Incorporating pharmacogenetics into clinical practice promises to improve therapeutic outcomes by optimizing drug selection and dosage based on genetic factors affecting drug response. A key advantage of PGx-guided therapy is to decrease the likelihood of adverse events. To evaluate the clinical impact of PGx risk variants, we performed a retrospective study using genetic and clinical data from the largest Han Chinese cohort, comprising 486,956 individuals, assembled by the Taiwan Precision Medicine Initiative. We found that nearly all participants carried at least one genetic variant that could affect drug response, with many carrying multiple risk variants. Here we show the detailed analyses of four gene-drug pairs, azathioprine (NUDT15/TPMT), clopidogrel (CYP2C19), statins (ABCG2/CYP2C9/SLCO1B1), and NSAIDs (CYP2C9), for which sufficient data exists for statistical power. While the results validate previous findings that PGx risk variants are significantly associated with drug-related adverse events or ineffectiveness, the excess risk of adverse events or lack of efficacy is small compared to that found in those without the PGx risk variants, and most patients with PGx variants do not suffer from adverse events. Our results point to the complexity of implementing PGx in clinical practice and the need for integrative approaches to optimize precision medicine.

Predicting complex disease risks on the basis of individual genomic profiles is an advancing field in human genetics1,2. However, most genetic studies have focused on populations of European ancestry, creating a global imbalance in precision medicine and underscoring the need for genomic research in non-European groups3,4. The Taiwan Precision Medicine Initiative recruited more than half a million Taiwanese residents, providing a large dataset of genetic profiles and electronic medical record data for people with Han Chinese ancestry. Using extensive phenotypic data, we conducted comprehensive genomic analyses across the medical phenome with individuals genetically similar to Han Chinese reference populations. These analyses identified population-specific genetic risk variants and new findings for various complex traits. We developed polygenic risk scores, demonstrating strong predictive performance for conditions such as cardiometabolic diseases, autoimmune disorders, cancers and infectious diseases. We observed consistent findings in an independent dataset, Taiwan Biobank, and among people of East Asian ancestry in the UK Biobank and the All of Us Project. The identified genetic risks accounted for up to 10.3% of the overall health variation in the Taiwan Precision Medicine Initiative cohort. Our approach of characterizing the phenome-wide genomic landscape, developing population-specific risk-prediction models, assessing their performance and identifying the genetic effect on health serves as a model for similar studies in other diverse study populations.

Han Chinese people comprise nearly 20% of the global population but remain under-represented in genetic studies1,2, so there is an urgent need for large-scale cohorts to advance precision medicine. Here we present the Taiwan Precision Medicine Initiative (TPMI), established by Academia Sinica in collaboration with 16 major medical centres around Taiwan, which has recruited 565,390 participants who consent to provide DNA samples for genetic profiling and grant access to their electronic medical records (EMRs) for research. EMR access is both retrospective and prospective, allowing longitudinal studies. Genetic profiling is done with population-optimized arrays of single-nucleotide polymorphisms for people of Han Chinese ancestry, which enable genome-wide association3,4, phenome-wide association5,6 and polygenic risk score7,8 studies to be performed to evaluate common disease risk and pharmacogenetic response. Participants also agreed to be re-contacted for future research and receive personalized genetic risk profiles with health management recommendations. The TPMI has established the TPMI Data Access Platform, a central database and analysis platform that both safeguards the security of the data and facilitates academic research. As a large cohort of individuals with non-European ancestry that merges genetic profiles with EMR data and enables longitudinal follow-up, TPMI provides a unique resource that could be used to validate genetic risk prediction models, perform clinical trials of risk-based health management and inform health policies. Ultimately, the TPMI cohort will contribute to global genetic research and serve as a model for population-based precision medicine.

AbstractDNA sequencing of patients with rare disorders has been highly successful in identifying “causal variants” for numerous conditions. However, there are many reports of healthy individuals who harbor these deleterious variants, leading to the concept of incomplete penetrance and doubt about the utility of genetic testing in clinical practice and population screening. As the deleterious variants are rare, the penetrance of these variants in the population is largely unknown. We analyzed the genetic and clinical data from 486,956 participants of the Taiwan Precision Medicine Initiative (TPMI) to determine the risk difference between those with and without deleterious variants. In all, we analyzed 292 disease-relevant variants and their clinical outcomes to assess their association. We found that only 15 variants show a risk difference exceeding 5% between those with or without the variants. In essence, 87.3% of deleterious variants exhibit minimal risk differences, suggesting a limited impact on the individual and population levels. Our analysis revealed increasing trends with age in six cardiovascular and degenerative diseases and bell-shaped trends in two cancers. Additionally, we identified three clinical outcomes exhibiting a dose-response relationship with the number of deleterious variants. Our findings show that large-scale testing of deleterious variants found in the literature is not warranted, except for those exhibiting large disease risk differences.

Predicting complex disease risks based on individual genomic profiles is an advancing field in human genetics. However, most genetic studies have focused on European populations, creating a global imbalance in precision medicine and underscoring the need for genomic research in non-European groups. The Taiwan Precision Medicine Initiative (TPMI) recruited over half a million Taiwanese residents, providing the largest datasets of genetic profiles and electronic medical records for the Han Chinese. Using extensive phenotypic data, we conducted the largest genomic analyses of Han Chinese across the medical phenome. These analyses identified population-specific genetic risk variants and novel findings on the genetic architecture of complex traits. We developed polygenic risk scores, demonstrating strong predictive performance for conditions such as cardiometabolic diseases, autoimmune disorders, cancers, and infectious diseases. We observed consistent findings in an independent dataset, Taiwan Biobank, and among East Asians in the UK Biobank and the All of Us Project. The identified genetic risks accounted for up to 9.1% of the disease burden variance in Taiwan. Our approach of characterizing the phenome-wide genomic landscape, developing population-specific risk prediction models, assessing their performance, and identifying the genetic impact on health, serves as a model for similar studies in other diverse study populations. ### Competing Interest Statement SDHH is a founder, shareholder, and serves on the Board of Directors of Genomic Prediction, Inc. (GP). EW is an employee and shareholder of GP. ### Funding Statement This study was funded in part by the Academia Sinica (40-05-GMM, AS-GC-110-MD02, and 236e-1100202 to P.-Y.K. and J.-Y.W.) and the National Development Fund, Executive Yuan (NSTC 111-3114-Y-001-001 to P.-Y.K.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Institutional Review Boards of Taipei Veterans General Hospital (2020-08-014A), National Taiwan University Hospital (201912110RINC), Tri-Service General Hospital (2-108-05-038), Chang Gung Memorial Hospital (201901731A3), Taipei Medical University Healthcare System (N202001037), Chung Shan Medical University Hospital (CS19035), Taichung Veterans General Hospital (SF19153A), Changhua Christian Hospital (190713), Kaohsiung Medical University Chung-Ho Memorial Hospital (KMUHIRB-SV(II)-20190059), Hualien Tzu Chi Hospital (IRB108-123-A),Far Eastern Memorial Hospital (110073-F), Ditmanson Medical Foundation Chia-Yi Christian Hospital (IRB2021128), Taipei City Hospital (TCHIRB-10912016), Koo Foundation Sun Yat-Sen Cancer Center (20190823A), Cathay General Hospital (CGH-P110041), Fu Jen Catholic University Hospital (FJUH109001) and Academia Sinica (AS-IRB01-18079), Taiwan. Written informed consent was obtained from the subjects in accordance with institutional requirements and the Declaration of Helsinki principles. All collected information was de-identified before statistical data analysis. The analysis with Health and Welfare Data Science Center (HWDC) was approved by Institutional Review Boards of Academia Sinica (AS-IRB-BM-23056). This research has been conducted using the UK Biobank Resource under UK Biobank Main Application 15326. Work with All of Us data was performed using the All of Us Researcher Workbench under the workspace, Duplicate of Prediction of Polygenic Traits. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The genotyping and electronic medical record (EMR) data analyzed in this study are from the Taiwan Precision Medicine Initiative (TPMI) with proper approval from the TPMI Data Access Committee. In compliance with the confidentiality laws governing genetic and health data in Taiwan, the de-identified TPMI data are kept in a secure server at the Academia Sinica and not released to the public.

The Taiwan Precision Medicine Initiative (TPMI), a project initiated by the Academia Sinica in collaboration with 16 major medical centers around Taiwan, has recruited 565,390 participants who consented to provide DNA samples for genetic profiling and grant access to their electronic medical records (EMR) for studies to develop precision medicine. Access to the EMR is both retrospective and prospective, allowing researchers to conduct prospective studies over time. Genetic profiling is done with population-optimized SNP arrays for the Han Chinese populations that enable genetic analyses such as genome-wide association, phenome-wide association, and polygenic risk score studies to evaluate common disease risk and pharmacogenetic response. Furthermore, the TPMI participants agree to be contacted for future research opportunities related to their genetic risks and receive personalized genetic risk profiles with health management recommendations. TPMI has established the TPMI Data Access Platform (TDAP), a central database and analysis platform that both safeguards the security of the data and facilitates academic research. The TPMI is the largest non-European cohort that merges genetic profiles with EMR in the world. With a cohort that can be followed over time, it can be utilized to validate genetic risk prediction models, conduct clinical trials to show the efficacy of risk-based health management, and optimize health policies based on genetic risks. In this report, we describe the TPMI study design, the population and genetic characteristics of the TPMI cohort, and the power it provides to conduct crucial studies in developing precision medicine on a population and personal level. As Han Chinese represent almost 20% of the world's population, the results of TPMI studies will benefit >1.4 billion people around the world and serve as a model for developing population-based precision medicine. ### Competing Interest Statement The authors have declared no competing interest.

Patients with coronary artery disease show high serum levels of interleukin (IL)-27, a novel member of the IL-6 family. However, the function of IL-27 in hearts suffering ischemia/reperfusion (IR) injury is unclear. Here, we showed increased expression of mRNA for the IL-27 subunits, EBI3 and p28, in rat hearts after 40 min of coronary ligation and release for 7 days. This increase was associated with a peak in the release of the cardiac enzyme, creatine kinase-MB, on day 2 post-release. Moreover, levels of IL-27 receptor subunit gp130 mRNA, but not those of subunit WSX-1 mRNA, decreased in post-ischemic hearts. These results suggest that increased IL-27 production may compensate for receptor downregulation during myocardial recovery. Lactate dehydrogenase release and crystal violet staining revealed that IL-27 or IL-6 significantly attenuated severe hypoxia (SH, 2 % O-2)-induced cell damage in H9c2 cardiomyoblasts and primary rat neonatal cardiomyocytes. Incubating cardiomyocytes with IL-27 or IL-6 resulted in time-dependent activation of signal transducers and activators of transcription 3 (STAT3). Interestingly, IL-27-induced STAT3 activation was attenuated by pre-treatment with a gp130-neutralizing antibody. Blocking gp130 also reduced the cytoprotective effects of IL-27 or IL-6. Moreover, IL-27-mediated protection against SH was blocked by stattic, a small-molecule inhibitor of STAT3. IL-27 markedly improved post-ischemic recovery and reduced tissue damage in isolated perfused hearts when administered 5 min before reperfusion. These results indicate that IL-27 protects the myocardium against IR injury and facilitates the recovery of damaged cardiomyocytes via the gp130/STAT3 pathway.

Background and objectiveEarly diagnosis of tuberculous pleural effusion (TPE) remains difficult. While some inflammatory markers in pleural effusion (PE) are helpful in diagnosis, the roles of anti-inflammatory cytokines and effector molecules of cytotoxic T lymphocytes have not been investigated.MethodsLymphocyte-predominant exudative PE samples were assayed for inflammatory and anti-inflammatory cytokines and effector molecules of cytotoxic T lymphocytes. Logistic regression analysis was used to predict the probability of TPE and identify independently associated factors. Receiver operating characteristic (ROC) curve analysis was applied to determine the optimal cut-off value for the predicted probability.ResultsOf 95 patients enrolled, 35 had TPE, 46 had malignant PE and 14 had PE due to other aetiologies. Interferon- (IFN-), adenosine deaminase (ADA), decoy receptor (DcR) 3, monocyte chemo-attractant protein (MCP)-1, IFN-induced protein (IP)-10, granzyme A and perforin were higher in TPE than in PE of other aetiologies. By logistic regression analysis, IFN-75pg/mL, ADA40IU/mL, DcR39.3ng/mL and soluble tumour necrosis factor receptor 1 (TNF-sR1)3.2ng/mL were independent factors associated with TPE. The predicted probability based on the four predictors had an area under the ROC curve of 0.920, with 82.9% sensitivity and 86.7% specificity under the cut-off value of 0.303. In the TPE group, patients with positive PE/pleural culture for Mycobacterium tuberculosis had higher pleural IFN-, MCP-1, IP-10 and perforin than those with positive sputum but negative PE culture.ConclusionsWhile pleural interferon- and ADA are conventional markers for diagnosing TPE, simultaneous measurements of DcR3 and TNF-sR1 can improve the diagnostic efficacy.Early diagnosis of tuberculous pleural effusion remains difficult. Measuring pleural interferon-, adenosine deaminase, decoy receptor 3 and soluble tumour necrosis factor receptor-1 together can improve the low sensitivity of assaying either interferon- or adenosine deaminase alone, and may avoid pleural biopsy which is in some patients a high-risk procedure.

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.

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.

Aggregatibacter aphrophilus (formerly Haemophilus aphrophilus/paraphrophilus) is a small Gram-negative coccobacillus with fastidious growth requirements. It is a normal commensal of the human oropharynx and upper respiratory tract, and it can infrequently cause invasive human diseases, including bone and joint infections and subacute infective endocarditis. Cases of liver abscess caused by Aggregatibacter aphrophilus have been sparsely recorded in the English-language literature, but have not yet been reported in Taiwan. Here we present a case of Aggregatibacter aphrophilus pyogenic liver abscess in an immunocompetent young woman. She recovered uneventfully after repeated percutaneous abscess aspiration and antibiotic treatment for 5 weeks.

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.

Background: Extended-spectrum beta-lactamase (ESBL)-producing bacteria coexpressing AmpC type beta-lactamase (ACBL) are associated with the laboratory issue of false susceptibility to third-generation cephalosporins. This study was to evaluate laboratory tests and clinical significance of bacteremic isolates of Escherichia coli and Klebsiella pneumoniae with both ESBL and ACBL [dual-type lactamases (DTL)].Methods: From 2006 to 2009, 78 E coli and 12 pneumoniae bacteremic isolates with reduced susceptibility to cefotaxime (CTX) or ceftazidime (CAZ) were identified and relevant patients' data were collected for analysis. Phenotypic and genotypic characterizations of these selected isolates were determined by inhibitor-based assays and polymerase chain reaction-based genetic analyses, respectively.Results: Among the 90 isolates, 47 had DTL production. There was an increasing annual prevalence from 29% in 2006 to 56% in 2009 (p = 0.02). Phenotypic assays had a sensitivity and specificity of 57% (43/76) and 93% (13/14) for ESBL detection and 95% (58/61) and 34% (10/29) for ACBL, respectively. Among the DTL-producing isolates, phenotypic assays yielded a higher false negative rate of ESBL detection than that of ACBL detection (70% versus 6%), while all false negative ESBL results were associated with ESBL genes other than bla(CTx-M). The majority of the OIL-producing isolates were in the category of resistance to CTX (47/47, 100%) and CAZ (44/47, 94%) by the Clinical and Laboratory Standards Institute (CLSI) 2010 interpretive criteria, of which many were considered intermediate or fully susceptible to CTX (25/47, 53%) and CAZ (15/47, 32%) by the previous ones (CLSI-2009). The DTL-producing isolates exhibited a lower susceptibility rate to fluoroquinolones, aztreonam, and beta-lactam/lactamase inhibitors than those with either ESBL or ACBL alone. The use of indwelling catheters or nasogastric tubes was associated with bacteremia due to the OIL isolates, but the mortality rates were not different among those due to isolates with ESBL, ACBL, or both. By multivariate analysis, Pittsburg bacteremia score and Charlson comorbidity index were the significant predictors for all-cause mortalities.Conclusion: Bacteremic episodes due to OIL-producing E coli and K pneumoniae became increasingly prevalent and were often associated with coresistance to antibiotics other than beta-lactams, but they were not associated with a worse prognosis than those due to ESBL- or ACBL-producing bacteria. Copyright (C) 2012, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rights reserved.

Aims: In the study of tumour genetics, formalin fixed, paraffin embedded (FFPE) tumours are the most readily available tissue samples and DNA derived from FFPE tissue has been validated for array comparative genomic hybridisation (aCGH) and single nucleotide polymorphism (SNP) array analysis. Furthermore, in the study of tumour precursor genetics, whole genome amplification (WGA) has been used to produce a sufficient amount of DNA for aCGH. However, it is unclear whether the same approach can be extended to high-resolution SNP analysis.Methods: In this study, we examined the utility and limitations of genotyping platforms performed on WGA DNA from FFPE mesenchymal tumour samples for both copy number and SNP analyses. We analysed the results obtained using DNA derived from matched FFPE and frozen tissue samples on the Affymetrix 250K Nsp SNP array. Two widely used WGA methods, Qiagen (isothermal protocol) and Sigma (thermocycling protocol) were employed to determine how WGA methods affect the results.Results: We found that the use of WGA DNA derived from FFPE mesenchymal tumours for high-resolution SNP array application can produce a significant amount of false positive and false negative findings. While some of these misinter-pretations appear to cluster in genomic regions with high or low GC contents, the majority appears to occur randomly. Only large scale chromosome loss of heterozygosity (LOH) (> 10 Mb) can be reliably detected from WGA FFPE tumour DNA samples but not smaller LOH or copy number alterations.Conclusions: Our findings here indicate a need for caution in SNP array data interpretation when using WGA FFPE tumour-derived DNA in determining genomic alterations less than 10 Mb.

BACKGROUND:The incidence of invasive Group B streptococcal (GBS) infections is increasing in the elderly and immunocompromised adults in many countries worldwide. There are, however, few reports regarding the current status of the infection in northern Taiwan. This study investigated retrospectively the molecular epidemiology and clinical syndromes of the invasive GBS diseases in a tertiary care hospital in northern Taiwan over the past decade. METHODS:One hundred twenty episodes of invasive GBS disease were recorded at Cathay General Hospital, a tertiary care, teaching hospital in northern Taiwan, from January 1998 to June 2009. Clinical information was acquired from medical records. Capsular serotypes and alpha family of surface proteins were genotyped with multiplex and specific polymerase chain reaction. RESULTS:Of all episodes, 58.3% was found in the elderly (age ≥ 65), 36.1% in nonpregnant women and young adults (age 18-64), and 5.9% in the neonates (0-90 days). Case-fatality rate was 6.7%. Eighty-three (69%) of the invasive isolates were available for genotyping. In sharp contrast to the studies in southern Taiwan (1991-2004), Type Ib (26.5%) was the most frequent invasive isolate, followed by V (22.9%), III (18.1%), VI (12%), Ia (10.8%), II (6%), VIII (2.4%), and nontypable strain (1.2%). In particular, Serotype VI, which had been rarely implicated in invasive infection, emerged as a significant pathogen. A significant trend of increase in incidence was observed for the infection (p<0.0001), with concurrent increase of cases in the elderly and of Serotype Ib and VI. There was significant association with young adults of Type II and III and chronic skin conditions and older adults with Type Ia and V and chronic cardiovascular diseases. Type V was closely associated with skin and soft tissue infection. Recurrent episodes (10%) occurred most often in patients with concomitant malignancy, with an average of 314 days for recurrence. CONCLUSIONS:The incidence of GBS invasive infection among nonpregnant women and adults is rising in northern Taiwan, particularly in the elderly caused by Serotype Ib and VI. Population-based surveillance program should be implanted for assessment of the disease burden to the susceptible adult population.

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.

Background: Clinical information about bacteremia due to extended-spectrum beta-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. Copyright (C) 2011, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rights reserved.