LTBI) was associated with use of biological agents for immune-mediated inflammatory disorders (IMIDs). For decreasing active TB, isoniazid prophylaxis therapy was administered before biologic therapy among IMID patients with LTBI. However, for patients who had been received biologics for a long time with unknown status of LTBI or exposure history of active TB, the prevalence of LTBI and efficacy of isoniazid therapy were unclear. METHOD: A retrospective cohort study was conducted during 2012-2014 in a tertiary medical center in Taiwan, and the incidence case of active TB was identified by the national TB registration system on October 1, 2015. RESULTS: All 382 patients with 1532 person-years were followed up, the initial prevalence of LTBI by positive interferon-gamma releasing assay (IGRA+) was 17.5%. The prevalence of LTBI was increased in elder age (>20%, p < 0.05), chronic kidney disease (33%, p < 0.05), metabolic syndrome (26.3%, p < 0.05), but not related to the type of IMIDs or biologics. The crude incidences of TB were increased in elders (53.3/1000 person-year), abnormal chest film (49.6/1000 person-year), administration of tocilizumab (13.6/1000 person-year), and metabolic syndrome (56.1/1000 person-year), respectively. Among patents with LTBI, the incidence of active TB was lower in patients with isoniazid therapy (9.2/1000 person-year, p = 0.02) than without isoniazid therapy (92.2/1000 person-years), regardless the timing of initiating isoniazid therapy (p > 0.05). CONCLUSION: Isoniazid therapy can prevent active TB from LTBI despite of the timing of biologics administration.

Effects of different resistance mechanisms on susceptibility to different classes of antibiotics in Klebsiella pneumoniae strains: a strategic system for the screening and activity testing of new antibiotics.

OBJECTIVES: A strategic system for the screening and testing of new antibiotics was created to facilitate the development of antibiotics that are robustly effective against MDR bacteria. METHODS: In-frame deletion, site-directed mutagenesis and plasmid transformation were used to generate genetically engineered strains with various resistance mechanisms from a fully susceptible clinical isolate of Klebsiella pneumoniae. Antimicrobial susceptibility testing and a mouse infection model were used to test antibiotics against these strains in vitro and in vivo, respectively. RESULTS: A total of 193 strains, including 29 strains with chromosome-mediated resistance, 33 strains with plasmid-mediated resistance and 131 strains with a combination of both resistance mechanisms were constructed; these strains covered resistance to ß-lactams, quinolones, aminoglycosides, tetracyclines, folate pathway inhibitors and other antibiotics. MICs for all strains were tested, and the effects of genetic modifications on increasing the MICs were assessed. Ceftazidime and cefotaxime were used to assess the correlation between antibacterial activities in vitro and in vivo. Against a K. pneumoniae strain with blaOXA-48, ceftazidime had a lower MIC (0.5 mg/L) than cefotaxime (2 mg/L). Ceftazidime had an ED50 of 30 mg/kg, and no mice survived treatment with the same dose of cefotaxime. A positive correlation was observed between these in vitro and in vivo results. CONCLUSIONS: The system developed here could reduce the considerable time required to evaluate the effectiveness of new antibiotics against MDR bacteria, particularly in the early stages of drug development. This system could also be expanded as new resistance mechanisms emerge.

Inhibition of nitric oxide production reverses diabetes-induced Kupffer cell activation and Klebsiella pneumonia liver translocation.

Klebsiella pneumoniae (KP) is the most common pathogen of pyogenic liver abscess in East and Southeast Asia and diabetes mellitus (DM) is a major risk factor. The effect and mechanism of diabetes on KP liver abscess was examined in streptozotocin-induced diabetic mice and Akita mice (C57BL/6J-Ins2Akita). KP translocation to liver and plasma alaine transaminase levels were increased and liver clearance of KP was decreased in DM mice. Diabetic mice exhibited overgrowth of Enterococcus as well as E.coli and decreased lactobacilli/bifidas growth in intestine, increased intestinal iNOS protein and nitrite levels in portal vein, and increased IL-1ß and TNF-α expression of Kupffer cells. Fructooligosaccharides (FOS) or dead L. salivarius (dLac) supplementation reversed diabetes-induced enteric dysbiosis, NO levels in portal vein, and KP translocation to liver. L-NAME treatment decreased intestinal iNOS protein expression as well as Kupffer cell activation and increased liver clearance of KP in DM mice. Dead E.coli (2×108 CFU/ml) feeding for one week induced iNOS and TLR4 expression of intestine in germ-free (GF) mice. Dead bacteria feeding induced IL-1ß and TNF-α expression of Kupffer cells in GF mice but not in GF TLR4-/- mice. In conclusion, balance of intestinal microflora is important for preventing intestinal iNOS expression, Kupffer cell activation, and KP liver translocation in diabetes. Reversal of diabetes-induced enteric dysbiosis with FOS or dead L. salivarius decreases diabetes-induced intestinal iNOS expression and KP liver translocation. Diabetes induces Kupffer cell activation and KP liver translocation through enteric dysbiosis and nitric oxide production.

Serum pentraxin-3 and tumor necrosis factor-like weak inducer of apoptosis (TWEAK) predict severity of infections in acute decompensated cirrhotic patients.

BACKGROUND: Pentraxin-3 (PTX3) and soluble tumor necrosis factor (TNF)-like weak inducer of apoptosis (sTWEAK) are new candidate prognostic markers for comorbidities and mortality in various inflammatory diseases. Acute decompensation of cirrhosis is characterized by acute exacerbation of chronic systemic inflammation. Recently, increased circulating PTX3 levels have been reported in nonalcoholic steatohepatitis patients and positively correlated with disease severity. This study aims to explore serum PTX3/sTWEAK levels and their relationship with clinical outcomes in cirrhotic patients with acute decompensation. METHODS: We analyzed serum PTX3/sTWEAK levels in relation to inhospital and 3-month new clinical events and survivals in cirrhotic patients with acute decompensation. RESULTS: During admission, serum PTX3/sTWEAK levels were significantly higher in acute decompensated cirrhotic patients than controls and positively correlated with protein-energy wasting (PEW), new infections, long hospital stays, high medical costs, and high mortality. During a 3-month follow-up, acute decompensated cirrhotic patients with high serum PTX3/sTWEAK levels had more episodes of unplanned readmission and high 3-month mortality. On multivariate analysis, high PTX3/sTWEAK levels and PEW were independent risk factors for high mortality. CONCLUSION: High serum PTX3/sTWEAK levels and PEW are common in cirrhotic patients with acute decompensation. As compared with low serum PTX3 and sTWEAK cases, cirrhotic patients with high serum PTX3/sTWEAK levels a have higher probability of new severe infections, severe sepsis, septic shock, type 1 hepatorenal syndrome, in-hospital, and 3-month follow-up mortalities. Therefore, high serum PTX3/sTWEAK levels on hospital admission predict disease severity and case fatality in cirrhotic patients with acute decompensation.

Effects of corticosteroid and neuraminidase inhibitors on survival in patients with respiratory distress induced by influenza virus.

BACKGROUND/PURPOSE: Neuraminidase inhibitors (NAIs) including oseltamivir and peramivir are used for influenza treatment. A systemic corticosteroid is usually administrated for acute respiratory distress syndrome. The aim of this study was to investigate the effect of a systemic corticosteroid and its interaction with NAIs in patients with influenza infection and respiratory distress. METHODS: A retrospective survey of hospitalized patients infected with influenza from January 2012 to May 2014 was conducted in a medical center in Taiwan. RESULTS: Eighty-six patients were hospitalized during the study period. Forty-eight patients had respiratory distress and 39 of them (81.3%, 39/48) were supported by a mechanical ventilator. All patients with respiratory distress received oseltamivir; 60.4% (29/48) and 31.3% (15/48) of them received a corticosteroid and salvage intravenous peramivir, respectively. All-cause mortality was 29.1% (14/48), 20% (3/15), and 31% (9/29) in patients with respiratory distress, patients who received salvage peramivir, and patients who received a systemic corticosteroid, respectively. Salvage peramivir seemed to improve prognosis in patients with H1pdm09 or type B virus infection and respiratory distress (p = 0.05). Early initiating corticosteroid had a worse prognosis than initiation after 72 hours of NAI treatment (p = 0.024). In particular, a systemic corticosteroid seemed to lead to a shorter survival time in patients with chronic lung disease (p = 0.05). CONCLUSION: Salvage peramivir provided a better prognosis than monotherapy with oseltamivir in patients who were infected with H1pdm09 or type B virus and who developed respiratory distress. A systemic corticosteroid should be administered after initiating NAI therapy, especially in patients with chronic lung disease.

Risk of hemophagocytic lymphohistiocytosis in adults with fevers of unknown origin: the clinical utility of a new scoring system on early detection.

The diagnosis of hemophagocytic lymphohistiocytosis (HLH) is delayed by most physicians. This study aimed to identify early parameters and suitable scoring systems for the risk of HLH. Clinical and laboratory data collected ≤3 days after admission were defined as early parameters and used to calculate the number of HLH-2004 criteria met and bone marrow (BM) score. Between January 2006 and February 2016, 233 immunocompetent adults with naïve fever of unknown origin who underwent a BM study were enrolled to mimic patients at risk of HLH and randomly assigned into the developmental or validation cohort. Hemophagocytic lymphohistiocytosis was finally diagnosed in 47 patients, with non-Hodgkin lymphoma as the major etiology (51.1%). Upon admission, four-fifths of patients who developed subsequent HLH fulfilled ≤3 of 8 HLH-2004 criteria, and 6 early parameters were independent predictors of HLH: anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelet count < 100 × 103 /µL), leukoerythroblastosis, hyperbilirubinemia (total bilirubin > 2 × upper normal limit), hyperferritinemia (ferritin > 1000 ng/mL), and splenomegaly. Compared with the HLH criteria met upon admission, the BM score was an independent predictor (odds ratio = 1.621; 95% confidence interval, 1.355-1.940) with excellent discrimination (area under the receiver operating characteristic curve = 0.920; 95% confidence interval, 0.883-0.958). The sensitivity and specificity for a BM score cutoff of 10 points were 95% and 75%, respectively. When approaching immunocompetent adults with a continuously high fever, the BM score at initial admission assists with early identification of patients at risk of HLH.

The Antimicrobial Susceptibility of Klebsiella pneumoniae from Community Settings in Taiwan, a Trend Analysis.

Drug-resistant Klebsiella pneumoniae, especially extended-spectrum ß-lactamase (ESBL)- and/or AmpC ß-lactamase-producing strains, is an emerging problem worldwide. However, few data focusing on drug susceptibility of K. pneumoniae from community is available. In this study, we analyzed 1016 K. pneumoniae isolates from outpatients or those visiting emergency rooms collected during 2002-2012 from Taiwan Surveillance of Antimicrobial Resistance program. Significantly decreased susceptibilities to 3rd generation cephalosporins and ciprofloxacin were found during the study period. By 2012, susceptibility to cefotaxime and ciprofloxacin was 83.6% and 81.6%, respectively. The prevalence of ESBL-producers increased from 4.8% in 2002 to 11.9% in 2012 (P = 0.012), while that of AmpC ß-lactamase-producers increased from 0% to 9.5% in the same period (P < 0.001). Phylogenic analysis of the ESBL and AmpC-ß-lactamase-producers by pulsed-field gel electrophoresis and multi-locus sequence typing revealed wide genetic diversity even among the most common sequence type 11 isolates (33.0%). By multivariate analysis, later study year, elderly, and urine isolates were associated with carriage of ESBL genes, while only urine isolates were associated with carriage of AmpC ß-lactamase genes. Further studies are needed to determine which antibiotics are reasonable empirical therapy options for patients presenting with severe sepsis that might be caused by K. pneumoniae.

Development of a Colloidal Gold-Based Immunochromatographic Strip for Rapid Detection of Klebsiella pneumoniae Serotypes K1 and K2.

In this study, a novel colloidal gold-based immunochromatographic strip (ICS) containing anti-Klebsiella pneumoniae capsular polysaccharide polyclonal antibodies was developed to specifically detect K. pneumoniae serotypes K1 and K2. Capsular polysaccharide K1 and K2 antigens were first used to produce polyclonal anti-K1 and anti-K2 antibodies. Reference strains with different serotypes, nontypeable K. pneumoniae strains, and other bacterial species were then used to assess the sensitivity and specificity of these test strips. The detection limit was found to be 105 CFU, and the ICSs were stable for 6 months when stored at room temperature. No false-positive or false-negative results were observed, and equivalent results were obtained compared to those of more conventional test methods, such as PCR or serum agglutination. In conclusion, the ICS developed here requires no technical expertise and allows for the specific, rapid, and simultaneous detection of K. pneumoniae serotypes K1 and K2.

High minimum inhibitory concentration of imipenem as a predictor of fatal outcome in patients with carbapenem non-susceptible Klebsiella pneumoniae.

Carbapenem resistance in Klebsiella pneumoniae is important because of its increasing prevalence and limited therapeutic options. To investigate the clinical and microbiological characteristics of patients infected or colonized with carbapenem non-susceptible K. pneumoniae (CnsKP) in Taiwan, we conducted a retrospective study at Taipei Veterans General Hospital from January 2012 to November 2013. Carbapenem non-susceptibility was defined as a minimum inhibitory concentration (MIC) of ≥2 mg/L for imipenem or meropenem. A total of 105 cases with CnsKP were identified: 49 patients with infection and 56 patients with colonization. Thirty-one isolates had genes that encoded carbapenemases (29.5%), including K. pneumoniae carbapenemase (KPC)-2 (n = 27), KPC-3 (n = 1), VIM-1 (n = 1) and IMP-8 (n = 2). The in-hospital mortality among patients with CnsKP was 43.8%. A MIC for imipenem ≥16 µg/mL, nasogastric intubation and Acute Physiology and Chronic Health Evaluation II score were independent risk factors for in-hospital mortality for all patients with CnsKP. A MIC for imipenem ≥16 µg/mL was also an independent risk factor for 14-day mortality in patients with CnsKP. In conclusion, a positive culture for CnsKP was associated with high in-hospital mortality. A high imipenem MIC of CnsKP can predispose a patient to a poor prognosis.