Dae Sun Jo

VraT/YvqF Is Required for Methicillin Resistance and Activation of the VraSR Regulon in Staphylococcus aureus

ABSTRACT Staphylococcus aureus infections caused by strains that are resistant to all forms of penicillin, so-called methicillin-resistant S. aureus (MRSA) strains, have become common. One strategy to counter MRSA infections is to use compounds that resensitize MRSA to methicillin. S. aureus responds to diverse classes of cell wall-inhibitory antibiotics, like methicillin, using the two-component regulatory system VraSR (vra) to up- or downregulate a set of genes (the cell wall stimulon) that presumably facilitates resistance to these antibiotics. Accordingly, VraS and VraR mutations decrease resistance to methicillin, vancomycin, and daptomycin cell wall antimicrobials. vraS and vraR are encoded together on a transcript downstream of two other genes, which we call vraU and vraT (previously called yvqF). By producing nonpolar deletions in vraU and vraT in a USA300 MRSA clinical isolate, we demonstrate that vraT is essential for optimal expression of methicillin resistance in vitro, whereas vraU is not required for this phenotype. The deletion of vraT also improved the outcomes of oxacillin therapy in mouse models of lung and skin infection. Since vraT expressed in trans did not complement a vra operon deletion, we conclude that VraT does not inactivate the antimicrobial. Genome-wide transcriptional microarray experiments reveal that VraT facilitates resistance by playing a necessary regulatory role in the VraSR-mediated cell wall stimulon. Our data prove that VraTSR comprise a novel three-component regulatory system required to facilitate resistance to cell wall agents in S. aureus. We also provide the first in vivo proof of principle for using VraT as a sole target to resensitize MRSA to β-lactams.

Improved Oxacillin Treatment Outcomes in Experimental Skin and Lung Infection by a Methicillin-Resistant Staphylococcus aureus Isolate with a vraSR Operon Deletion

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) strains are major pathogens causing infections of the skin and soft tissues and more serious, life-threatening diseases, including sepsis and necrotizing pneumonia. The vraSR operon encodes the key regulatory system that modulates the stress response of S. aureus elicited upon exposure to cell wall antibiotics. Mutation of vraS and vraR results in decreased oxacillin resistance in vitro. We investigated the effect of oxacillin treatment in experimental models employing a clinical USA300 MRSA strain (strain 923) and an isogenic vraSR deletion mutant (strain 923-M23). In a murine model of S. aureus necrotizing pneumonia, animals were treated with oxacillin, beginning 15 min after inoculation. Among mice infected with mutant strain 923-M23, oxacillin treatment significantly improved survival compared with saline treatment, whereas oxacillin treatment had no effect in mice infected with strain 923. Similarly, treatment with oxacillin decreased the bacterial burden among animals infected with strain 923-M23 but not among animals infected with strain 923. In a murine skin infection model, oxacillin eliminated the development of dermonecrosis among 923-M23-infected mice and decreased the bacterial burden in the lesions, but not among strain 923-infected mice. We conclude that deletion of the vraSR operon allowed an oxacillin regimen to be effective in murine models of MRSA pneumonia and skin infection. These findings provide proof-of-principle for development of a new antibiotic that could restore the usefulness of oxacillin against MRSA by inhibiting VraS or VraR.

Preproghrelin Leu72Met polymorphism in obese Korean children.

Ghrelin is a novel gut-brain peptide that has somatotropic, orexigenic, and adipogenic effects. We examined the preproghrelin Leu72Met polymorphism in 222 obese Korean children to determine whether it is associated with obesity. The frequencies of the Leu72Met polymorphism were 29.3% in obese, 32.3% in overweight, and 32.5% in lean Korean children. No significant difference was found between Met72 carrier and non-carrier obese children with respect to BMI, total body fat, serum triglycerides, total cholesterol, or LDL-cholesterol levels. Our data suggest that the preproghrelin Leu72Met polymorphism is not associated with obesity in children.

Serotype distribution and antibiotic resistance of Streptococcus pneumoniae isolated from invasive infections after optional use of the 7-valent conjugate vaccine in Korea, 2006-2010

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.

Varicella and Varicella Vaccination in South Korea

ABSTRACT With continuing occurrence of varicella despite increasing vaccine coverage for the past 20 years, a case-based study, a case-control study, and an immunogenicity and safety study were conducted to address the impact of varicella vaccination in South Korea. Varicella patients under the age of 16 years were enrolled for the case-based study. For the case-control study, varicella patients between 12 months and 15 years of age were enrolled with one control matched for each patient. For the immunogenicity and safety study, otherwise healthy children from 12 to 24 months old were immunized with Suduvax (Green Cross, South Korea). Fluorescent antibody to membrane antigen (FAMA) varicella-zoster virus (VZV) antibody was measured before and 6 weeks after immunization. In the case-based study, the median age of the patients was 4 years. Among 152 patients between 1 and 15 years of age, 139 children received varicella vaccine and all had breakthrough infections. Clinical courses were not ameliorated in vaccinated patients, but more vaccinated patients received outpatient rather than inpatient care. In the case-control study, the adjusted overall effectiveness of varicella vaccination was 54%. In the immunogenicity and safety study, the seroconversion rate and geometric mean titer for FAMA antibody were 76.67% and 5.31. Even with increasing varicella vaccine uptake, we illustrate no upward age shift in the peak incidence, a high proportion of breakthrough disease, almost no amelioration in disease presentation by vaccination, and insufficient immunogenicity of domestic varicella vaccine. There is need to improve the varicella vaccine used in South Korea.

Recommendation for use of the newly introduced pneumococcal protein conjugate vaccines 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.

Recommendation for the use of newly introduced Tdap vaccine in Korea

Pertussis is an acute respiratory infection characterized by paroxysmal cough and inspiratory whoop for over 2 weeks. The incidence of pertussis has decreased markedly after the introduction of DTwP/DTaP vaccine, but the incidence of pertussis has increased steadily among young infant and among adolescents and adults in many countries. Td vaccine was used in this age group but the increase in pertussis has lead to the development of a Tdap vaccine. The Tdap vaccine is a Td vaccine with a pertussis vaccine added and is thought to decrease the incidence and transmission of pertussis in the respective age group. In Korea, two products are approved by the KOREA FOOD & DRUG ADMINISTRATION, which are ADACEL™ (Sanofi-Pasteur, Totonto, Ontario, Canada) and BOOSTRIX® (GlaxoSmithKline Biologicals, Rixensart, Belgium) for those aged between 11-64. This report summarizes the recommendations approved by the Committee on Infectious Diseases, the Korean Pediatric Society.

Clinical significance of serotype V among infants with invasive group B streptococcal infections in South Korea

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 cMLSB 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 ermB. 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.

Genotype Characterization of Group B Streptococcus Isolated from Infants with Invasive Diseases in South Korea

Background: 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. Methods: 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. Results: 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%). Conclusions: 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.

Recommended immunization schedule for children and adolescents: the Korean Pediatric Society, 2013.

This article contains the recommended immunization schedule by the Committee on Infectious Diseases of the Korean Pediatric Society, updated in March 2013, when Haemophilus influenzae type b vaccine is now included in the National Immunization Program in Korea. It also includes catch-up immunization schedule for children and adolescents who are behind the recommended schedule. These schedules are a minor revision of the corresponding parts of Immunization Guideline, 7th edition, of the Korean Pediatric Society, released in 2012. Pediatricians should be aware of these schedules to provide adequate immunization to Korean children and adolescents.