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Replacement with nonvaccine serotypes (NVTs) among invasive pneumococcal diseases (IPDs) after the introduction of extended-valency pneumococcal conjugate vaccines varies in predominant serotypes across countries. This study analyzed changes in serotype distribution through serotyping, multilocus sequence typing, and antimicrobial susceptibility testing of 168 pediatric IPD isolates obtained from a multihospital-based surveillance system during 2014-2019 in South Korea. Vaccine serotypes (VTs) accounted for 16.1% (19A, 10.1%; 6A, 1.8%; and 19F 1.8%), 82.1% were NVTs (10A, 23.8%; 15A, 8.3%; 12F, 6.5%; 15C, 6.5%; and 15B, 6.0%), and three (1.8%) were nontypeable. Serotype 10A was the most common serotype, with a significant increase from 11.5% in 2014 to 33.3% in 2019 (p < 0.05 for the trend). Other NVTs decreased from 70.4% to 41.7% between 2015 and 2019, most notably in serotype 12F (from 14.8% to 0%). Almost all (95.0%) serotype 10A isolates were ST11189, which were multidrug resistant.

This study investigated the roles of β-lactamase and penicillin-binding protein 3 (PBP3) alterations in the development of recent antimicrobial resistance in nontypeable Haemophilus influenzae (NTHi) isolated from Korean children. Nasopharyngeal NTHi isolates from children at a tertiary children's hospital were tested for antimicrobial susceptibility using E-test. β-lactamase production was screened by the paper disc test, and polymerase chain reaction amplification of blaTEM and blaROB-1 was performed. The ftsI gene was amplified to identify PBP3 alteration. Of the 53 NTHi isolates, 69.8% were ampicillin nonsusceptible. The nonsusceptibility rates for cefaclor were 81.1%, cefpodoxime 69.8%, and amoxicillin/clavulanate 32.1%. About 60.3% and 32.1% of the isolates were genetically β-lactamase-nonproducing ampicillin-resistant (gBLNAR) and genetically β-lactamase-producing amoxicillin/clavulanate-resistant (gBLPACR) strains, respectively. Group III amino acid substitutions comprised 65.6% of the gBLNAR strains and 70.6% of the gBLPACR strains. MIC50 for amoxicillin/clavulanate, cefaclor, cefuroxime, cefpodoxime, and cefixime were more than 2-80 times higher in the gBLNAR and gBLPACR strains compared with gBLPAR strains. Group III gBLNAR strains had significantly higher ampicillin, amoxicillin/clavulanate, cefpodoxime, and cefixime minimum inhibitory concentrations than group II strains. Group III gBLNAR and gBLPACR NTHi strains are highly prevalent in Korea, raising the alarm about increasing β-lactam resistance in NTHi.

Escherichia coli sequence type (ST) 131 has emerged as a higher virulent and multidrug-resistant pathogen worldwide. This study aimed to identify the prevalence and characteristics of E. coli ST131 isolated from Korean children with bacteremia at a single center for 16 years. We retrospectively reviewed culture-proven E. coli bacteremia cases of children aged ≤18 years between 2000 and 2015. E. coli isolates were analyzed using multilocus sequence typing, fimH typing, and CTX-M typing. Among 177 children with E. coli bacteremia, a total of 21 (11.9%) ST131 isolates and 37 (20.9%) extended spectrum β-lactamase (ESBL)-producing E. coli were identified. Nineteen (90.5%) isolates of ST131 E. coli had the fimH gene, of which three were assigned to subclone H30. There was a significant difference in prevalence of ESBL production between ST131 (n = 8, 38.1%) and non-ST131 (n = 29, 18.6%) isolates (p = 0.039). Five ESBL-producing ST131 E. coli isolates had the blaCTX-M gene: two carried blaCTX-M-14, two carried b...

Background Understanding the population genetics of pneumococci will allow detection of changes in the prevalence of circulating genotypes and evidence for capsular switching. We aimed to analyze the genetic structure of invasive pneumococcal isolates obtained from children before and after the use of pneumococcal conjugate vaccines (PCVs) in Korea. Methods A total of 285 invasive pneumococcal isolates were analyzed using serotyping, multilocus sequence typing, and antimicrobial susceptibility testing. We classified the isolation year to pre-PCV7 (1995–2003; n = 70), post-PCV7 (2004–2010; n = 142), and post-PCV13 (2011–2013; n = 73) periods. Results Of the 10 clonal complexes (CCs), antibiotic-resistant international clones, CC320 (31.6%), CC81 (14.7%), and CC166 (6.7%) were the main complexes. Serotype 19A was the main serotype of CC320 throughout the periods. Serotypes of CC81 mainly comprised of 23F (53.3%) in pre-PCV7 period and replaced by non-vaccine types (NVTs; 6C [10%], 13 [30%], 15A [40%], and 15B/C [20%]) in post-PCV13 period. The main serotype responsible for CC166 also changed from 9 V (80%) in pre-PCV7 to NVT 11A (50%) in post-PCV13 periods. Non-susceptibility to penicillin (42.3%) was the highest in CC320, increasing from 0 to 76%. Conclusion The genetic structures of invasive pneumococcal isolates in Korean children have changed concomitantly with serotype after the implementation of PCVs.

Background Neisseria meningitidis serogroup B is a significant cause of septicaemia and meningitis worldwide. This phase 3 randomised, controlled study assessed the immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine, 4CMenB, in healthy Korean adolescents. Methods 264 adolescents (11–17 years old) were randomised to receive two doses, one month apart, of 4CMenB or control vaccines [placebo followed by one dose of a quadrivalent meningococcal ACWY glycoconjugate vaccine (MenACWY-CRM)]. Immunogenicity was evaluated by serum bactericidal assay with human complement (hSBA) against three serogroup B test strains specific for individual vaccine antigens (fHbp, NadA or PorA P1.4), and by enzyme-linked immunosorbent assay (ELISA) against the NHBA antigen. Solicited reactions and adverse events (AEs) were assessed. Results One month post-second vaccination, 98%, 97%, and 97% of subjects in the 4CMenB group achieved hSBA titres ≥4 against the fHbp, NadA and PorA test strains, respectively, while percentages in the Control group were comparable to baseline (27%, 16%, and 17%, respectively). Geometric mean ELISA concentrations (GMCs) against NHBA increased 52-fold relative to baseline in the 4CMenB group, while there was no substantial increase in GMCs in the Control group (1.05-fold). Frequencies of solicited reactions after any vaccination were higher in the 4CMenB group than in the Control group, although most reactions were of short duration and mild to moderate intensity. There were no vaccine-related serious AEs. Conclusions Two doses of 4CMenB induced robust immune responses against the vaccine antigens and were well tolerated, with no safety concerns identified, in Korean adolescents (NCT01973218).

To investigate the genetic background for the emergence of macrolide resistance, we characterized the genetic features of Mycoplasma pneumoniae using multilocus sequence typing. Of the 146 M. pneumoniae strains collected during the 5 consecutive outbreaks of M. pneumoniae pneumonia during 2000–2016 in South Korea, macrolide resistance increased from 0% in the first outbreak to 84.4% in the fifth. Among the 8 sequence types (STs) identified, ST3 (74.7%) was the most prevalent, followed by ST14 (15.1%). Macrolide-susceptible strains comprised 8 different STs, and all macrolide-resistant strains were ST3 (98.3%) except 1 with ST14. The proportion of macrolide-resistant strains in ST3 remained 2.2% (1/46) until the 2006–2007 outbreak and then markedly increased to 82.6% (19/23) during the 2010–2012 outbreak and 95.0% (38/40) during the 2014–2016 outbreak. The findings demonstrated that clonal expansion of ST3 M. pneumoniae was associated with the increase in macrolide resistance in South Korea.

Background Invasive bacterial infections in apparently immunocompetent children were retrospectively analyzed to figure causative bacterial organisms in Korea. Methods A total of 947 cases from 25 university hospitals were identified from 2006 to 2010 as a continuance of a previous 10-year period study from 1996 to 2005. Results Escherichia coli (41.3%), Streptococcus agalactiae (27.7%), and Staphylococcus aureus (27.1%) were the most common pathogens in infants < 3 months of age. S. agalactiae was the most prevalent cause of meningitis and pneumonia and E. coli was the major cause of bacteremia without localizing signs in this group. In children 3 to 59 months of age, Streptococcus pneumoniae (54.2%), S. aureus (20.5%), and Salmonella spp. (14.4%) were the most common pathogens. S. pneumoniae was the leading cause of pneumonia (86.0%), meningitis (65.0%), and bacteremia without localizing signs (49.0%) in this group. In children ≥ 5 years of age, S. aureus (62.8%) was the predominant pathogen, followed by Salmonella species (12.4%) and S. pneumoniae (11.5%). Salmonella species (43.0%) was the most common cause of bacteremia without localizing signs in this group. The relative proportion of S. aureus increased significantly over the 15-year period (1996–2010) in children ≥ 3 months of age (P < 0.001), while that of Haemophilus influenzae decreased significantly in both < 3 months of age group (P = 0.036) and ≥ 3 months of age groups (P < 0.001). Conclusion S. agalactiae, E. coli, S. pneumoniae, and S. aureus are common etiologic agents of invasive bacterial infections in Korean children., Graphical Abstract

Mycoplasma pneumoniae is an important cause of community-acquired pneumonia in children and young adolescents. Macrolides are recommended as the first-line therapy however, macrolide resistance rates in M. pneumoniae among children have been increasing substantially. Areas covered: This review focused on clinical characteristics and treatment of macrolide-resistant M. pneumoniae pneumonia in children. Expert commentary: Antibiotic choice should be based on in vitro activity, clinical efficacy and in consideration of potential adverse events. Macrolide resistance did not contribute to the clinical severity of M. pneumoniae pneumonia, but resistance may be an aggravating factor. Antibiotics may not be required for treatment in mild cases due to the self-resolving nature of M. pneumonia infection, regardless of macrolide resistance. In contrast, antibiotic treatment of severe cases of M. pneumoniae pneumonia is complicated. The clinical benefit of tetracyclines and fluoroquinolones has been shown in terms of shortening duration of symptoms and rapid defervescence in some reports. However, due to safety concerns regarding these two alternative antibiotics, clinicians should weigh the risks and benefits when choosing treatment options. Alternative antibiotics may be considered when patients remain febrile or when chest x-rays show deterioration at least 48-72 hours after macrolide treatment.

Central line-associated bloodstream infections (CLABSIs) account for significant morbidity and mortality in patients with long-term central venous catheters (CVCs). This study was performed to identify the characteristics and risk factors of CLABSIs among children with long-term CVCs.A retrospective review of children who had a long-term CVC in Seoul National University Children's Hospital between 2011 and 2015 was performed. Data on patient demographics, the isolated pathogens and the status of CVC placement were collected. Clinical variables were compared between subjects with and without CLABSIs to determine the risk factors for CLABSIs.A total of 629 CVCs were inserted in 499 children during the 5-year period. The median age at insertion was 6.0 years (14 days-17.9 years), and hemato-oncologic disease was the most common underlying condition (n = 497, 79.0%). A total of 235 CLABSI episodes occurred in 155 children, with a rate of 0.93 per 1,000 catheter days. The most common pathogens were Klebsiella pneumoniae (n = 64, 27.2%), coagulase-negative staphylococci (n = 40, 17.0%) and Staphylococcus aureus (n = 28, 12.0%). In the univariate analysis, the gender, underlying disease, catheter characteristics and insertion technique did not increase the risk for CLABSI. In both the univariate and logistic regression analyses, patients with prior BSIs (odds ratio 1.66; 95% confidence interval: 1.090-2.531; P = 0.018) were more likely to have a CLABSI.CLABSI prevention is of particular concern for children with a prior BSI. Furthermore, the antimicrobial resistance of major pathogens should be monitored to enable the empiric selection of appropriate antibiotics in patients with long-term CVCs.

Summary Background Group B Streptococcus (GBS) strains are classified by the polysaccharide capsule, which is an important virulence factor and stimulator of antibody-associated immunity. As GBS infections in neonates may be life-threatening, GBS screening and intrapartum antibiotic prophylaxis have been implemented for prevention. In Korea, there are few reports on the GBS serotype distribution and antibiotic resistance patterns because GBS screening and intrapartum prophylaxis are not done routinely. Methods The serotype distribution and antibiotic resistance of GBS in infants in Korea with invasive bacterial infections were examined for the 19-year period 1995–2013. Isolates obtained previously from hospitals located in three different regions were analyzed for capsular serotype by PCR and sequencing and for antimicrobial susceptibility. Results Among 56 isolates serotyped, the most common serotypes were III (44.6%) and V (28.6%), followed by Ia (14.3%), Ib (10.7%), and VI (1.8%). No penicillin-resistant strains were detected, however 51.8% of the strains had resistance to erythromycin and 55.4% showed clindamycin resistance. Resistance was highest (93.8%) to both erythromycin and clindamycin for serotype V; all 15 isolates resistant to erythromycin were cMLS B phenotype and had a high level of resistance to both erythromycin and clindamycin with MIC levels >256μg/ml, and all but one were positive for erm B. Conclusion In this study in Korea, serotype V was identified in a relatively large proportion of GBS isolates and this serotype showed a high level of resistance to erythromycin and clindamycin in a statistically significant majority. Continuous monitoring of changes in clinical disease and molecular characteristics is important for the treatment and prevention of invasive GBS disease in infants.

We analyzed 155 clinical group A Streptococcus (GAS) isolates from children at the Seoul National University Children's Hospital between 1991 and 2012 and the Seoul National University Bundang Hospital between 2006 and 2012. The erythromycin resistance rate was 10.3% (16/155), and all isolates during the recent 3 years were susceptible to erythromycin. Among isolates, emm1 (19.4%), emm12 (18.7%), and emm4 (18.1%) were the most prevalent emm types. According to clinical disease, emm1 was most common in invasive GAS infections (47.4%), and emm4, in scarlet fever (48.8%). From 2010 to 2012, an increase in invasive GAS infections and scarlet fever that correlated with an increase in emm1 and emm4 types was observed. The speC detection rate was higher in patients with scarlet fever than in those with other GAS infections (P=0.017). Recently, invasive GAS infections and scarlet fever were associated with an increase in emm1 and emm4, respectively.

Group B streptococcus (GBS) is one of the leading causes of invasive infections in infants. This study aimed to investigate the genotypic diversity of GBS causing invasive infections in infants and to observe the prevalence of the highly virulent clone in South Korea.Invasive strains of GBS were collected prospectively from infants admitted at 4 hospitals during 1995-2015. Serotype and multilocus sequence typing were determined. All isolates underwent polymerase chain reaction amplification to detect the presence of the hypervirulent GBS adhesin (hvgA) gene. Antibiotic susceptibility testing was done by E-test, and erythromycin resistance genes were detected using polymerase chain reaction amplification.Among 98 GBS isolates collected, 14 sequence types (STs) were found; ST1 (20.4%), ST17 (19.4%) and ST19 (18.4%) were the most prevalent. The dominant serotype capsule expressed by ST1 was serotype V, ST17 and ST19 were all serotype III and ST23 was serotype Ia. hvgA gene was detected in 19.4% (n = 19) of the isolates; all were ST17, serotype III. A significant temporal trend of serotype III isolates was observed; as ST17 increased (P = 0.001) in proportion, ST19 decreased (P = 0.009). Erythromycin resistance was found in 42.9% (42/98); dominant strains were ermB-positive ST1 serotype V (n = 18/20, 90%), ermB-positive ST17 serotype III (n = 10/19, 52.6%) and ermA-positive ST335 serotype III (n = 7/7, 100%).The predominant STs causing invasive infections in South Korea were ST1, ST19 and ST17. Among serotype III isolates, an increase in proportion of the hypervirulent ST17 strains was observed. Erythromycin resistance was significantly associated with ST1.

Background With the emergence of macrolide resistance, concerns about the efficacy of macrolides for the treatment of Mycoplasma pneumoniae (MP) pneumonia in children have been raised. This study aimed to determine the effect of macrolide resistance on the outcome of children who were hospitalized with MP pneumonia. Methods Between 2010 and 2015, we performed culture of MP from nasopharyngeal samples obtained from children who were hospitalized with pneumonia at five hospitals in Korea. Macrolide resistance was determined by the analysis of 23S rRNA gene transition and the minimal inhibitory concentrations of four macrolides. Medical records were reviewed to analyze the clinical response to treatment with macrolides. Results MP was detected in 116 (4.8%) of the 2436 children with pneumonia. MP pneumonia was prevalent in 2011 and 2015. Of the 116 patients with MP pneumonia, 82 (70.7%) were macrolide-resistant. There were no differences in the age distribution, total duration of fever, and chest x-ray patterns between the macrolide-susceptible and macrolide-resistant groups. After macrolide initiation, mean days to defervescence were longer in the macrolide-resistant group than in macrolide-susceptible group (5.7 days vs. 4.1 days, P = 0.021). However, logistic regression analysis revealed that the presence of extrapulmonary signs (P = 0.039), homogeneous lobar consolidation (P = 0.004), or parapneumonic effusion (P

Background This study was performed to determine the priority of vaccine introduction for five vaccine-preventable diseases (VPDs) caused by Haemophilus influenzae type b (Hib), pneumococcus (Spn), hepatitis A virus (HepA), rotavirus (RV), and human papillomavirus (HPV) to the future Korean National Immunization Program (NIP) and to suggest framework programs to assist decision makers on implementation of the NIP. Methods Following analysis of the disease burden and economics of the five VPDs by the core team and Korean Advisory Committee on Immunization Practices sub-committee members, a Delphi survey was administered to 94 Korean experts using structured questionnaires that provided the reference data. The two evaluation frameworks for NIP prioritization were (1) a disease-related framework and (2) a vaccine-related framework. After analyzing the responses, a meeting of experts was held to build a consensus for determining how to prioritize NIP implementation. Results The average scores for relative importance were 63.29 for the disease-related framework and 36.71 for the vaccine-related framework. Within the disease-related framework, the mortality and case fatality rate was the highest scored factor (8.97), whereas within the vaccine-related framework, efficacy of the vaccine was considered the most important factor (9.56). On average, Spn, Hib, and HepA had the highest priority scores. Conclusion The Korean experts suggested that the main factors influencing the decision to adopt new vaccines in the Korean NIP should be disease mortality, case fatality, and the efficacy and effectiveness of the vaccine. Among the five selected VPDs, Spn, Hib, and HepA were considered to be of higher priority than RV and HPV.

Background This study investigated the genetic structure of Streptococcus pneumoniae isolates from invasive pneumococcal disease (IPD) in Korean children after national immunization program (NIP) of extended-valency pneumococcal conjugate vaccines (PCVs) in Korea from 2014 to 2017. Methods Invasive isolates were collected from 23 hospitals throughout Korea. IPD cases were identified by isolating pneumococci from normally sterile sites. Each isolate was analyzed using standard microbiological techniques, Quellung reaction, multilocus sequence typing, and antimicrobial susceptibility testing. eBURST v3 software was used to estimate the relationships among the isolates and to assign the strains to a clonal complex (CC). Results Ninety-two pneumococcal isolates were analyzed. The source of isolates were blood (77), cerebrospinal fluid (7), pleural fluid (2), joint fluid (2), deep tissue abscess (2), and peritoneal fluid (2). A total of 38 STs and 17 singletons were assigned. Ten clonal complexes were identified: CC320, CC81, CC166, CC439, CC558, CC880, CC3280, CC9395, CC180, and CC310. New STs were assigned: ST13552, ST13553, ST13554, and ST13602. The serotypes were mostly non-vaccine type (NVTs) (82.6%). The most prevalent STs were ST11189 (17.4%, n = 16, all serotype 10A), ST6945 (10.9%, n = 10, all serotype 12F), ST166 (9.8%, n = 9, serotype 11A [22.2%, n = 2], 13 [22.2%, n = 2], 15B/C [22.2%, n = 2], and 23A [33.3%, n = 3]), and ST320 (6.5%, n = 6, all serotype 19A). Major CCs identified were CC166 (11.9%), CC320 (10.9%), and CC81 (10.9%). Serotypes constituting CC81 and CC166 were all NVTs except 6A (n = 1) and 23F (n = 1) in CC81. CC320 consisted of 19A (n = 9) and 19F (n = 1). The relative proportion of NVTs was 61.3% in major CCs. All major three CCs showed multi-drug resistance. Nonsusceptibility to penicillin (80%) and cefotaxime (100%) was the highest in CC320 (serotype 19A [n = 9, 90.0%] and 19F [n = 1, 10.0%]). Conclusion The introduction of extended-valency PCVs has resulted in the change of genetic structure of isolates from IPD of Korean children. In particular, two common CCs (CC81 and CC166), which previously contained vaccine types, were replaced with the NVTs, while CC320 remains unchanged. Disclosures All authors: No reported disclosures.

BackgroundRadiologic evaluation of children with Mycoplasma pneumoniae is important for diagnosis and management.ObjectiveTo investigate the correlation between chest radiographic findings and the clinical features in children with Mycoplasma pneumoniae pneumonia.Materials and methodsThis study included 393 hospitalized children diagnosed with M. pneumoniae pneumonia between January 2000 and August 2016. Their clinical features and chest radiographs were reviewed. Radiographic findings were categorized and grouped as consolidation group (lobar or segmental consolidation) and non-consolidation group (patchy infiltration, localized reticulonodular infiltration, or parahilar peribronchial infiltration).ResultsLobar or segmental consolidation (37%) was the most common finding, followed by parahilar or peribronchial infiltration (27%), localized reticulonodular infiltration (21%) and patchy infiltration (15%). The consolidation group was more frequently accompanied by pleural effusions (63%), compared to the non-consolidation group (16%). Compared with patients in the non-consolidation group, those in the consolidation group were associated with a significantly higher rate of hypoxia, tachypnea, tachycardia, extrapulmonary manifestations, prolonged fever, and longer periods of anti-mycoplasma therapy and hospitalization. Lobar or segmental consolidation was significantly more frequent in children ≥5 years old (44%) compared with children 2-5 years old (34%) and ConclusionThe chest radiographic findings of children with M. pneumoniae pneumonia correlate well with the clinical features. Consolidative lesions were frequently observed in older children and were associated with more severe clinical features.

In Korea, Mycoplasma pneumoniae was detected in 255/2,089 respiratory specimens collected during 2000–2011; 80 isolates carried 23S rRNA gene mutations, and 69/123 culture-positive samples with the mutation were resistant to 5 macrolides. During 2000–2011, prevalence of the mutation increased substantially. These findings have critical implications for the treatment of children with mycoplasma pneumonia.

Summary Objectives Increasing antimicrobial resistance is related to the selective pressure exerted by antibiotic usage. This study evaluated the impact of the increased use of piperacillin/tazobactam (TZP) on the selection of antibiotic resistance. Methods From 1999 to 2010, Escherichia coli and Klebsiella pneumoniae invasive isolates obtained from hospitalized Korean children were analyzed in antibiotic susceptibility tests and subjected to characterization of the β-lactamase types. Antibiotic consumption data were also analyzed. Results Between January 1999 and December 2010, 409 invasive isolates of E. coli ( n =170) and K. pneumoniae ( n =239) were obtained. A rebound of extended-spectrum β-lactamase (ESBL) prevalence with an increase in total antibiotics was noted. Non-susceptibility to TZP was determined in 7.6% of E. coli isolates and 20.9% of K. pneumoniae isolates. Despite the increase in TZP usage, the overall prevalence of TZP resistance did not significantly increase over time, especially in E. coli. The mechanisms for TZP resistance included the presence of AmpC producers, possible TEM-1 hyperproducers, and multiple β-lactamases in individual organisms of a given isolate. Conclusions Replacement of only the antibiotic class appears to be insufficient to control antibiotic resistance, and continued efforts to decrease overall antibiotic pressure are needed, especially in highly endemic situations.

The wide use of antimicrobial agents and 7-valent pneumococcal conjugate vaccine (PCV7) has led to major changes in the epidemiology of childhood pneumococcal diseases. In Korea, data on the population-based incidence of childhood invasive pneumococcal diseases (IPD) are not available; however, institution-based surveillance data suggest a substantial burden of childhood IPD. Following the introduction of the PCV7 in Korea in 2003, the proportion of IPD caused by vaccine-type pneumococci has decreased, while non-PCV7 serotypes, especially serotypes 19A and 6A, whose proportions had been increasing before the introduction of the vaccine, became predominant among childhood IPD isolates. This article reviews the overall impact of PCV7 utilization and summarizes the results obtained so far. Continuous monitoring and gathering of scientific evidence for the epidemiological transition of pneumococcal carriage and IPD will be important for the management of pneumococcal infections in Korea.

The major aims of this study were to estimate the infection rate and recognize the risk factor for ventriculoperitoneal (VP) shunt infections in children. To analyze shunt infection rate and identify risk factors, a retrospective cohort analysis of 333 consecutive VP shunt series was performed at Seoul National University Children's Hospital in Korea between January 2005 and February 2011. Overall, 35 shunts (10.5%) were infected, which represented an infection rate of 0.075 infection cases per shunt per year. VP shunt infection occurred at a median of 1 month (range, 6 days to 8 months) after insertion. An independent risk factor for shunt infection was undergoing an operation before the first year of life (relative risk 2.31; 95% confidence interval, 1.19-4.48). The most common causative microorganism was coagulase-negative staphylococci in 16 (45.7%) followed by Staphylococcus aureus in 8 (22.9%). Methicillin resistance rate was 83.3% among coagulase-negative staphylococci and S. aureus. In this study, cerebrospinal fluid shunt infection rate was 10.5%. Infection was frequently caused by methicillin-resistant coagulase-negative staphylococci and S. aureus within two months after shunt surgery. Vancomycin may be considered as the preoperative prophylaxis for shunt surgery in a situation where methicillin resistance rate is very high.

This study was performed to differentiate vaccine-type strains from wild-type strains and determine the genotype of varicella-zoster virus (VZV) in 51 Korean children. A sequencing analysis of ORF 62 identified two cases of herpes zoster caused by the vaccine-type virus, without a previous history of varicella, 22 months and 5 months after VZV vaccination. The wild-type strain was identified in the remaining children. A genotype analysis of ORF 22 amino acids revealed genotype J in all children except one. Genotype E was identified in an infant with varicella imported from Egypt.

This study was performed to assess the serotype distribution and antibiotic nonsusceptibility of pneumococcal carriage isolates from children in Korea following the introduction of extended-valency pneumococcal conjugate vaccines (PCVs).From April to June 2014, nasopharyngeal swabs were collected from children who were attending daycare centers in Korea. The collection was conducted in accordance with the World Health Organization Pneumococcal Carriage Working Group standards. Isolates were identified based on colony morphology, the presence of alpha-hemolysis, and inhibition by optochin test. Serotype was determined by Quellung reaction and sequencing analysis (for serogroup 6). The E-test was performed to determine antibiotic susceptibility.A total of 267 pneumococcal isolates were collected from 734 children. Non-PCV13 serotypes accounted for 88.3% and 23A (12.6%), 15B (10.4%), and 15C (9.5%) were most common. Younger age was associated with higher carriage (65.6% vs. 31.2%, P0.001), while completion of PCV vaccination was associated with lower carriage caused by PCV13 serotypes (7.4% vs. 20.8%, P=0.007). Overall, nonsusceptibility rates were 86.0% to penicillin and 90.5% to erythromycin, with a multidrug resistance rate of 81.5%. Among penicillin-nonsusceptible isolates, those caused by PCV13 serotypes were 11% and non-PCV13 serotypes were 89%. Frequent non-PCV13 serotypes (23A, 15B, and 15C) were all nonsusceptible to both penicillin and erythromycin except one.High rates of carriage caused by non-PCV13 serotypes such as 23A, 15B, and 15C that show nonsusceptibilities to penicillin and erythromycin were noted following the introduction of extended-valency PCVs in Korea.

ObjectivesThis study aims to describe the clinical characteristics of enteroviral meningitis in association with the absence of cerebrospinal fluid (CSF) pleocytosis.DesignThis was a retrospective analysis of databases of patients diagnosed with enteroviral meningitis by CSF reverse transcription-PCR testing. Presence of CSF non-pleocytosis at each age group was analysed by use of the two criteria. Clinical variables were compared with regard to the presence of CSF pleocytosis. Multiple logistic regression analysis was used to identify factors that were associated with CSF pleocytosis.SettingTwo hospitals in South Korea, between January 2008 and August 2011.Patients390 infants and children with enteroviral meningitis.InterventionsNone.Main outcome measuresProportion of enteroviral meningitis without CSF pleocytosis.ResultsAmong the 390 patients with enteroviral meningitis, 16–18% did not have CSF pleocytosis. In particular, CSF pleocytosis was not present in 68–77% of the neonates with enteroviral meningitis, demonstrating that the proportion of CSF pleocytosis decreased significantly with age (pConclusionsThis study demonstrated high proportion of non-pleocytic enteroviral meningitis in young infants and identified several clinical factors that contributed to the absence of CSF pleocytosis. We suggest that CSF enterovirus PCR testing is likely to detect more cases of enteroviral meningitis, especially in young infants.

Summary Objectives This study was performed to investigate the molecular characterization of methicillin-resistant Staphylococcus aureus (MRSA) isolated from the anterior nares of Korean children attending daycare centers. Methods During September and October 2008, a survey of nasal carriage of MRSA was conducted among healthy children who were attending daycare centers in Seoul, Korea. Nasal swab samples were cultured to isolate S. aureus , and antimicrobial susceptibility was assessed using a disk diffusion test. All MRSA isolates were archived for subsequent molecular tests, including multilocus sequence typing, Panton–Valentine leukocidin (PVL) genes polymerase chain reaction (PCR), and staphylococcal cassette chromosome mec (SCC mec ) typing. Results Among 428 preschool-aged children enrolled, 9.3% (40/428) were colonized with MRSA. Among the 40 MRSA isolates, antibiotic susceptibilities to clindamycin and erythromycin were 97.5% (39/40) and 45% (18/40), respectively. All of the 21 strains susceptible to clindamycin and resistant to erythromycin had MLS B -inducible phenotypes. Sequence type (ST) 72–SCC mec type IV was the predominant clone ( n =23; 57.5%), followed by ST72–SCC mec type II ( n =6; 15%), ST1765–SCC mec type IV ( n =4; 10%), ST1765–SCC mec type II ( n =2; 5%), and ST1–SCC mec type IV ( n =2; 5%). No clone was positive for PVL genes. Conclusions ST72 strains, which were previously found in hospital-associated MRSA, are now widely distributed in healthy Korean children. In addition, the prevalence of inducible resistance of clindamycin should be considered when selecting empirical antibiotics for community-associated MRSA infections in Korea.

Streptococcus pneumoniae remains a leading cause of invasive infections including bacteremia and meningitis, as well as mucosal infections such as otitis media and pneumonia among children and adults. The 7-valent pneumococcal conjugate vaccine (PCV7) was licensed for use among infants and young children in many countries including Korea. The routine use of PCV7 has resulted in a decreased incidence of invasive pneumococcal disease (IPD) by the vaccine serotypes among the vaccinees and substantial declines in IPD among unvaccinated populations such as older children and adults as well. In addition, there are increasing evidences to suggest that routine immunization with PCV7 is changing the epidemiology of pneumococcal diseases such as serotype distribution of IPD, nasopharyngeal colonization, and antibiotic resistance patterns. In contrast, there is an increase in the number of IPDs caused by nonvaccine serotypes, though it is much smaller than overall declines of vaccine serotype diseases. Several vaccines containing additional serotypes have been developed and tested clinically in order to expand the range of serotypes of Streptococcus pneumoniae. Recently two new pneumococcal protein conjugate vaccines, 10-valent pneumococcal conjugate vaccine (PCV10) and 13-valent pneumococcal conjugate vaccine (PCV13), have been approved for use in several countries including Korea. This report summarizes the recommendations approved by the Committee on Infectious Diseases, the Korean Pediatric Society.

This study was conducted to determine the immunogenicity and safety of an inactivated split-virus influenza A/H1N1 vaccine in healthy Korean children from 6 months to

A single, multidrug-resistant strain was responsible for increased incidence of this serotype before introduction of the pneumococcal 7-valent conjugate vaccine., Despite the concern of replacement disease, notably by serotype 19A after 7-valent conjugate vaccine (PCV7) use, serotype 19A was increasingly recognized in Korean children before the introduction of PCV7. To understand the dynamics of serogroup 19 prevalence from 1991–2006, we serotyped 538 pediatric pneumococcal isolates. Serogroup 19 isolates (n = 126) were characterized by antimicrobial drug susceptibility, presence of mefA/ermB, and multilocus sequence typing. Overall, the proportion of serotype 19A isolates increased but serotype 19F decreased. Among children

This study was conducted to determine the immunogenicity and safety of a 7-valent CRM197 protein conjugated pneumococcal vaccine (PCV7) in Korean infants immunized at 2, 4 and 6 months. A total of 202 infants were enrolled and 146 and 141 infants were, respectively, included in post-2nd dose and post-3rd dose immunogenicity evaluations conducted on a per protocol basis. After two and three PCV7 vaccinations, 63.0–98.0 and 97.2–100% of infants achieved an antibody level of ≥0.35 μg/mL, respectively, with a lowest against serotype 6B. No vaccination-related serious adverse reactions were observed. Thus, PCV7 appears safe and highly immunogenic in Korean infants, and adopting two doses for a primary series could be a feasible option for facilitating vaccine coverage rate.

Amino acid sequences 200-225 and 255-278 of the F protein of human respiratory syncytial virus (HRSV) are T cell epitopes (Bourgeois et al., 1991; Corvaisier et al, 1993). Peptides corresponding to these two regions were synthesized and coupled with keyhole limpet haemocyanin (KLH). The two conjugated proteins were administered intranasally to BALB/c mice alone or together with cholera toxin B (CTB). ELISAs revealed that the mixture of the conjugates with CTB increased not only the systemic response but also the mucosal immune response of the saliva. The systemic response was lower and the mucosal immune response was undetectable in mice immunized with the conjugates on their own. These results suggest that these two peptide sequences are effective epitopes for inducing systemic and mucosal immune responses in conjunction with CTB, and may provide the basis for a nasal peptide vaccine against RSV for human use.

Pneumolysin (Ply) and pneumococcal histidine triad protein D (PhtD) are candidate proteins for a next-generation pneumococcal vaccine. We aimed to analyze the genetic diversity and antigenic heterogeneity of Ply and PhtD for 173 pneumococci isolated from invasive diseases in Korean children. Allele was designated based on the variation of amino acid sequence. Antigenicity was predicted by the amino acid hydrophobicity of the region. There were seven and 39 allele types for the ply and phtD genes, respectively. The nucleotide sequence identity was 97.2%-99.9% for ply and 91.4%-98.0% for phtD gene. Only minor variations in hydrophobicity were noted among the antigenicity plots of Ply and PhtD. Overall, the allele types of the ply and phtD genes were remarkably homogeneous, and the antigenic diversity of the corresponding proteins was very limited. The Ply and PhtD could be useful antigens for universal pneumococcal vaccines.

The shortage of donor organs occasionally mandates the use of hepatic allografts from anti-HBc (+) donors. HBIG and/or lamivudine are recommended for the prevention of de novo HBV infection in naive patients, but there are attendant problems, such as mutant strain emergence and high cost. Active immunization presents a better alternative than the use of HBIG or lamivudine, if it can be proven to be effective. Accordingly, we investigated the outcome of HBV vaccination in pediatric hepatic transplant recipients. Between July 1999 and October 2001, 19 pediatric recipients were administered HBV vaccinations after liver transplantation at Seoul National University Hospital. Nine patients received a graft from anti-HBc (+) donors and 10 from anti-HBc (-) donors. When steroid was withdrawn, recombinant HBV vaccine was administered. The median follow-up period after vaccination was 10.0 +/- 5.2 months. Seventeen of the 19 patients showed a positive response to vaccination. In 9 patients who received grafts from anti-HBc (+) donors, 2 patients showed no response, 4 patients low response (peak HBsAb titer1,000 IU/L), and 3 patients high response (peak HBsAb titer/=1,000 IU/L). De novo HBV infection developed in 1 of 2 patients who showed no response to vaccination. In 10 patients who received grafts from anti-HBc (-) donors, 5 showed a low response and 5 a high response. In conclusion, HBV vaccination in pediatric patients after liver transplantation appeared to exhibit some effectiveness at protecting young children that received a graft from anti-HBc (+) donors from de novo HBV infection.

Background The aim of this study is to investigate the serotype distribution and antimicrobial resistance of nasopharyngeal isolates of Streptococcus pneumoniae from children after the introduction of the extended-valency pneumococcal conjugate vaccines (PCVs) in Korea. Methods From July 2010 to June 2015, 3,820 nasopharyngeal aspirates obtained from infants and children who presented with respiratory symptoms at the Seoul National University Children’s Hospital were plated on trypticase soy agar containing 5% sheep blood for isolation of pneumococci. Serotype was determined by Quellung reaction and antimicrobial susceptibility was tested by E-test. Trend analysis was performed for serotype distribution and antimicrobial non-susceptibility rates. Results S. pneumoniae was isolated from 397 (10.4%) specimens. The most common serotypes were 19A (14.0%), 23A (12.8%), 15B/C (10.7%), 11A (10.1%), 6C (7.8%), and 6A (6.3%) among the typeable pneumococci (n = 335). The PCV serotype proportions significantly decreased (59.1% in 2010/11 to 17.0% in 2014/15, P < 0.001), whereas the non-PCV serotype proportions significantly increased (40.9% in 2010/11 to 83.0% in 2014/15, P < 0.001). The non-susceptibility rates for penicillin (oral), penicillin (parenteral, non-meningitis), cefotaxime, and erythromycin were 97.8%, 22.8%, 27.7%, and 95.5%, respectively. The proportions of PCV serotypes responsible for non-susceptibility to penicillin (parenteral, non-meningitis) and multidrug resistance significantly decreased (80.8% to 21.1%, P < 0.001, 64.3% to 12.3%, P < 0.001, respectively), whereas the non-PCV serotype proportions significantly increased (19.2% to 78.9%, P < 0.001, 35.7% to 87.7%, P < 0.001, respectively). Serotypes 23A and 15B/C demonstrated significant proportional increase among the antibiotics resistant strains. Conclusion The PCV serotype proportions decreased and the non-PCV serotype proportions increased among nasopharyngeal carriage pneumococci after the introduction of extended-valency PCVs in Korea. Antimicrobial non-susceptibility rates for penicillin and erythromycin remain high despite the decrease in the proportion of PCV serotypes responsible for antimicrobial resistance over time. Disclosures All authors: No reported disclosures.

This study investigated the serotype distribution and antimicrobial resistance of 3,820 nasopharyngeal Streptococcus pneumoniae isolates from infants and children who presented with respiratory symptoms at Seoul National University Children's Hospital from July 2010 to June 2015 after the introduction of the extended-valency pneumococcal conjugate vaccines (PCVs). Serotypes and antimicrobial susceptibility were determined using the Quellung reaction and E-test, respectively. S. pneumoniae was isolated from 397 (10.4%) specimens. The most common serotypes were 19A (14.0%), 23A (12.8%), 15B/C (10.7%), 11A (10.1%), 6C (7.8%), and 6A (6.3%) among the typeable pneumococci (n = 335). The PCV serotype proportions significantly decreased (59.1% in 2010/11 to 17.0% in 2014/15, P < 0.001), whereas the non-PCV serotype proportions significantly increased (40.9% in 2010/11 to 83.0% in 2014/15, P < 0.001). The non-susceptibility rates for penicillin (oral), penicillin (parenteral, non-meningitis), cefotaxime, and erythromycin were 97.8%, 22.8%, 27.7%, and 95.5%, respectively. The proportions of PCV serotypes responsible for non-susceptibility to penicillin (parenteral, non-meningitis) and multidrug resistance significantly decreased (80.8% to 21.1%, P < 0.001 and 64.3% to 12.3%, P < 0.001, respectively), whereas the non-PCV serotype proportions significantly increased (19.2% to 78.9%, P < 0.001 and 35.7% to 87.7%, P < 0.001, respectively). Serotypes 23A and 15B/C demonstrated significant proportional increase among the antibiotics resistant strains. Thus, the PCV serotype proportions decreased and the non-PCV serotype proportions increased among nasopharyngeal carriage pneumococci after the introduction of extended-valency PCVs in Korea. Antimicrobial non-susceptibility rates for penicillin and erythromycin remain high despite the decrease in the proportion of PCV serotypes responsible for antimicrobial resistance over time., Graphical Abstract

Herpes simplex virus (HSV) type I causes a fulminant necrotising meningoencephalitis distinguished from other encephalitides by its focal and often haemorrhagic nature. Specific antiviral therapy with acyclovir can significantly improve the prognosis. We present MRI findings of two cases of herpes simplex encephalitis (HSE) confirmed by PCR analysis, focusing on the serial changes after acyclovir therapy: gyral swelling, high signal intensity on T2-weighted images in the subfrontal region, temporal lobe and insula in the initial stage, then regional extension with enhancement and haemorrhage despite appropriate acyclovir therapy, and finally encephalomalacia and brain atrophy.

To determine prevalence and genetic structures of new serotype 6D strains of pneumococci, we examined isolates from diverse clinical specimens in South Korea during 1991–2008. Fourteen serotype 6D strains accounted for 10.4% of serogroup 6 pneumococci from blood, sputum, nasopharynx, and throat samples. Serotype 6D strains consisted of 3 sequence types.

One hundred six cases of invasive pneumococcal infections diagnosed from 1985 to 1996 were analyzed retrospectively. The types of infection were bacteremia without focus (45%), meningitis (19%), peritonitis (17%), pneumonia (bacteremic) (16%), and others (3%). Penicillin-nonsusceptible Streptococcus pneumoniae was first detected in 1989, and its incidence increased rapidly thereafter, reaching 89% in 1995. Initial empirical regimens were of parenteral beta-lactam antimicrobials with or without an aminoglycoside, but these were modified subsequently. Among the 72 nonmeningeal infections analyzed, a favorable response at 72 hours and death were observed in 83% and 2.5%, respectively, of 40 penicillin-susceptible infections, as compared with 86% (P = 1.0) and 7.1% (P = .45) of 14 infections due to intermediate strains and 61% (P = .07) and 11% (P = .22) of 18 due to resistant strains. The favorable-response rate and mortality among 49 patients not in initially critical condition were 92% and zero, respectively, as compared with 52% (P = .00027) and 17% (P = .008) of 23 in critical condition. The data suggest that clinical outcome of penicillin-nonsusceptible pneumococcal infection outside the CNS may be more closely related to clinical condition at presentation than to the level of resistance of the causative strain when such infection is treated with parenteral beta-lactams.

This study examined the serotype distribution and antimicrobial resistance of pneumococcal isolates from invasive infections in children between 2006 and 2010, when the 7-valent pneumococcal conjugate vaccine (PCV7) was offered as an optional vaccine in Korea. Among 140 isolates collected from 8 centers, the common serotypes were 19A (22.9%), 19 F (12.1%), and 6B (8.6%). Between 2006 and 2010, PCV7 serotypes decreased from 62.5% to 21.4% ( P = 0.002), whereas three 13-valent pneumococcal conjugate vaccine (PCV13)–specific serotypes (3, 6A, and 19A) increased from 18.8% to 42.9% ( P = 0.016). Among 102 multidrug-resistant isolates, the proportion of PCV7 serotypes decreased from 65.2% to 21.7% ( P = 0.001), and 3 PCV13-specific serotypes increased from 17.4% to 47.8% ( P = 0.008). Optional PCV7 vaccination has influenced the proportion of PCV7 serotypes in Korea, resulting in a decrease, whereas the proportions of 3 PCV13-specific serotypes, particularly 19A, have increased.

A total of 279 isolates of Escherichia coli (n = 128) and Klebsiella pneumoniae (n = 151) were obtained from blood samples from children at the Seoul National University Children's Hospital, Seoul, Korea from 1999 to 2007. Five plasmid-mediated quinolone resistance (PMQR) genes, qnrA, qnrB, qnrS, qepA, and aac(6')-Ib-cr, and the minimal inhibitory concentration (MIC) values for ciprofloxacin were tested for all the strains. Mutations in both gyrA and parC were analyzed in 57 representative strains. Twenty-seven strains (9.7%) had at least 1 of the 5 PMQR genes: qnrB in 20 isolates, qnrS in 1, aac(6')-Ib-cr in 5, and both qnrB and aac(6')-Ib-cr in 1 isolate. The overall PMQR prevalence rates tended to increase over time (P = 0.001). The non-susceptibility rate to ciprofloxacin was 11.0% (31/279). PMQR-harboring isolates tended to have increased ciprofloxacin MIC values among both quinolone resistance-determining region (QRDR) mutation-present (P = 0.016) and QRDR mutation-absent isolates (P < 0.001). The increasing prevalence of PMQR genes was associated with increase in quinolone use over time (P < 0.001) and increasing frequency of non-susceptibility to ciprofloxacin (P < 0.001).

This study was performed to measure early changes in the serotype distribution of pneumococci isolated from children with invasive disease during the 3-year period following the introduction of 10- and 13-valent pneumococcal conjugate vaccines (PCVs) in Korea. From January 2011 to December 2013 at 25 hospitals located throughout Korea, pneumococci were isolated among children who had invasive pneumococcal disease (IPD). Serotypes were determined using the Quellung reaction, and the change in serotype distribution was analyzed. Seventy-five cases of IPD were included. Eighty percent of patients were aged 3-59 months, and 32% had a comorbidity that increased the risk of pneumococcal infection. The most common serotypes were 19A (32.0%), 10A (8.0%), and 15C (6.7%). The PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F, and 6A) accounted for 14.7% of the total isolates and the PCV13 minus PCV7 types (1, 3, 5, 7F and 19A) accounted for 32.0% of the total isolates. Serotype 19A was the only serotype in the PCV13 minus PCV7 group. The proportion of serotype 19A showed decreasing tendency from 37.5% in 2011 to 22.2% in 2013 (P = 0.309), while the proportion of non-PCV13 types showed increasing tendency from 45.8% in 2011 to 72.2% in 2013 (P = 0.108). Shortly after the introduction of extended-valent PCVs in Korea, serotype 19A continued to be the most common serotype causing IPD in children. Subsequently, the proportion of 19A decreased, and non-vaccine serotypes emerged as an important cause of IPD. The impact of extended-valent vaccines must be continuously monitored., Graphical Abstract

Widespread emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has changed the epidemiology of S. aureus infections. We examined the molecular types and antibiotic susceptibility of CA-MRSA and health care–associated MRSA (HA-MRSA) among Korean children. MRSA isolates were obtained from patients admitted to university-affiliated tertiary hospitals in Korea, between 2006 and 2010. Molecular studies including multilocus sequence typing, SCC mec typing, and polymerase chain reaction amplification of PVL genes and antibiotic susceptibility tests were performed. SCC mec type IV was most frequently found for both CA-MRSA (80.0%) and HA-MRSA (56.4%). ST72-MRSA-SCC mec type IV and its single-locus variants were the most prevalent MRSA clones in the Korean pediatric population, both in community and in health care settings. The PVL genes were detected in 10% (4/40) of CA-MRSA isolates. Most of the clinical MRSA isolates showed vancomycin MIC ≥1.0 μg/mL. In conclusion, the molecular characteristics of HA-MRSA have been changing and CA-MRSA genotype overtook HA-MRSA genotype in health care settings.

Background The World Health Organization (WHO) recommends that all countries adopt Haemophilus influenzae type b (Hib) vaccine into routine child immunization programs to protect children from the significant burden of life-threatening pneumonia and meningitis. Methods In this blind, comparative, randomized, phase-III Korean multicenter study, we assessed immunogenicity and safety following primary vaccination of a new H. influenzae type b tetanus toxoid conjugate vaccine, LBVH0101 (LG Life Sciences, Ltd., Seoul, Korea) compared with Hiberix™ (GSK, Rixensart, Belgium) in Korean children at 2, 4 and 6 months of age followed by a booster vaccination at 12–15 months. Serum anti-PRP IgG concentration and bactericidal activity were determined. Local/systemic symptoms were assessed after vaccination. Serious adverse events were recorded throughout the study. Results A total of 185 infants were included in immunogenicity evaluations. After the second and third doses of LBVH0101, 90.32% and 100% of infants achieved an antibody level ≥1 μg/mL, respectively, compared with 78.26% and 96.74% of those who received Hiberix™. After the second vaccination, the geometric mean concentration (GMC) of LBVH0101 recipients was 7.34 μg/mL and was higher than that of Hiberix™ recipients (3.55 μg/mL). After the third vaccination, the GMCs were 14.59 μg/mL and 12.15 μg/mL in the LBVH0101 and Hiberix™ recipients, respectively. The booster dose produced higher antibody concentrations: 30.25 μg/mL and 71.64 μg/mL for LBVH0101 and Hiberix™ recipients, respectively. Bactericidal capacity and antibody potency of anti-PRP IgG induced by LBVH0101 was 35.05 and 116.27 after the second and third vaccinations, respectively, compared with 53.76 and 79.64 for Hiberix™. Anti-PRP IgG seroprotection rate and GMC were similar post-primary immunization between the groups; both showed functional maturation and similar booster responses. LBVH0101 had comparable safety results as the control vaccine, Hiberix™, as most of the solicited adverse events and unsolicited adverse events upon LBVH0101 administration were mild in severity. No serious vaccination-related adverse reactions were observed. Conclusions LBVH0101 showed a good immunogenicity and safety profile in infants and children. The two-dose infant-priming schedule with a booster dose may suffice for Hib immunization in Korean infants (Clinical trial registration numbers: NCT01019772 and NCT01251133 ).

Blood culture isolates of Escherichia coli and Klebsiella pneumoniae were collected from Seoul National University Children's Hospital between 1994 and 1999. Among 16 isolates of extended-spectrum β-lactamase (ESBL)-producing E. coli and 36 isolates of ESBL-producing K. pneumoniae, 12 and 18 isolates, respectively, produced TEM-derived enzymes. Ten E. coli and 15 K. pneumoniae isolates produced TEM-52 β-lactamase, two K. pneumoniae strains produced TEM-15 β-lactamase, and two E. coli isolates and one K. pneumoniae isolate produced a novel TEM-related ESBL (unpublished data). In this study, we characterized the novel TEM-type ESBL TEM-88 and compared its biochemical characteristics to those of the TEM-15 and TEM-52 β-lactamases. K. pneumoniae strain K28 was isolated from the blood of a patient in a pediatric oncology unit in 1998. Analytical isoelectric focusing (7) demonstrated that strain K28 produced β-lactamases with isoelectric point (pI) values of 5.6 and 7.6. The gene for ceftazidime resistance, along with that for a pI 5.6 enzyme and a plasmid of about 150 kb termed pMG272, was transferred by conjugation to E. coli J53Azir (9). For nucleotide sequencing, the blaTEM gene was amplified with pMG272 as the template and primers T1 (5′-ATA AAA TTC TTG AAG ACG AAA-3′) and T2 (5′-GAC AGT TAC CAA TGC TTA ATC A-3′) (6). The amplified PCR product was purified using a QIAEX gel extraction kit (Qiagen, Chatsworth, Calif.). Both strands were sequenced using published TEM primers (6) and a dideoxy termination cycle sequencing kit (Perkin-Elmer Cetus, Norwalk, Conn.). The deduced amino acid sequence of TEM-88 had four amino acid substitutions from TEM-1: Glu-104→Lys, Met-182→Thr, Gly-196→Asp, and Gly-238→Ser (numbered according to the proposal of Ambler et al. [1]) (Table ​(Table1).1). The amino acid replacement at position 196 has not been observed in other TEM-related ESBL genes (http://www.lahey.org/studies/webt.htm). TEM-88 differed from TEM-52 by 1 amino acid at position 196, and TEM-52 differed from TEM-15 by 1 amino acid at position 182 (11) (Table ​(Table1).1). TEM-15, TEM-52, and TEM-88 are the only TEM-type ESBLs identified in Korea to date. With these findings, we speculated that TEM-15 developed into TEM-52 and that TEM-52 evolved into TEM-88 (Table ​(Table1).1). In order to find out whether there was a functional advantage in such changes, we analyzed and compared the biochemical characteristics of TEM-15, TEM-52, and TEM-88. TABLE 1 Amino acid substitutions in TEM-type β-lactamases The blaTEM-88 gene was cloned from plasmid pMG272 with EcoRI as an 18-kb insert into the vector plasmid pBC SK (Stratagene, La Jolla, Calif.) to produce plasmid pMG273. Plasmid pMG273 was introduced by electroporation into E. coli XL1-Blue (Stratagene), which was used for the kinetic assays. To represent TEM-52 β-lactamase, a clinical isolate (9) and E. coli transconjugant J53 Azir(pMG276) were used. The blaTEM-15 gene was cloned by PCR into the pPCR-Script Cam vector (Stratagene) from K. pneumoniae strain 23 (unpublished), and the resulting plasmid, pMG275, was transformed by electroporation into E. coli XL1-Blue. The identity of blaTEM-15 was reconfirmed by sequencing. Antimicrobial susceptibility testing was performed using Etest strips (AB Biodisk, Dalvagen, Sweden). The MICs of amoxicillin, amoxicillin-clavulanic acid, cephalothin, cefotaxime, ceftazidime, and aztreonam were similar for transformant or transconjugant E. coli strains producing TEM-15, TEM-52, or TEM-88 (Table ​(Table2).2). TEM-52 and TEM-88, but not TEM-15, augmented resistance to moxalactam. TABLE 2 MICs of β-lactams for strains producing TEM-related extended-spectrum β-lactamases Kinetic assays for β-lactam hydrolysis were performed with E. coli XL1-Blue(pMG275), E. coli J53(pMG276), and E. coli XL1-Blue(pMG273). β-Lactamase extracts were prepared by three freeze-thaw cycles followed by Sephadex G-75 chromatography with 0.1 M phosphate buffer, pH 7.0 (Pharmacia Biotech Inc., Piscataway, N.J.) (3). Antimicrobials used for hydrolysis assays were benzylpenicillin, cephaloridine, cefotaxime, moxalactam (Sigma, St. Louis, Mo.), ceftazidime (Glaxo Group Research, Ltd., Greenford, England), and aztreonam (Bristol-Myers Squibb, Princeton, N.J.). Initial hydrolysis rates were determined spectrophotometrically at 37°C with 0.1 M phosphate buffer, pH 7.0. The computer program GraFit (Erithacus Software Ltd., Staines, United Kingdom) and linear regression using a Hanes plot (10) were used for calculating kinetic parameters. For benzlypenicillin, half-time analysis with a single-process curve was used (12). Although moxalactam is stable in the presence of most ESBLs, it was included as a substrate because TEM-52 is known to have a higher affinity for moxalactam than TEM-3 or TEM-1 (11). For moxalactam, a 50% inhibitory concentration (IC50) was determined using cephaloridine as the substrate at five times the Km for each enzyme, because hydrolysis rates were too small to determine. The relative values for maximum rate of hydrolysis (Vmax) and Km were determined as the means of two or three determinations. All 3 enzymes showed similar biochemical characteristics such as similar relative Vmax and Km values for cefotaxime, ceftazidime, cephaloridine, and benzylpenicillin; more effective hydrolysis of cefotaxime than ceftazidime; and very weak hydrolysis of aztreonam (Table ​(Table3).3). The IC50 of TEM-52 or TEM-88 for moxalactam was three- or fourfold lower than that of TEM-15 (Table ​(Table3),3), indicating that TEM-52 had a higher affinity for moxalactam than TEM-15 and that TEM-88 with a further Gly-196→Asp substitution retained this property. TABLE 3 Kinetic parameters of TEM-15, TEM-52, and TEM-88 β-lactamases In molecular modeling, TEM residue 196 is quite far from the binding site of the enzyme and positioned on the surface of an α-helix behind the B3 sheet (5). Mutagenesis studies have also indicated that residue 196 is tolerant of substitutions that have no effect on activity (4). The Gly-196→Asp change in TEM-88 compared to TEM-52 is thus functionally silent, similar to substitutions observed in TEM-57 and TEM-90 (2, 8). Evolution from TEM-15 to TEM-52 to TEM-88 in Korea does not seem to be based on improved ability to hydrolyze oxyimino-β-lactams. Nucleotide sequence accession number. The nucleotide sequence of the blaTEM-88 gene has been submitted to GenBank under accession no. {"type":"entrez-nucleotide","attrs":{"text":"AY027590","term_id":"13236847","term_text":"AY027590"}}AY027590.

CTX-M-14 β-lactamase was identified in a stool isolate of Shigella sonnei and in blood isolates of Escherichia coli (one isolate) and Klebsiella pneumoniae (two isolates) from different parts of Korea. The amino acid sequence differed by one amino acid from CTX-M-9 (Ala-231→ Val) and was identical to that of β-lactamases recently found in China and Japan.

Human coronavirus NL63 (HCoV-NL63) has recently been implicated as a common cause of croup in children. This study was performed to evaluate viruses associated with croup in children, with an emphasis on HCoV-NL63.Nasopharyngeal aspirates were prospectively collected from 182 children hospitalized with croup at Seoul National University Bundang Hospital from January 2005 to June 2009. Multiplex reverse-transcriptase polymerase chain reaction was conducted for detection of 11 respiratory viruses, and medical records were reviewed.Viruses were identified in 147 (80.8%) of the 182 croup patients. The 3 most commonly detected viruses were parainfluenza virus type 1 (PIV1) in 44 (24.2%) patients, HCoV-NL63 in 30 (16.5%) patients, and influenza A virus in 25 (13.7%) patients. Other detected viruses were rhinovirus in 22 (12.1%) patients, PIV type 3 and respiratory syncytial virus in 15 (8.2%) patients, human bocavirus in 8 (4.4%) patients, and several others in a few patients. Coinfections withor = 2 viruses were found in 20 (11%) patients. HCoV-NL63 was identified primarily in winter, which coincides with the peak occurrence of croup. Patients with HCoV-NL63 infection were younger than those who were positive for PIV1 (median age 13 months versus 21 months, P = 0.006) and had shorter fever duration than influenza A virus infection (median 1.5 days versus 4 days, P = 0.000).PIV1 and HCoV-NL63 were most commonly associated with patients who were hospitalized with croup. HCoV-NL63 is prevalent in winter and is associated with younger age and with shorter fever duration.

We investigated the genetic structure of Streptococcus pneumoniae isolated from Korean children prior to the use of heptavalent pneumococcal conjugate vaccine (PCV7). A total of 278 pneumococcal isolates were obtained from invasive (n = 77) and noninvasive (n = 201) specimens from children

Diagnosis of Mycoplasma pneumoniae pneumonia is challenging because of the lack of standardized rapid tests. Many serologic tests and polymerase chain reaction (PCR) based methods are used with different diagnostic criteria.This retrospective study was conducted to compare the diagnostic values of the indirect particle agglutination test and nested PCR of nasopharyngeal aspirates for the diagnosis of M. pneumoniae pneumonia in children. These assays were evaluated in 234 hospitalized children with community-acquired lower respiratory tract infections during 2 outbreaks of M. pneumoniae pneumonia in 2000 and 2003.The cumulative PCR positive rate was 26.7% in patients with maximum antibody titers ofor =1:320 and 78.2% in those with titers ofor =1:640. Based on these data, a positive PCR, a 4-fold increase in antibody titer, or a single titeror =1:640 were considered to indicate acute M. pneumoniae infection. Overall, 152 children were diagnosed to have M. pneumoniae pneumonia; 27 (18%) by serology only, 26 (17%) by PCR only, and 99 (65%) by both methods. Children who were diagnosed by PCR only were significantly younger (P = 0.003) and were more often immunocompromised (P = 0.019) than those that were PCR negative. Duration of cough before PCR diagnosis was shorter in cases diagnosed by PCR only than those that were PCR negative (P = 0.045).In conclusion, during the 2 outbreaks of M. pneumoniae infection, we found that the PCR test may be useful for the rapid diagnosis of M. pneumoniae pneumonia, particularly in young children and in immunocompromised patients and in early stage disease.

Mycoplasma pneumoniae (MP) is a major cause of community-acquired pneumonia in children. The aim of this study was to investigate the long-term epidemiology of MP pneumonia in Korean children.A retrospective analysis of a database of 2405 patients with pneumonia at the Seoul National University Children's Hospital between 1986 and 2004 was performed. Serologic diagnosis for MP infection was made based on a 4-fold rise or single titers/=1:640, which were measured by an indirect agglutination test.MP pneumonia was diagnosed in 568 patients over 18 years. The mean age was 5.7 years. Children younger than 5 years of age accounted for 44% of the cases. Six outbreaks were observed at intervals of 3-4 years. The earlier epidemics up until 1996 peaked in the summer, while the later epidemics peaked in the fall or early winter. Children5 years old were more commonly affected during large epidemics compared to endemic periods. The geometric mean antibody titers were maintained/=1:320 up to 7 months after the onset of illness.The results of this study revealed community outbreaks of MP pneumonia at 3-4-year intervals among Korean children. A significant proportion of young Korean children were affected by MP pneumonia, especially during large epidemics.

Liver recipients who have antibodies to hepatitis B core antigen (anti-HBc) or received an anti-HBc positive liver graft are at risk of acquiring de novo hepatitis B infection so a life long prophylaxis is required. A post-transplant vaccination against hepatitis B virus (HBV) can offer a better alternative than either hepatitis B hyperimmune globulin (HBIG) or lamivudine. This study investigated the course of anti-HBs titer after vaccination and analyzed the factors that influence the response. Between October 1999 and February 2003, 37 pediatric patients were given a post-transplant vaccination when an anti-HBc positive graft was used, the recipient was anti-HBc positive, or when anti-HBs titer was below 20 IU/L irrespective of the serological status. Thirty-three patients responded to the vaccine and did not require further HBIG injections at a mean follow up of 33.6 months. Fifteen patients were good responder and only needed a single set of vaccines, and 18 were poor responder needing additional boosters. Two patients developed de novo hepatitis B infection and two required additional HBIG injections. Preoperative severity of liver disease, serological status of HBV of recipient or donor, use of HBIG or pulse steroid therapy, type of vaccines, and dose or time interval between doses had no influence on response rate. Recipients with a high preoperative anti-HB titer, small graft-recipient weight ratio (GRWR), greater catch up growth, heavier body weight, lower tacrolimus level at the time of vaccination, and longer time interval between transplant or steroid medication and vaccination yielded good response. If well tailored, post-transplant vaccination can be effective and offer patients prophylaxis against de novo hepatitis B infection for a prolonged period of time.