Chulmin Park

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.

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.

Lymph node micrometastasis in node negative early gastric cancer

AIMS The clinical significance of lymph node micrometastasis for histologically node negative gastric cancer is not well documented. This study was to assess the incidence and to clarify the risk factors of lymph node micrometastasis in patients with node negative early gastric cancer (EGC). METHODS We investigated the lymph node micrometastasis with using an anticytokeratin immunohistochemical stain in 90 patients with node negative EGC who underwent curative resection between 1991 and 2000. RESULTS Among 3526 nodes from 90 patients, there were 17 cytokeratin immunohistochemical stain positive nodes from nine patients. The incidence of micrometastasis was higher in patients with lymphatic invasion (p=0.012), venous invasion (p=0.026) and larger tumor (p=0.003). The independent risk factors for lymph node micrometastasis were lymphatic invasion (p=0.004, RR=22.915, 95% CI = 2.709 ~ 193.828) and tumor size (p=0.029, RR=1.493, 95% CI = 1.042 ~ 2.138). Although there were 10 deaths during the follow-up period of mean 67.6 months (1 month ~ 147 months), there was no death from a cancer recurrence. CONCLUSIONS The incidence of lymph node micrometastasis in patients with node negative early gastric cancer was 10%, and the independent risk factors for micrometastasis were lymphatic invasion and tumor size.

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.

Molecular Epidemiologic Analysis of Methicillin-Resistant Staphylococcus aureus Isolates from Bacteremia and Nasal Colonization at 10 Intensive Care Units: Multicenter Prospective Study in Korea

We investigated molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) isolated at 10 intensive care units (ICUs) in Korea. MRSA isolates from bacteremia and nasal colonization were collected prospectively from October 2008 through May 2009 at 10 University-affiliated hospital ICUs. A total of 83 and 175 MRSA strains were isolated from bacteremia and nasal colonization, respectively. Acquired group accounted for 69.9% (n = 58) of bacteremia and 73.1% (n = 128) of nasal colonization. Pulsed-field gel electrophoresis (PFGE) type B (SCCmec type II/ST5) was dominant in the acquired group followed by PFGE type D (SCCmec type IVA/ST72; a community genotype). Seven of 58 (12.1%) acquired bacteremia and 15 of 128 (11.8%) acquired nasal colonizations had SCCmec type IVA/ST72 genotype, which indicated that the community genotype had already emerged as a cause of ICU acquired MRSA infection or colonization. Antibiotic resistance rates to ciprofloxacin, tetracycline, clindamycin and trimethoprim/ sulfamethoxazole were 84.4%, 67.1%, 78.1%, and 12.0%, respectively. Susceptibility to ciprofloxacin best predicted a community genotype (sensitivity 96.5%; specificity 96.9%; odds ratio 861; 95% confidence interval 169-4,390, P < 0.001) and the positive predictive value was 90.2%. Among 23 nasal re-colonized strains, 7 MRSA strains (30.4%) were different from the originally colonized strains on the basis of PFGE types.

Genetic diversity of the ftsI gene in β-lactamase-nonproducing ampicillin-resistant and β-lactamase-producing amoxicillin-/clavulanic acid-resistant nasopharyngeal Haemophilus influenzae strains isolated from children in South Korea.

Haemophilus influenzae frequently colonizes the nasopharynx of children and adults, which can lead to a variety of infections. We investigated H. influenzae carriage in the nasopharynx of 360 children, in terms of (1) the prevalence of strains with decreased susceptibility, and (2) the presence of amino acid substitutions in PBP3. One hundred twenty-three strains were isolated (34.2%, 123/360), 122 of which were classified as nontypable H. influenzae (NTHi). Of these, β-lactamase-nonproducing ampicillin-susceptible strains accounted for 26.2%, β-lactamase-producing-ampicillin-resistant strains for 9.0%, β-lactamase-nonproducing ampicillin-resistant (BLNAR) strains for 40.2%, and β-lactamase-producing amoxicillin-/clavulanic acid-resistant (BLPACR) for 24.6%, respectively. Pulsed field gel electrophoresis (PFGE) patterns were so diverse that they were clustered into 41 groups. The amino acid substitutions in the transpeptidase domain (292 amino acids) of ftsI in BLNAR isolates showed that group IIb accounted for 30.6%, IIc for 8.2%, IId for 16.3%, III for 32.7%, and the others for 12.2%. Moreover, groups IIb (56.7%; 17/30) and III (23.3%; 7/30) were prevalent among BLPACR strains. They were subclassified into more diverse sequence subtypes by analysis of the entire PBP3 (610 amino acids). Groups IIb, IIc, IId, and III exhibited 13, four, six, and four sequence subtypes, respectively. Such a genetic diversity is likely indicative of significant potential for decreased antimicrobial susceptibility in nasopharyngeal-colonizing NTHi strains.

Clinical Impact of Cytochrome P450 2C19 Genotype on the Treatment of Invasive Aspergillosis under Routine Therapeutic Drug Monitoring of Voriconazole in a Korean Population

Background Genetic polymorphisms of cytochrome P450 enzymes, especially CYP2C19 influence voriconazole pharmacokinetics. However, the impact of CYP2C19 genetic polymorphisms on the therapeutic efficacy and toxicity of voriconazole therapy are not well established. Materials and Methods In this prospective observational study, we analyzed all consecutive adult patients with hematologic diseases who were treated for invasive aspergillosis (IA) with voriconazole between January 2011 and June 2012. CYP2C19 genotype and routine therapeutic drug monitoring of voriconazole were performed. The target range for voriconazole trough levels was 1-5.5 mg/L. Results A total of 104 consecutive patients were enrolled, including 39 homozygous extensive metabolizers (EMs, 38%), 50 heterozygous extensive metabolizers (HEMs, 48%), and 15 poor metabolizers (PMs, 14%). The initial voriconazole trough levels were 1.8, 2.7, and 3.2 mg/L in EMs, HEMs, and PMs, respectively (P = 0.068). Out-of-range initial trough levels were most frequently observed in EMs (46%) followed by HEMs (26%) and PMs (0%) (P = 0.001). The frequency of initial trough levels < 1 mg/L but not > 5.5 mg/L differed significantly among the 3 groups (P = 0.005). However, treatment response, all-cause and IA-attributable mortality, and the occurrence of voriconazole-related adverse events did not differ significantly among the 3 groups (P = 0.399, P = 0.412, P = 0.317, and P = 0.518, respectively). Conclusions While none of the initial voriconazole trough levels in PMs was outside the target range, subtherapeutic initial trough levels were frequent in EMs. Although there was no significant relationship between CYP2C19 genotype and either the clinical outcomes of IA or toxicity of voriconazole, further large-scale multicenter studies using clinical data from homogeneous populations are required.

Detection and genotyping of vancomycin-resistant Enterococcus spp. by multiplex polymerase chain reaction in Korean aquatic environmental samples

The distribution characteristics of Enterococcus spp., which are indicators of fecal pollution, were investigated at 33 sites within the 3 major water systems of Korea. Enterococci were detected at concentrations ranging from 1 to 37 CFU/100mL in 41 of 132 samples (31.1%) from the 3 major water systems. The overall average detected concentration was 1.2 CFU/100mL, while the average concentration for all detection sites was 5.3 CFU/100mL. After optimized multiplex polymerase chain reaction (PCR) was performed with newly developed VanA, VanB, VanC-1, and VanC-2/3 primers, concentrations of vancomycin-resistant Enterococcus spp. (VRE) ranging from 1 to 23 CFU/100mL were detected in 17 of 132 samples (12.9%). Of 216 individual enterococcal colonies, 64 (29.6%) displayed the VanC genotype. The results of a susceptibility test to vancomycin showed that the range of the minimal inhibitory concentration (MIC), an indicator of bacterial resistance, was 4 to 24μg/mL, with the average MIC at 9.2±4.5μg/mL. Of the bacterial isolates, 1 colony with the VanC-1 genotype was identified as E. gallinarum by 16S rDNA sequencing, whereas the other 63 colonies had the VanC-2/3 genotype and were identified as E. casseliflavus. Although these results imply that the major head bays of Korea are not contaminated with the highly vancomycin-resistant VanA- or VanB-type VREs, the misuse of antibiotics should be prohibited to minimize the presence of VREs and to maintain a safe water supply for protecting the health of the general population. Based on the study results, we also recommend the implementation of a continuous, broad-spectrum inspection program for Enterococcus spp. and VRE contamination in the major head bays. Furthermore, the multiplex PCR method described in this study can be used effectively for this purpose.

Immunomodulatory effects of antifungal agents on the response of human monocytic cells to Aspergillus fumigatus conidia

We evaluated the immunomodulatory effects of three different classes of antifungal agents on the human monocytic cell line, THP-1, which had been stimulated in vitro with Aspergillus fumigatus conidia. Cells treated with amphotericin B (AmB), micafungin (MF), and voriconazole (VCZ), at concentrations not affecting cell viability, reduced production of tumor necrosis factor (TNF)-alpha in response to conidia, with the greatest reduction noted with VCZ. The reduction of TNF-alpha production correlated with TNF-alpha gene expression assessed by PCR and nuclear factor kappaB (NF kappaB) levels. Co-stimulation with granulocyte-macrophage colony stimulating factor abolished immunomodulatory effects of the drugs. Antifungal agents affect the immune reaction caused by A. fumigatus conidia in stimulated monocytes at clinically relevant drug concentrations. Because drugs with different mechanisms of action produced this effect, this suggests that it is the result of factors mediated by the cells. The impact of these immunomodulatory effects needs assessment.