Proton pump inhibitors increase the risk of carbapenem-resistant Enterobacteriaceae colonization by facilitating the transfer of antibiotic resistance genes among bacteria in the gut microbiome.

Carbapenem-resistant Enterobacteriaceae (CRE) pose a global health threat; however, there is still limited understanding of the risk factors and underlying mechanisms of CRE colonization in the gut microbiome. We conducted a matched case-control study involving 282 intensive care unit patients to analyze influencing covariates on CRE colonization. Subsequently, their effects on the gut microbiome were analyzed in a subset of 98 patients (47 CRE carriers and 51 non-CRE carriers) using whole metagenome sequences. The concomitant use of proton pump inhibitors (PPIs) and antibiotics was a significant risk factor for CRE colonization. The gut microbiome differed according to PPI administration, even within the CRE and non-CRE groups. Moreover, the transfer of mobile genetic elements (MGEs) harboring carbapenem resistance genes (CRGs) between bacteria was higher in the PPI-treated group than in the PPI-not-treated group among CRE carriers. The concomitant use of PPIs and antibiotics significantly alters the gut microbiome and increases the risk of CRE colonization by facilitating the transfer of CRGs among bacteria of the gut microbiome. Based on these findings, improved stewardship of PPIs as well as antibiotics can provide strategies to reduce the risk of CRE colonization, thereby potentially improving patient prognosis.

Alteration of Gut Microbiota in Carbapenem-Resistant Enterobacteriaceae Carriers during Fecal Microbiota Transplantation According to Decolonization Periods.

Fecal microbiota transplantation (FMT) has been suggested as an alternative therapeutic option to decolonize carbapenem-resistant Enterobacteriaceae (CRE). However, the analysis of gut microbiota alteration in CRE carriers during FMT is still limited. Here, gut microbiota changes in CRE carriers were evaluated during FMT according to decolonization periods. The decolonization of 10 CRE carriers was evaluated after FMT, using serial consecutive rectal swab cultures. Alterations of gut microbiota before and after FMT (56 serial samples) were analyzed using high-throughput sequencing. The decolonization rates of CRE carriers were 40%, 50%, and 90% within 1, 3 and 5 months after initial FMT, respectively. Gut microbiota significantly changed after FMT (p = 0.003). Microbiota alteration was different between the early decolonization carriers (EDC) and late decolonization carriers (LDC). Microbiota convergence in carriers to donors was detected in EDC within 4 weeks, and keystone genera within the Bacteroidetes were found in the gut microbiota of EDC before FMT. The relative abundance of Klebsiella was lower in EDC than in LDC, before and after FMT. Our results indicate that FMT is a potential option for CRE decolonization. The gut microbiota of CRE carriers could be used to predict decolonization timing after FMT, and determine repeated FMT necessity.

Immunogenicity and safety of a modified three-dose priming and booster schedule for the Hantaan virus vaccine (Hantavax): A multi-center phase III clinical trial in healthy adults.

BACKGROUND: Hemorrhagic fever with renal syndrome is a serious health problem in Eurasian countries. This study aimed to evaluate the immunogenicity and safety of formalin-inactivated Hantaan virus vaccine (Hantavax®) with a 3 + 1 vaccination schedule. METHODS: A phase III, multi-center clinical trial was conducted to evaluate the immunogenicity and safety of Hantavax® (three primary doses and a booster dose schedule at 0, 1, 2 and 13 months) among healthy adults. Immune responses were assessed using the plaque reduction neutralizing antibody test (PRNT) and immunofluorescent antibody assay (IFA). Systemic and local adverse events were assessed. RESULTS: A total of 320 healthy subjects aged ≥19 years were enrolled. Following three primary doses of Hantavax®, the seroconversion rate was 80.97% and 92.81% by PRNT and IFA, respectively. With booster administration, seropositive rates were 67.47% and 95.68% at one-month post-vaccination according to PRNT and IFA, respectively. Solicited local and systemic adverse events were reported in 30.50-42.81% and 16.67-33.75% during the three primary dose vaccination, while those were reported 36.57% and 21.36% after the booster doses. Both local and systemic adverse events did not increase with repeated vaccinations. CONCLUSION: Hantavax® showed a high seroconversion rate after the three-dose priming, and additional dose administration with 11-month interval induced good booster effects. (ClinicalTrials.gov Identifier: NCT02553837).

The clinical and economic burden of community-onset complicated skin and skin structure infections in Korea.

BACKGROUND/AIMS: To investigate epidemiologic characteristics, clinical and economic burdens, and factors associated with mortality in complicated skin and skin structure infection (cSSSI) patients in Korea. METHODS: A retrospective, observational, nationwide study was conducted between April to July 2012 at 14 tertiary-hospitals in Korea. Eligible patients were hospitalized adults with community acquired cSSSI, who underwent surgical intervention and completed treatment between November 2009 and October 2011. Data on demography, clinical characteristics, outcomes and medical resource utilization were collected through medical record review. Direct medical costs were calculated by multiplying quantities of resources utilized by each unit price in Korea. RESULTS: Of 473 patients enrolled, 449 patients (except 24 patients with no record on surgical intervention) were eligible for analysis. Microbiological testing was performed on 66.1% of patients and 8.2% had multiple pathogens. Among culture confirmed pathogens (n = 297 patients, 340 episodes), 76.2% were gram-positive (Staphylococcus aureus; 41.2%) and 23.8% were gram-negative. The median duration of hospital stay was 16 days. Among treated patients, 3.3% experienced recurrence and 4.2% died in-hospital. The mean direct medical costs amounted to $4,195/ person, with the greatest expenses for hospitalization and antibiotics. The in-hospital mortality and total medical costs were higher in combined antibiotics therapy than monotherapy (p < 0.05). Charlson's comorbidity index ≥ 3, standardized early warning scoring ≥ 4, sub-fascia infections and combined initial therapy, were all found to be associated with higher mortality. CONCLUSION: Korean patients with community-onset cSSSI suffer from considerable clinical and economic burden. Efforts should be made to reduce this burden through appropriate initial treatment.

Immunogenicity and safety of an egg-based inactivated quadrivalent influenza vaccine (GC3110A) versus two inactivated trivalent influenza vaccines with alternate B strains: A phase â ¢ randomized clinical trial in adults.

Two antigenically distinct influenza B lineage viruses (Yamagata/Victoria) have been co-circulating globally since the mid-1980s. The quadrivalent influenza vaccine (QIV) may provide better protection against unpredictable B strains. We conducted a randomized, double-blind, phase III trial to evaluate the immunogenicity and safety of an egg-based inactivated, split-virion QIV (GC3110A). Subjects aged ≥ 19 years were randomized 2:1:1 to be vaccinated with QIV- GC3110A, trivalent influenza vaccine (TIV) containing the Yamagata lineage strain (TIV-Yamagata), or TIV containing the Victoria lineage strain (TIV-Victoria). Hemagglutination inhibition assays were performed 21 days post-vaccination. Solicited/unsolicited adverse events (AEs) were assessed within 21 days after vaccination, while serious AEs were reported up to six months after vaccination. A total of 1,299 were randomized to receive QIV-GC3110A (648 subjects), TIV-Yamagata (325 subjects), or TIV-Victoria (326 subjects). Compared to the TIVs, the QIV-GC3110A met the non-inferiority criteria for all four subtype/lineage strains with respect to the geometric mean titer (GMT) ratio and the difference of seroconversion rate. The safety profiles of QIV-GC3110A were consistent with those of TIV. In conclusion, QIV-GC3110A is safe, immunogenic, and comparable to strain-matched TIV.

Hospital-based Influenza Morbidity and Mortality (HIMM) Surveillance for A/H7N9 Influenza Virus Infection in Returning Travelers.

Since 2013, the Hospital-based Influenza Morbidity and Mortality (HIMM) surveillance system began a H7N9 influenza surveillance scheme for returning travelers in addition to pre-existing emergency room (ER)-based influenza-like illness (ILI) surveillance and severe acute respiratory infection (SARI) surveillance. Although limited to eastern China, avian A/H7N9 influenza virus is considered to have the highest pandemic potential among currently circulating influenza viruses. During the study period between October 1st, 2013 and April 30th, 2016, 11 cases presented with ILI within seven days of travel return. These patients visited China, Hong Kong, or neighboring Southeast Asian countries, but none of them visited a livestock market. Seasonal influenza virus (54.5%, 6 among 11) was the most common cause of ILI among returning travelers, and avian A/H7N9 influenza virus was not detected during the study period.

Immunogenicity and safety of a cell culture-derived inactivated quadrivalent influenza vaccine (NBP607-QIV): A randomized, double-blind, multi-center, phase III clinical trial in adults and elderly subjects.

BACKGROUND: The influenza B virus has two lineages; Yamagata and Victoria. The two lineages are antigenically distinct and it is difficult to expect cross-protection between the lineages. Actually, the mismatch between circulating influenza B viruses and vaccine strains has been occurred frequently. The cell-culture system for the production of influenza vaccine can contribute to improve vaccine strain selection and expand vaccine supplies. We investigated the immunogenicity and safety of cell culture-derived quadrivalent inactivated influenza vaccine (NBP607-QIV) in adults and elderly subjects. METHODS: A randomized controlled phase III trial was undertaken in 10 university hospitals in the Republic of Korea (Clinical trial Number-NCT02467842). Adults (aged 19-59 years) and elderly subjects (aged ≥60 years) were randomly assigned in a 2:1:1 ratio to NBP607-QIV versus cell culture-based trivalent inactivated influenza vaccine-Yamagata (NBP607-Y) and cell culture-based trivalent inactivated influenza vaccine-Victoria (NBP607-V). Immunogenicity was assessed 3 weeks after vaccination by hemagglutination inhibition assay. Safety was assessed for 6 months post-vaccination: solicited adverse events (AEs) for 7 days, unsolicited AEs for 21 days and serious adverse events (SAEs) for 6 months. AEs were sub-classified as adverse drug reactions (ADRs) according to the causality. RESULTS: A total of 1,503 participants were randomly assigned to NBP607-QIV (n = 752), NBP607-Y (n = 373) and NBP607-V (n = 378). The seroconversion rates of NBP607-QIV were 52.4%, 51.2%, 43.7% and 55.8% against A/H1N1, A/H3N2, B/Yamagata and B/Victoria, respectively. Non-inferiority against shared strains and superiority against alternate-lineage B strains were demonstrated for NBP607-QIV vs. NBP607-Y and NBP607-V. A total of 730 reactions occurred in 324 (43.1%) subjects of NBP607-QIV group. Majority of ADRs was solicited (99.2%) and mild (90.3%) in intensity. In adults (aged 19-59 years), solicited local AEs were slightly more frequent in NBP607-QIV group than NBP607-Y or NBP607-V group (40.9%, 33.4% and 32.5%, respectively). One SAE was observed among NBP607-QIV group, which was considered to be unrelated to the study vaccine within 3 weeks of vaccination and no vaccine-related SAEs were reported up to 6 months after vaccination. CONCLUSIONS: NBP607-QIV is a safe, well-tolerated and immunogenic influenza vaccine in Korean adults and elderly subjects.

Long-term immunogenicity and safety of inactivated Hantaan virus vaccine (Hantavax™) in healthy adults.

BACKGROUND: Hemorrhagic fever with renal syndrome is a serious health problem in Eurasian countries, including Korea and China. This study evaluated the long-term immunogenicity and safety of formalin-inactivated Hantaan virus vaccine (Hantavax™). METHODS: A phase III, multi-center clinical trial was undertaken to evaluate the immunogenicity and safety of Hantavax™ (three-dose schedule at 0, 1, and 13 months) among healthy adults. Immune response was assessed using the plaque reduction neutralizing antibody test (PRNT) and immunofluorescent antibody assay (IFA). Antibody levels were measured pre-vaccination and at 2, 13, 14, 25, 37, and 49 months after the initial vaccination. Systemic and local adverse events were assessed. RESULTS: A total of 226 healthy subjects aged 19-75 years were enrolled. Following two primary doses of Hantavax™, the seroconversion rate was 90.14% by IFA, but it was only 23.24% by PRNT50. With booster administration, seropositive rates were 87.32% and 45.07% at one month post-vaccination according to IFA and PRNT50, respectively. In young adults (19-39 years), the seropositive rate according to PRNT50 reached about 60% after booster vaccination. The mean duration of seropositive response was 735 days for PRNT50 and 845 days for IFA. Solicited local and systemic adverse events occurred in 47.79% and 25.22% of study subjects, respectively, and most were grade 1. CONCLUSION: Hantavax™ showed a booster effect and immunogenicity lasting two years with a three-dose schedule. The neutralizing antibody response was quite poor with two primary doses, so an early booster vaccination at 2-6 months might be warranted to provide timely protection to high-risk subjects.

Immunogenicity and safety of a cell culture-derived inactivated trivalent influenza vaccine (NBP607): A randomized, double-blind, multi-center, phase 3 clinical trial.

BACKGROUND: Cell culture-derived influenza vaccines (CCIVs) have several important advantages over egg-based influenza vaccines, including shorter production time, better preservation of wild-type virus antigenicity and large-scale production capacity. METHODS: A randomized, double-blind, phase 3 trial was undertaken to evaluate the immunogenicity and safety of a novel cell culture-derived inactivated, subunit, trivalent influenza vaccine (NBP607, SK Chemicals, Seongnam, Korea) compared to the control vaccine (AgrippalS1, Novartis Vaccines and Diagnostics Srl, Siena, Italy) among healthy adults aged 19 years or older (Clinical trial Number-NCT02344134). Immunogenicity was determined at pre-vaccination, 1 month and 6 month post-vaccination by the hemagglutination inhibition assay. Solicited and unsolicited adverse events were assessed after vaccination. RESULTS: A total of 1156 healthy subjects were recruited. NBP607 met all of the criteria of Committee for Medicinal Products for Human Use (CHMP) at 21 days post-vaccination. Contrary to NBP607, the control vaccine did not satisfy the seroconversion criteria for influenza B irrespective of age. Although the geometric mean titer for each influenza subtype declined gradually, seroprotection rate still remained ≥80% for all subtypes up to six month after NBP607 administration. NBP607 recipients met the seroprotection criteria for all three influenza subtypes up to 6 month post-vaccination. There was no significant difference in the occurrence of adverse events between the NBP607 and control groups. CONCLUSION: NBP607, a novel CCIV, showed excellent immunogenicity that lasted ≥6 months after vaccination and had tolerable safety profiles. In particular, NBP607 was more immunogenic against influenza B compared to the control, an egg-based subunit vaccine.

Immunogenicity and safety of trivalent inactivated influenza vaccine: a randomized, double-blind, multi-center, phase 3 clinical trial in a vaccine-limited country.

Influenza vaccines are the primary method for controlling influenza and its complications. This study was conducted as a phase 3, randomized, double-blind, controlled, multi-center trial at seven university hospitals to evaluate the immunogenicity and safety of an inactivated, split, trivalent influenza vaccine (GC501, Green Cross Corporation, Yongin, Korea), which was newly manufactured in Korea in 2008. Between September 21 and 26, a total of 329 healthy subjects were recruited for the immunogenicity analysis, while 976 subjects were enrolled for the safety analysis. The GC501 vaccine met both FDA and EMEA criteria with ≥ 80% of subjects achieving post-vaccination titers ≥ 40 for all three subtypes, even in the elderly. The vaccine was well tolerated with only mild systemic and local adverse events. In summary, GC501 showed excellent immunogenicity and a good safety profile in both young adults and the elderly. The licensure of GC501 might be an important basis in preparation for the future influenza pandemic.

Atypical pathogens as etiologic agents in hospitalized patients with community-acquired pneumonia in Korea: a prospective multi-center study.

Local epidemiologic data on the etiologies of patients hospitalized with community-acquired pneumonia (CAP) is needed to develop guidelines for clinical practice. This study was conducted prospectively to determine the proportion of atypical bacterial pathogens in adults patients hospitalized with CAP in Korea between October 2001 and December 2002. Microbiological diagnosis was determined by serology for antibodies to Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. Nucleic acid of M. pneumoniae and C. pneumoniae in respiratory samples and Legionella antigen in urine samples were detected. The study population consisted of 126 patients (71 males, 55 females), averaging 54.6 yr (SD+/-17.8), whose paired sera were available. An etiologic diagnosis for atypical pathogens was made in 18 patients (14.3%): C. pneumoniae 9 (7.1%), M. pneumoniae 8 (6.3%), and L. pneumophila 3 patients (2.4%). Streptococcus preumoniae and other typical pathogens were isolated from 36 patients (28.6%). Of 126 patients, 16 (12.7%) were admitted to intensive care unit and atypical pathogens were identified in 5 patients (31.3%). Initial clinical features of patients with pneumonia due to atypical, typical or undetermined pathogens were indistinguishable. We conclude that atypical pathogens should be seriously considered in hospitalized patients with CAP, when initiating empiric treatment in Korea.