Gender-Dimorphic Impact of PXR Genotype and Haplotype on Hepatotoxicity During Antituberculosis Treatment.

Women have a higher risk of drug-induced hepatotoxicity during antituberculosis treatment (HATT) than men. We hypothesized that single nucleotide polymorphism (SNP) genotype and derived haplotype of pregnane X receptor (PXR) gene, which could regulate the expression of phase I enzyme cytochrome P450 (CYP) 3A4, had a sex-specific influence on the risk of HATT. Six SNPs of the PXR gene were sequenced. Genotypes and haplotypes of the PXR SNPs, and other potential risk factors for HATT were compared between pulmonary TB patients with and those without HATT. HATT was defined as an increase in serum transaminase level >3 times the upper limit of normal (ULN) with symptoms, or >5 times ULN without symptoms. We performed the study in a derivation and a validation cohort. Among the 355 patients with pulmonary TB in the derivation cohort, 70 (19.7%) developed HATT. Logistic regression analysis revealed the risk of HATT increased in female genotype AA at rs2461823 (OR: 6.87 [2.55-18.52]) and decreased in female genotype AA at rs7643645 (OR: 0.14 [0.02-1.02]) of PXR gene. Haplotype analysis showed that female h001101 (OR: 2.30 [1.22-4.32]) and female h000110 (OR: 2.25 [1.08-4.69]) haplotype were associated with increased HATT risk. The identified predictors were also significantly associated with female HATT risk among the 182 patients in the validation cohort. Two PXR SNP genotypes and 2 haplotypes influenced the risk of HATT only in females. The PXR SNP showed a sex-specific impact that contributed to an increased HATT risk in females.

Central venous catheter-associated bloodstream infections in pediatric hematology-oncology patients and effectiveness of antimicrobial lock therapy.

BACKGROUND: Central line-associated bloodstream infection (CLABSI) is a serious complication in hematology-oncology patients. This study aimed to analyze the prevalence of CLABSI and the effectiveness of antimicrobial lock therapy (ALT) in pediatric patients. METHODS: BSIs of all pediatric hematology-oncology patients admitted to a children's hospital between January 2009 and December 2013 were reviewed. The United States National Healthcare Safety Network and Infectious Diseases Society of America guidelines were used to define CLABSI and catheter-related BSI (CRBSI). The incidence, laboratory and microbiology characteristics, poor outcome, and effectiveness of ALT were analyzed. RESULTS: There were 246 cases of CLABSI in 146 patients (mean age, 10.0 years), including 66 (26.8%) cases of CRBSI. The incidence of CLABSI was 4.49/1000 catheter-days, and the infection was responsible for 32.9% of the complications these patients developed and 9.3% of contributable mortality. Patients with acute myeloid leukemia had the highest infection density (5.36/1000 patient-days). Enterobacteriaceae (40.2%) and coagulase-negative staphylococci (CoNS; 20.7%) were the predominant pathogens. In multivariate analysis, older age, male sex, elevated C-reactive protein, acute lymphoblastic leukemia, and candidemia were associated with poor outcome. The success rate of ALT was 58.6% (17/29) for the treatment of CoNS and 78.3% (29/37) for Enterobacteriaceae infections. Patients with candidemia (n = 18) had the highest mortality (33.4%) and catheter removal rate (66.7%). Chlorhexidine as the disinfectant decreased the 1-year CLABSI rate from 13.7/1000 to 8.4/1000 catheter-days (p = 0.02). CONCLUSION: CoNS and Enterobacteriaceae are the predominant pathogens in CLABSI among pediatric hematology-oncology patients. ALT is effective and showed no significant side effect. New disinfection practice and infection control measures can decrease CLABSI.

Drug susceptibility and treatment response of common urinary tract infection pathogens in children.

BACKGROUND/PURPOSE: To document the trends of sensitivity and to find whether it is necessary to change antibiotics in selected patients according to the sensitivity test results in our clinical practice. METHODS: We collected urine culture results from 0-18-year-old patients in the National Taiwan University Hospital from January 1, 2003 to October 31, 2012. Their medical chart was reviewed to identify true pathogens responsible for their urinary tract infection (UTI). We checked the percentage of susceptibility of these pathogens to ampicillin, amoxicillin-clavulanate (AMC), cefazolin, cefmetazole, ceftriaxone, gentamicin, and trimethoprim-sulfamethoxazole (TMP-SMX) according to the Clinical and Laboratory Standards Institute (CLSI) guideline. The extended-spectrum-beta-lactamases (ESBLs) rate was also checked. In addition, we reviewed the treatment response of different antibiotics. Defervescence within 48 hours after initial antibiotics use was considered responsive. RESULTS: A total of 7758 urine cultures positive for Escherichia coli infection were collected during the 10-year period. The E. coli cefazolin susceptibility rate was 62-73% during 2003-2010, but it dropped to 23% in 2011 and 28% in 2012 after the new CLSI guideline (M100-S21) was released. However, other antibiotics did not show a significant difference. In UTI caused by E. coli, on average, the sensitivity rates for various antibiotics were as follows: cefmetazole, 90%; ceftriaxone, 85%; gentamicin, 77%; AMC, 61%; TMP-SMX, 47%; and ampicillin, 20%. The ESBL rate was also found to increase (2-11%; p < 0.01). The overall response rate of UTI caused by E. coli to first-line antibiotics such as first-generation cephalosporin and/or gentamicin was 78%. CONCLUSION: The susceptibility of common urinary tract pathogens to cefazolin has decreased dramatically since 2010. This trend may be due to the change in the CLSI guideline. Although the susceptibility rate to first-line empirical antibiotics shows a decreasing trend, we found that the clinical response was acceptable for our first-line empirical antibiotics.

Epidemic pleurodynia caused by coxsackievirus B3 at a medical center in northern Taiwan.

Epidemic pleurodynia is seldom reported in Southeast Asia and there has been no report from Taiwan. We conducted a retrospective chart review of children = 18 years of age in the National Taiwan University Hospital from January 1 to December 31, 2005. Epidemic pleurodynia was defined as an acute illness characterized by sharp localized pain over the chest or upper abdomen. Patients with known heart diseases or pulmonary consolidations were excluded. In total, 28 patients met the case definition of epidemic pleurodynia. Coxsackievirus B3 (CB3) was isolated in 15 (60%) of the 25 throat swab specimens. Four (14%) of the 28 patients presented chest wall tenderness and only one (6%) of the 18 patients tested had an elevated creatinine kinase level. Twenty-one (75%) of the 28 patients described pleuritic chest pains and 10 (45%) of the 22 chest radiographies exhibited pulmonary infiltrates or pleural effusions. Six patients were observed with tonsillar exudates and one was confirmed to have a CB3 urinary tract infection. The clinical features and radiological findings suggest that CB3-associated epidemic pleurodynia might be a disease of the pleura and occasionally spreads to nearby tissues, resulting in chest wall myositis, pulmonary infiltrates and myopericarditis.