Jin-Hong Yoo

Emergence of Community‐Associated Methicillin‐Resistant Staphylococcus aureus Strains as a Cause of Healthcare‐Associated Bloodstream Infections in Korea

BACKGROUND The prevalence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains causing bloodstream infection (BSI) has not been studied in Korea. OBJECTIVE We sought to determine the prevalence of CA-MRSA strains among isolates recovered from patients with MRSA BSIs and to explore epidemiological changes in Korea. We also sought to evaluate clinical characteristics relevant to the development of healthcare-associated BSIs. METHODS We prospectively collected consecutive MRSA isolates from patients with BSI at 4 hospitals from July 1 through November 30, 2007, and we also included MRSA isolates recovered from culture of blood samples collected during a previous year (October 1, 2004 through September 30, 2005) at a different hospital. Molecular typing studies were performed, including pulsed-field gel electrophoresis (PFGE), multilocus sequence typing, Staphylococcus protein A (spa) typing, and staphylococcal cassette chromosome mec (SCCmec) typing. We compared the clinical characteristics and outcomes of patients with healthcare-associated BSI due to CA-MRSA strains with those of patients with healthcare-associated BSI due to healthcare-associated MRSA (HA-MRSA) strains. RESULTS There were 76 cases of MRSA BSI, of which 4 (5.3%) were community-associated and 72 (94.7%) were healthcare-associated. Among the 72 HA-MRSA BSIs, 18 (25%) were community onset, and 54 (75%) were hospital onset. PFGE type D-ST72-spa B-SCCmec type IVA MRSA, the predominant genotype of CA-MRSA in Korea, accounted for 19 (25%) of all 76 MRSA BSIs, including 17 (23.6%) of 72 HA-MRSA BSIs and 11 (20.8%) of 53 hospital-onset HA-MRSA BSIs. Patients with healthcare-associated BSIs due to CA-MRSA strains carrying SCCmec type IVA tended to have fewer healthcare-associated risk factors, compared with patients with healthcare-associated BSIs due to HA-MRSA strains carrying other SCCmec types. The presence of a central venous catheter or other invasive device was the only independent factor differentiating patients infected with hospital-associated genotype strains from patients infected with other strains. Clinical outcomes were similar between both groups. CONCLUSIONS CA-MRSA strains are emerging as a major cause of BSI in healthcare settings in Korea. This changing epidemiology of MRSA poses a challenge to public health and infection control in hospital settings.

Application of Nucleic Acid Sequence–Based Amplification for Diagnosis of and Monitoring the Clinical Course of Invasive Aspergillosis in Patients with Hematologic Diseases

BACKGROUND AND METHODS We evaluated nucleic acid sequence-based amplification (NASBA) and a galactomannan enzyme immunosorbent assay (GM-EIA) for the diagnosis of invasive aspergillosis (IA) in neutropenic febrile patients and for monitoring of its clinical course and outcome. Blood samples were collected twice per week from 128 patients with hematologic diseases during periods of neutropenic fever after undergoing chemotherapy or hematopoietic stem cell transplantation. A total of 448 blood samples were tested. RESULTS There were 14 patients with IA (2 patients with proven IA and 12 with probable IA). The median index of the initial NASBA in the IA group was more than 10-fold higher than that in the non-IA group. Galactomannan antigenemia (index, >0.5) was detected with a sensitivity of 86%. In receiver-operator characteristic analysis, the cutoff index of NASBA for the presumptive diagnosis of IA was determined to be 5.0. Combination of these 2 parameters (either a GM-EIA index of >or=0.5 or a NASBA index of >or=5.0) improved the sensitivity of diagnosis to 100%. There was a close relationship between patient outcome and the kinetics of NASBA values: failure of negative conversion during treatment resulted in death in almost all cases. CONCLUSION If either GM-EIA or NASBA results suggest IA, the diagnostic yield for IA could be improved, and NASBA could be a useful marker for predicting the clinical course and outcome of treatment.

Predominance of Community-Associated Methicillin-Resistant Staphylococcus aureus Strains Carrying Staphylococcal Chromosome Cassette mec Type IVA in South Korea

ABSTRACT Studies on the molecular epidemiologic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains have demonstrated their genetic and geographical diversity. In addition, it has been reported that there are genetic differences between community-associated (CA) and health care-associated (HA) MRSA strains. Therefore, we investigated the major epidemiologic characteristics of CA MRSA isolates in South Korea and compared them with those of HA MRSA strains. Distributions of staphylococcal chromosome cassette mec (SCCmec) types and other molecular features, including the Panton-Valentine leukocidin (PVL) gene, were studied in 138 invasive MRSA isolates. Multiplex type IVA SCCmec was identified as the major CA MRSA infection type (53.1%), with a significantly higher prevalence than in HA MRSA (P < 0.001). One major group of type IVA strains carried a larger atypical class B mec element and new subtypes of ccrA2 (96% amino acid homology). The PVL gene was detected in one USA300-like isolate only. Seven major clone types determined by combinational grouping (genetic background SCCmec typing) showed representative patterns of antimicrobial susceptibilities. We concluded that less multi-drug-resistant strains of clone types B-I and D-1 (genetic background, B and D complexes; type IVA SCCmec) predominate in CA MRSA and that international PVL-positive strains have not spread in South Korea as yet.

Molecular epidemiology of extended-spectrum β-lactamase-producing Escherichia coli in the community and hospital in Korea: emergence of ST131 producing CTX-M-15

BackgroundThe prevalence of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli has been increased not only in the hospital but also in the community worldwide. This study was aimed to characterize ESBL- producing E. coli isolates and to investigate the molecular epidemiology of community isolates in comparison with hospital isolates at a single center in Korea.MethodsA total of 142 ESBL-producing E. coli isolates were collected at Daejeon St Mary’s Hospital in Korea from January 2008 to September 2009. The ESBLs were characterized by PCR sequencing using specific primers. The genetic relatedness was determined by pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST).ResultsOf 142 isolates, 139 were positive for CTX-M type ESBLs; CTX-M-14 (n = 69, 49.6 %), CTX-M-15 (n = 53, 38.1 %) and both CTX-M-14 and -15 (n = 17, 12.2 %). CTX-M-14 and CTX-M-15 were detected in both community and hospital isolates whereas isolates producing both CTX-M14 and-15 were mainly identified in the hospital. CTX-M producing E. coli isolates were genetically heterogeneous, revealing 75 distinct PFGE types. By MLST, 21 distinctive STs including 5 major STs (ST131, ST405, ST38, ST10, and ST648) were identified. Major STs were distributed in both community and hospital isolates, and ST131 was the predominant clone regardless of the locations of acquisition. No specific major STs were confined to a single type of ESBLs. However, ST131 clones were significantly associated with CTX-M-15 and the majority of them were multidrug-resistant. Distinctively, we identified a hospital epidemic caused by the dissemination of an epidemic strain, ST131-PFGE type 10, characterized by multidrug resistance and co-producing both CTX-Ms with OXA-1 or TEM-1b.ConclusionsThe epidemiology of ESBL-producing E. coli is a complex and evolving phenomenon attributed to the horizontal transfer of genetic elements and clonal spread of major clones, predominantly ST131. The multidrug resistant ST131 clone producing CTX-M-15 has emerged as a major clone in both the community and hospital, suggesting the widespread of this epidemic clone in Korea.

Voriconazole-related severe adverse events: clinical application of therapeutic drug monitoring in Korean patients

BACKGROUND Voriconazole is a triazole agent with excellent antifungal activity against Aspergillus species. However, despite its potential advantages, the occurrence of unpredictable toxicities might be critical in immunocompromised patients. The aim of this study was to analyze risk factors for voriconazole-related severe adverse events (SAEs). METHODS This prospective observational study was conducted in Korean patients with hematological malignancies and invasive aspergillosis on intravenous voriconazole therapy between June 2008 and April 2009. RESULTS Of the 25 patients enrolled, eight (32%) showed voriconazole-related SAEs, which included hepatotoxicities (n=5), cardiac tachyarrhythmias (n=2), and neurotoxicity (n=1). Sex, age, underlying hematological malignancies, voriconazole dose, the co-administration of a proton pump inhibitor, and CYP2C19 genotype were not found to be related to the occurrence of SAEs. However, trough plasma concentrations of voriconazole were found to be significantly higher in the patients with an SAE: median 6.32 mg/l (interquartile range (IQR) 2.86-9.71 mg/l) vs. median 2.15 mg/l (IQR 0.92-4.00 mg/l); p=0.011. Receiver operating characteristic curve analysis identified a cut-off trough concentration for SAEs of 5.83 mg/l (sensitivity 62.5% and specificity 94.1%). Furthermore, multivariate analysis showed that a trough concentration of ≥ 5.83mg/l was the only significant independent risk factor of an SAE. CONCLUSIONS This study shows that therapeutic drug monitoring is indicated in patients with a voriconazole-related SAE and that dose adjustment is required if the trough concentration of voriconazole exceeds 5.83 mg/l.

In vitro effects of ciprofloxacin and roxithromycin on apoptosis of jurkat T lymphocytes.

ABSTRACT Ciprofloxacin (CPFX) and roxithromycin (RXM) induced apoptosis of activated Jurkat T cells in vitro. CPFX showed concentration-dependent acceleration of apoptosis of activated Jurkat T cells by enhancing the expression of FasL and activities of caspase-3 and -8. RXM accelerated cell death, enhanced expression of FasL and caspase-3 but not caspase-8, and did not show the concentration dependency.

Effect of Moxifloxacin on Production of Proinflammatory Cytokines from Human Peripheral Blood Mononuclear Cells

ABSTRACT The effects of moxifloxacin, a new methoxyfluoroquinolone, on the production of proinflammatory cytokines from human peripheral blood mononuclear cells (PBMCs) were evaluated. Moxifloxacin inhibited the production of tumor necrosis factor alpha (TNF-α) and/or interleukin-6 (IL-6) by PBMCs stimulated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), and heat-killed bacteria in a concentration-dependent manner without cytotoxic effects. The addition of moxifloxacin reduced the population of cells positive for CD-14 and TNF-α and for CD-14 and IL-6 among the LPS- or LTA-stimulated PBMCs. By Western blot analysis, moxifloxacin pretreatment reduced the degradation of IκBα in LPS-stimulated PBMCs. In conclusion, moxifloxacin could interfere with NF-κB activation by inhibiting the degradation of IκBα and reduce the levels of production of proinflammatory cytokines.

Comparison of Quantitative Cytomegalovirus Real-time PCR in Whole Blood and pp65 Antigenemia Assay: Clinical Utility of CMV Real-time PCR in Hematopoietic Stem Cell Transplant Recipients

Successful preemptive therapy for cytomegalovirus (CMV) infection in transplant patients depends on the availability of sensitive, specific, and timely diagnostic tests for CMV infection. Although the pp65 antigenemia assay has been widely used for this purpose, real-time quantification of CMV DNA has recently been recognized as an alternative diagnostic approach. However, the guidelines for antiviral therapy based on real-time quantitative polymerase chain reaction (RQ-PCR) have yet to be established. From November 2004 to March 2005, a total of 555 whole blood samples from 131 hematopoietic stem cell transplant (HSCT) recipients were prospectively collected. RQ-PCR was conducted using an Artus® CMV LC PCR kit (QIAGEN). Both qualitative and quantitative correlations were drawn between the two methods. Exposure to the antiviral agent influenced the results of the two assays. Additionally, the discrepancy was observed at low levels of antigenemia and CMV DNA load. Via ROC curve analysis, the tentative cutoff value for preemptive therapy was determined to be approximately 2×104 copies/mL (sensitivity, 80.0%; specificity, 50.0%) in the high risk patients, and approximately 3×104 copies/mL (sensitivity, 90.0%; specificity, 70.0%) in the patients at low risk for CMV disease. Further study to validate the optimal cutoff value for the initiation of preemptive therapy is currently underway.

Molecular Epidemiological Analysis of Quinolone-Resistant Escherichia coli Causing Bacteremia in Neutropenic Patients with Leukemia in Korea

We analyzed an outbreak of Escherichia coli bacteremia in eight patients with leukemia in a hematology-oncology unit from July to September 1994. The antibiograms and genotypic patterns of the isolates were different, thus suggesting that the outbreak did not originate from a single clone. However, all the isolates were resistant to quinolones, which led us to examine the microbiological records from 1992 to 1994. The incidence of quinolone-resistant E. coli bacteremia in the hematology-oncology unit ranged from 81.8% to 94.6% during this period. We then analyzed 36 more isolates recovered from late 1994 to 1995. Field inversion gel electrophoresis patterns of these isolates were also different. Analysis of the quinolone resistance determining region in gyrA revealed that all the isolates had a double mutation in gyrA. In conclusion, quinolone-resistant E. coli could be an emerging threat to neutropenic patients with leukemia who receive a quinolone prophylactically, and attention must be paid to this trend of resistance.

The efficacy of non-carbapenem antibiotics for the treatment of community-onset acute pyelonephritis due to extended-spectrum β-lactamase-producing Escherichia coli

OBJECTIVE Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli has become an important cause of community-onset urinary tract infections. We aimed to evaluate the efficacy of non-carbapenem antibiotics for acute pyelonephritis (APN) due to ESBL-producing E. coli. METHODS We conducted a retrospective cohort study of patients with community-onset APN due to ESBL-producing E. coli at a single centre in Korea from 2007 to 2013. Outcomes included both microbiological and clinical failure. To adjust for non-random assignment of antibiotics, the propensity score method of inverse probability of treatment weighting and a multivariable analysis using Cox proportional hazards modelling were employed to estimate the efficacy of non-carbapenem antibiotics as compared with carbapenems. RESULTS Of 152 eligible patients, 85 (55.9%) received carbapenems and 67 (44.1%) received non-carbapenems. Non-carbapenem antibiotics used in this cohort included aminoglycosides (n = 30), β-lactam/β-lactamase inhibitors (n = 13), fluoroquinolones (n = 12) and trimethoprim/sulfamethoxazole (n = 5). Microbiological failure was observed in 16 patients receiving carbapenems (16/83, 19.3%) versus 4 patients receiving non-carbapenem (4/67, 6.0%). After weighting, the risk of microbiological failure was similar between the two groups [weighted hazard ratio (HR) 0.99; 95% CI 0.31-3.19]. In a multivariable regression analysis combined with weights, the estimate did not change (weighted adjusted HR 0.96; 95% CI 0.41-2.27). The clinical failure rate was also similar in the two groups (weighted HR 1.05; 95% CI 0.24-4.62). CONCLUSIONS These results suggest that non-carbapenem antibiotics were as effective as carbapenems as definitive therapy for treating community-onset APN caused by ESBL-producing E. coli if they are active in vitro.