Persistent differences in the immunogenicity of the two COVID-19 primary vaccines series, modulated by booster mRNA vaccination and breakthrough infection.

INTRODUCTION: The long-term impact of initial immunogenicity induced by different primary COVID-19 vaccine series remains unclear. METHODS: A prospective cohort study was conducted at 10 tertiary hospitals in Korea from March 2021 to September 2022. Immunogenicity assessments included anti-spike protein antibody (Sab), SARS-CoV-2-specific interferon-gamma releasing assay (IGRA), and multiplex cytokine assays for spike protein-stimulated plasma. Spike proteins derived from wild-type SARS-CoV-2 and alpha variant (Spike1) and beta and gamma variant (Spike2) were utilized. RESULTS: A total of 235 healthcare workers who had received a two-dose primary vaccine series of either ChAdOx1 or BNT162b2, followed by a third booster dose of BNT162b2 (166 in the ChAdOx1/ChAdOx1/BNT162b2 (CCB) group and 69 in the BNT162b2/BNT162b2/BNT162b2 (BBB) group, based on the vaccine series) were included. Following the primary vaccine series, the BBB group exhibited significantly higher increases in Sab levels, IGRA responses, and multiple cytokines (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1ß, interleukin (IL)-1ra, IFN-γ, IL-2, IL-4, and IL-10) compared to the CCB group (all P < 0.05). One month after the third BNT162b2 booster, the CCB group showed Sab levels comparable to those of the BBB group, and both groups exhibited lower levels after six months without breakthrough infections (BIs). However, among those who experienced BA.1/2 BIs after the third booster, Sab levels increased significantly more in the BBB group than in the CCB group (P < 0.001). IGRA responses to both Spike1 and Spike2 proteins were significantly stronger in the BBB group than the CCB group after the third booster, while only the Spike2 response were higher after BIs (P = 0.007). The BBB group exhibited stronger enhancement of T-cell cytokines (IL-2, IL-4, and IL-17A) after BIs than in the CCB group (P < 0.05). CONCLUSION: Differences in immunogenicity induced by the two primary vaccine series persisted, modulated by subsequent booster vaccinations and BIs.

Antimicrobial Use and Carbapenem-Resistant Enterobacterales in Korea: A Nationwide Case-Control Study With Propensity Score Matching.

BACKGROUND: Nationwide research on the association between carbapenem-resistant Enterobacterales (CREs) and antibiotic use is limited. METHODS: This nested case-control study analyzed Korean National Health Insurance claims data from April 2017 to April 2019. Based on the occurrence of CRE, hospitalized patients aged ≥ 18 years were classified into CRE (cases) and control groups. Propensity scores based on age, sex, modified Charlson comorbidity score, insurance type, long-term care facility, intensive care unit stay, and acquisition of vancomycin-resistant Enterococci were used to match the case and control groups (1:3). RESULTS: After matching, the study included 6,476 participants (1,619 cases and 4,857 controls). Multivariable logistic regression analysis revealed that the utilization of broad-spectrum antibiotics, such as piperacillin/tazobactam (adjusted odds ratio [aOR], 2.178; 95% confidence interval [CI], 1.829-2.594), third/fourth generation cephalosporins (aOR, 1.764; 95% CI, 1.514-2.056), and carbapenems (aOR, 1.775; 95% CI, 1.454-2.165), as well as the presence of comorbidities (diabetes [aOR, 1.237; 95% CI, 1.061-1.443], hemiplegia or paraplegia [aOR, 1.370; 95% CI, 1.119-1.679], kidney disease [aOR, 1.312; 95% CI, 1.105-1.559], and liver disease [aOR, 1.431; 95% CI, 1.073-1.908]), were significantly associated with the development of CRE. Additionally, the CRE group had higher mortality (8.33 vs. 3.32 incidence rate per 100 person-months, P < 0.001) and a total cost of healthcare utilization per person-month (15,325,491 ± 23,587,378 vs. 5,263,373 ± 14,070,118 KRW, P < 0.001) than the control group. CONCLUSION: The utilization of broad-spectrum antibiotics and the presence of comorbidities are associated with increasing development of CRE. This study emphasizes the importance of antimicrobial stewardship in reducing broad-spectrum antibiotic use and CRE disease burden in Korea.

Prevalence and Associated Factors of Depression and Anxiety Among Healthcare Workers During the Coronavirus Disease 2019 Pandemic: A Nationwide Study in Korea.

BACKGROUND: A healthcare system's collapse due to a pandemic, such as the coronavirus disease 2019 (COVID-19), can expose healthcare workers (HCWs) to various mental health problems. This study aimed to investigate the impact of the COVID-19 pandemic on the depression and anxiety of HCWs. METHODS: A nationwide questionnaire-based survey was conducted on HCWs who worked in healthcare facilities and public health centers in Korea in December 2020. Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) were used to measure depression and anxiety. To investigate factors associated with depression and anxiety, stepwise multiple logistic regression analysis was performed. RESULTS: A total of 1,425 participating HCWs were included. The mean depression score (PHQ-9) of HCWs before and after COVID-19 increased from 2.37 to 5.39, and the mean anxiety score (GAD-7) increased from 1.41 to 3.41. The proportion of HCWs with moderate to severe depression (PHQ-9 ≥ 10) increased from 3.8% before COVID-19 to 19.5% after COVID-19, whereas that of HCWs with moderate to severe anxiety (GAD-7 ≥ 10) increased from 2.0% to 10.1%. In our study, insomnia, chronic fatigue symptoms and physical symptoms after COVID-19, anxiety score (GAD-7) after COVID-19, living alone, and exhaustion were positively correlated with depression. Furthermore, post-traumatic stress symptoms, stress score (Global Assessment of Recent Stress), depression score (PHQ-9) after COVID-19, and exhaustion were positively correlated with anxiety. CONCLUSION: In Korea, during the COVID-19 pandemic, HCWs commonly suffered from mental health problems, including depression and anxiety. Regularly checking the physical and mental health problems of HCWs during the COVID-19 pandemic is crucial, and social support and strategy are needed to reduce the heavy workload and psychological distress of HCWs.

Effect of Regdanvimab on Mortality in Patients Infected with SARS-CoV-2 Delta Variants: A Propensity Score-Matched Cohort Study.

INTRODUCTION: Regdanvimab, a monoclonal antibody pharmaceutical, is the first Korean drug approved for treating coronavirus disease 2019 (COVID-19). We analyzed the therapeutic efficacy of regdanvimab in patients with the COVID-19 delta variant infection. METHODS: We retrospectively reviewed the electronic medical records of patients hospitalized at two Korean tertiary COVID-19 hospitals with COVID-19 delta variant infection between May 26, 2021, and January 30, 2022. To analyze the therapeutic efficacy of regdanvimab, the patients were divided into regdanvimab and non-regdanvimab groups and were 1:1 propensity-score (PS)-matched on age, severity at admission, and COVID-19 vaccination history. RESULTS: Of 492 patients, 262 (53.3%) and 230 (46.7%) were in the regdanvimab and non-regdanvimab groups, respectively. After PS matching the groups on age, severity at admission, and COVID-19 vaccination history, each group comprised 189 patients. The 30-day hospital mortality rates (0.0% vs. 1.6%, p = 0.030), proportions of patients with exacerbated conditions to severe/critical/died (9.5% vs. 16.4%, p = 0.047), proportions who received oxygen therapy because of pneumonia exacerbation (7.4% vs. 16.4%, p = 0.007), and proportions with a daily National Early Warning Score ≥ 5 from hospital day 2 were significantly lower in the regdanvimab group. CONCLUSIONS: We showed that regdanvimab reduced the exacerbation rates of conditions and mortality in patients with the COVID-19 delta variant infection. Thus, it is recommended to streamline the drug approval system during epidemics of new variant viruses to improve the availability and usage of therapeutics for patients. To facilitate this, relevant institutional support is required.

Principles and practices of antimicrobial stewardship programs in Korea.

This review addresses the escalating challenge posed by antibiotic resistance, highlighting its profound impact on global public health, including increased mortality rates and healthcare expenditures. The review focuses on the need to adopt the One Health approach to effectively manage antibiotic usage across human, animal, and environmental domains. Antimicrobial stewardship programs (ASPs) are considered as comprehensive strategies that encompass both core and supplementary initiatives aimed at enhancing prudent antibiotic use. The 2021 "Guidelines on Implementing ASP in Korea" introduced such strategies, with a strong emphasis on fostering multidisciplinary and collaborative efforts. Furthermore, the "Core Elements for Implementing ASPs in Korean General Hospitals," established in 2022, provide a structured framework for ASPs, delineating leadership responsibilities, the composition of interdisciplinary ASP teams, a range of interventions, and continuous monitoring and reporting mechanisms. In addition, this review examines patient-centric campaigns such as "Speak Up, Get Smart" and emphasizes the pivotal role of a multidisciplinary approach and international cooperation in addressing the multifaceted challenges associated with antibiotic resistance.

Clonal Distribution and Its Association With the Carbapenem Resistance Mechanisms of Carbapenem-Non-Susceptible Pseudomonas aeruginosa Isolates From Korean Hospitals.

Background: Carbapenem resistance in Pseudomonas aeruginosa is a serious global health problem. We investigated the clonal distribution and its association with the carbapenem resistance mechanisms of carbapenem-non-susceptible P. aeruginosa isolates from three Korean hospitals. Methods: A total of 155 carbapenem-non-susceptible P. aeruginosa isolates collected between 2011 and 2019 were analyzed for sequence types (STs), antimicrobial susceptibility, and carbapenem resistance mechanisms, including carbapenemase production, the presence of resistance genes, OprD mutations, and the hyperproduction of AmpC ß-lactamase. Results: Sixty STs were identified in carbapenem-non-susceptible P. aeruginosa isolates. Two high-risk clones, ST235 (N=41) and ST111 (N=20), were predominant; however, sporadic STs were more prevalent than high-risk clones. The resistance rate to amikacin was the lowest (49.7%), whereas that to piperacillin was the highest (92.3%). Of the 155 carbapenem-non-susceptible isolates, 43 (27.7%) produced carbapenemases. Three metallo-ß-lactamase (MBL) genes, blaIMP-6 (N=38), blaVIM-2 (N=3), and blaNDM-1 (N=2), were detected. blaIMP-6 was detected in clonal complex 235 isolates. Two ST773 isolates carried blaNDM-1 and rmtB. Frameshift mutations in oprD were identified in all isolates tested, regardless of the presence of MBL genes. Hyperproduction of AmpC was detected in MBL gene-negative isolates. Conclusions: Frameshift mutations in oprD combined with MBL production or hyperproduction of AmpC are responsible for carbapenem resistance in P. aeruginosa. Further attention is required to curb the emergence and spread of new carbapenem-resistant P. aeruginosa clones.

Colistin heteroresistance in Citrobacter freundii clinical isolates from Republic of Korea.

We investigated colistin heteroresistance in Citrobacter freundii isolates from Korean hospitals. Using population analysis profiling (PAP), we detected colistin heteroresistance in 31.3% of isolates. Among these, ST217 was the most prevalent clone (58.5%), particularly within colistin-heteroresistant isolates (80.0%). Interestingly, the second most common clone, ST248, was not found in heteroresistant isolates. We identified amino acid changes in PhoQ, PmrA, and PmrB, along with mRNA overexpression in pmrB and arnD. Colistin monotherapy showed no efficacy, but a combination of colistin and ciprofloxacin successfully eradicated all five isolates, even at 0.5 × minimum inhibitory concentrations. This study underscores the high prevalence of colistin heteroresistance in C. freundii isolates, limiting the effectiveness of colistin monotherapy. Combining colistin with ciprofloxacin may offer a viable treatment option for C. freundii infections.

Analysis of microbiological tests in patients withholding or withdrawing life-sustaining treatment at the end stage of life in 2 Korean hospitals.

OBJECTIVE: We evaluated the adequacy of microbiological tests in patients withholding or withdrawing life-sustaining treatment (WLST) at the end stage of life. SETTING: The study was conducted at 2 tertiary-care referral hospitals in Daegu, Republic of Korea. DESIGN: Retrospective cross-sectional study. METHODS: Demographic findings, clinical and epidemiological characteristics, statistics of microbiological tests, and microbial species isolated from patients within 2 weeks before death were collected in 2 tertiary-care referral hospitals from January to December 2018. We also reviewed the antimicrobial treatment that was given within 3 days of microbiological testing in patients on WLST. RESULTS: Of the 1,187 hospitalized patients included, 905 patients (76.2%) had WLST. The number of tests per 1,000 patient days was higher after WLST than before WLST (242.0 vs 202.4). Among the category of microbiological tests, blood cultures were performed most frequently, and their numbers per 1,000 patient days before and after WLST were 95.9 and 99.0, respectively. The positive rates of blood culture before and after WLST were 17.2% and 18.0%, respectively. Candida spp. were the most common microbiological species in sputum (17.4%) and urine (48.2%), and Acinetobacter spp. were the most common in blood culture (17.3%). After WLST determination, 70.5% of microbiological tests did not lead to a change in antibiotic use. CONCLUSIONS: Many unnecessary microbiological tests are being performed in patients with WLST within 2 weeks of death. Microbiological testing should be performed carefully and in accordance with the patient's treatment goals.

Conversion to colistin susceptibility by tigecycline exposure in colistin-resistant Klebsiella pneumoniae and its implications to combination therapy.

OBJECTIVES: This study investigated the effect of tigecycline exposure on susceptibility of colistin-resistant Klebsiella pneumoniae isolates to colistin and explored the possibility of antibiotic combination at low concentrations to treat colistin-resistant K. pneumoniae isolates. METHODS: Twelve tigecycline-resistant (TIR) mutants were induced in vitro from wild-type, colistin-resistant, and tigecycline-susceptible K. pneumoniae isolates. Antibiotic susceptibility was determined using the broth microdilution method. The deduced amino acid alterations were identified for genes associated with colistin resistance, lipid A biosynthesis, and tigecycline resistance. Expression levels of genes were compared between wild-type stains and TIR mutants using quantitative real-time polymerase chain reaction (PCR). Lipid A modification was explored using MALDI-TOF mass spectrometry. Time-killing assay was performed to assess the efficiency of combination therapy using low concentrations of colistin and tigecycline. RESULTS: All TIR mutants except one were converted to be susceptible to colistin. These TIR mutants had mutations in the ramR gene and increased expression levels of ramA. Three genes associated with lipid A biosynthesis, lpxC, lpxL, and lpxO, were also overexpressed in TIR mutants, although no mutation was observed. Additional polysaccharides found in colistin-resistant, wild-type strains were modified in TIR mutants. Colistin-resistant K. pneumoniae strains were eliminated in vitro by combining tigecycline and colistin at 2 mg/L. In this study, we found that tigecycline exposure resulted in reduced resistance of colistin-resistant K. pneumoniae to colistin. Such an effect was mediated by regulation of lipid A modification involving ramA and lpx genes. CONCLUSION: Because of such reduced resistance, a combination of colistin and tigecycline in low concentrations could effectively eradicate colistin-resistant K. pneumoniae strains.

Clinical utility of quantitative immunoassays and surrogate virus neutralization tests for predicting neutralizing activity against the SARS-CoV-2 Omicron BA.1 and BA.5 variants.

Developing new antibody assays for emerging SARS-CoV-2 variants is challenging. SARS-CoV-2 surrogate virus neutralization tests (sVNT) targeting Omicron BA.1 and BA.5 have been devised, but their performance needs to be validated in comparison with quantitative immunoassays. First, using 1749 PRNT-positive sera, we noticed that log-transformed optical density (OD) ratio of wild-type (WT) sVNT exhibited better titer-correlation with plaque reduction neutralization test (PRNT) than % inhibition value. Second, we tried 798 dilutional titration tests with 103 sera, but nonlinear correlation between OD ratio and antibody concentration limited titration of sVNT. Third, the titer-correlations of two sVNT kits for BA.1 and two quantitative immunoassays for WT were evaluated with BA.1 and BA.5 PRNT. All tested kits exhibited a linear correlation with PRNT titers, but the sVNT kits exhibited high false-negative rates (cPass-BA.1 kit, 45.4% for BA.1 and 44.2% for BA.5; STANDARD F-BA.1 kit, 1.9% for BA.1 and 2.2% for BA.5), while quantitative immunoassays showed 100% sensitivity. Linear mixed-effects model suggested superior titer-correlation with PRNT for quantitative immunoassays compared to sVNT kits. Taken together, the use of quantitative immunoassays for WT, rather than rapid development of new kits, would be practical for predicting neutralizing activities against emerging new variants.

Safety and Effectiveness of Regdanvimab for COVID-19 Treatment: A Phase 4 Post-marketing Surveillance Study Conducted in South Korea.

INTRODUCTION: Regdanvimab, a neutralising monoclonal antibody (mAb) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), received approval for the treatment of coronavirus disease 2019 (COVID-19) in South Korea in 2021. The Ministry of Food and Drug Safety in South Korea mandate that new medications be re-examined for safety and effectiveness post-approval in at least 3000 individuals. This post-marketing surveillance (PMS) study was used to evaluate the safety and effectiveness of regdanvimab in real-world clinical care. METHODS: This prospective, multicentre, phase 4 PMS study was conducted between February 2021 and March 2022 in South Korea. Eligible patients were aged ≥ 18 years with confirmed mild COVID-19 at high risk of disease progression or moderate COVID-19. Patients were hospitalised and treated with regdanvimab (40 mg/kg, day 1) and then monitored until discharge, with a follow-up call on day 28. Adverse events (AEs) were documented, and the COVID-19 disease progression rate was used to measure effectiveness. RESULTS: Of the 3123 patients with COVID-19 infection identified, 3036 were eligible for inclusion. Approximately 80% and 5% of the eligible patients were diagnosed with COVID-19 during the delta- and omicron-dominant periods, respectively. Median (range) age was 57 (18-95) years, and 50.6% of patients were male. COVID-19 severity was assessed before treatment, and high-risk mild and moderate COVID-19 was diagnosed in 1030 (33.9%) and 2006 (66.1%) patients, respectively. AEs and adverse drug reactions (ADRs) were experienced by 684 (22.5%) and 363 (12.0%) patients, respectively. The most common ADR was increased liver function test (n = 62, 2.0%). Nine (0.3%) patients discontinued regdanvimab due to ADRs. Overall, 378 (12.5%) patients experienced disease progression after regdanvimab infusion, with extended hospitalisation/re-admission (n = 300, 9.9%) as the most common reason. Supplemental oxygen was required by 282 (9.3%) patients. Ten (0.3%) patients required intensive care monitoring and 3 (0.1%) died due to COVID-19. CONCLUSION: This large-scale PMS study demonstrated that regdanvimab was effective against COVID-19 progression and had an acceptable safety profile when used in real-world clinical practice.

Incidence and Distribution of the Pathogens Causing GI Infections at a University Hospital of Korea.

BACKGROUND: Gastrointestinal (GI) infections, caused by various pathogens such as bacteria, viruses, protozoa, and parasites, are the second most common infectious diseases. Molecular diagnostics that can simultaneously detect these pathogens are commonly used in syndromic approaches. The authors aimed to identify the causative pathogens of GI infections to provide clinically useful information. METHODS: This retrospective study used molecular diagnostic methods to determine the incidence and distribution of GI pathogens according to gender, age, and season and analyze their coinfection from August 2020 to December 2022. RESULTS: The overall incidence of at least one GI pathogen was 40.1% (991/2, 471). The positivity rates for bacteria and viruses were 33.1% (817/2, 471) and 9.2% (227/2,471), respectively; the positivity rate for bacteria was significantly higher than that for viruses (p < 0.001). The incidence of GI pathogens according to age group was highest in group 3 (59.9%), followed by group 4 (57.0%). The most common bacterial pathogen associated with GI infections was C. difficile, followed by diarrheagenic E. coli, Campylobacter spp., and Salmonella spp. Enteropathogenic E. coli accounted for a large percentage of diarrheagenic E. coli (63.6%, 157/247). Among the viral pathogens, norovirus GI/GII was the most commonly detected virus, followed by adenovirus F40/41 and rotavirus A. For bacterial- or viral-positive cases, the distribution of GI pathogens according to age group showed the highest proportion of C. difficile in all groups, except for group 2. In group 2, rotavirus A accounted for the highest percentage (61.1%, 22/36). The incidence of GI pathogens was the highest in summer (36.1%), followed by autumn (32.7%), and winter (18.0%). The co-infection rate with two or more pathogens was 16.9% (167/991). The rates of co-infection with two or more bacteria, bacteria and viruses, and two viruses were 58.1%, 31.7%, and 10.2%, re-spectively. CONCLUSIONS: Information on the incidence and distribution of GI pathogens might be clinically useful; however, unlike the distribution of other infectious pathogens, it is necessary to consider that microorganisms identified through molecular diagnostics can be detected even in healthy people without clinical symptoms.

Immunogenicity and safety of SARS-CoV-2 recombinant protein nanoparticle vaccine GBP510 adjuvanted with AS03: interim results of a randomised, active-controlled, observer-blinded, phase 3 trial.

Background: GBP510 vaccine contains self-assembling, recombinant nanoparticles displaying SARS-CoV-2 spike receptor-binding domains. We report interim phase 3 immunogenicity results for GBP510 adjuvanted with AS03 (GBP510/AS03) compared with ChAdOx1-S (Vaxzevria, AstraZeneca) in healthy adults aged ≥18 years, up to 6 months after the second dose. Methods: This was a randomised, active-controlled, observer-blinded, parallel group, phase 3 study, conducted at 38 sites across six countries (South Korea, Philippines, Thailand, Vietnam, Ukraine and New Zealand). Cohort 1 (no history of SARS-CoV-2 infection/COVID-19 vaccination) was randomised 2:1 to receive two doses of GBP510/AS03 or ChAdOx1-S (immunogenicity and safety), while Cohort 2 (regardless of baseline serostatus) was randomised 5:1 (safety). Primary objectives were to demonstrate superiority in geometric mean titre (GMT) and non-inferiority in seroconversion rate (SCR; ≥4-fold rise from baseline) of GBP510/AS03 vs. ChAdOx1-S for neutralising antibodies against the ancestral strain by live-virus neutralisation assay. Secondary objectives included assessment of safety and reactogenicity (long-term 6 months cut-off date: 09 August 2022). This study was registered on ClinicalTrials.gov (NCT05007951). Findings: Between 30 August 2021 and 11 January 2022, a total of 4913 participants were screened and 4036 participants (1956 in Cohort 1 and 2080 in Cohort 2) who met eligibility criteria were enrolled and randomised to receive 2 doses of GBP510/AS03 (n = 3039) or ChAdOx1-S (n = 997). Most participants were Southeast Asian (81.5%) and aged 18-64 years (94.7%). The primary objectives assessed in per-protocol set included 877 participants in GBP510/AS03 and 441 in ChAdOx1-S group: at 2 weeks after the second vaccination, the GMT ratio (GBP510/AS03/ChAdOx1-S) in per-protocol set was 2.93 (95% CI 2.63-3.27), demonstrating superiority (95% CI lower limit >1) of GBP510/AS03; the between-group SCR difference of 10.8% (95% CI 7.68-14.32) also satisfied the non-inferiority criterion (95% CI lower limit > -5%). Neutralizing antibody titres sustained higher for the GBP510/AS03 group compared to the ChAdOx1-S group through 6 months after the second vaccination. In Safety analysis (Cohort 1 & 2), the proportion of participants with adverse events (AEs) after any vaccination was higher with GBP510/AS03 vs. ChAdOx1-S for solicited local AEs (56.7% vs. 49.2%), but was similar for solicited systemic AEs (51.2% vs. 53.5%) and unsolicited AEs (13.3% vs. 14.6%) up to 28 days after the second vaccination. No safety concerns were identified during follow-up for 6 months after the second vaccination. Interpretation: Our interim findings suggested that GBP510/AS03 met the superiority criterion for neutralising antibodies and non-inferiority criterion for SCR compared with ChAdOx1-S, and showed a clinically acceptable safety profile. Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investments INV-010680 and INV-006462. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

Immune Response Kinetics Following a Third Heterologous BNT162b2 Booster Dose After Primary 2-Dose ChAdOx1 Vaccination in Relation to Omicron Breakthrough Infection: A Prospective Nationwide Cohort Study in South Korea.

Background: Immune responses to each vaccine must be investigated to establish effective vaccination strategies for the ongoing coronavirus disease (COVID-19) pandemic. We investigated the long-term kinetics of immune responses after heterologous booster vaccination in relation to Omicron breakthrough infection (BI). Methods: Our study included 373 healthcare workers who received primary ChAdOx1 vaccine doses and a third BNT162b2 vaccine dose. BIs that occurred after the third vaccine were investigated. Blood specimens were collected before and 3 months after the booster dose from participants without BI and 1, 4, and 6 months after BI from participants who experienced BI. Spike-specific binding and neutralizing antibody levels against the wild-type virus, Omicron BA.1, and Omicron BA.5, as well as cellular responses, were analyzed. Results: A total of 346 participants (82 in the no BI group; 192 in the BI group during the BA.1/BA.2 period; 72 in the BI group during the BA.5 period) were included in the analysis. Participants without BI exhibited the highest binding and neutralizing antibody concentrations and greatest cellular response 1 month after the third vaccination, which reached a nadir by the ninth month. Antibody and cellular responses in participants who experienced BI substantially increased postinfection. Neutralizing antibody titers in individuals who experienced BI during the BA.1/BA.2 period showed more robust increase against wild-type virus than against BA.1 and BA.5. Conclusions: Our findings provide evidence of antigenic imprinting in participants who received a heterologous booster vaccination, thereby serving as a foundation for further studies on the impact of BIs on immune responses.

Multiple heteroresistance to tigecycline and colistin in Acinetobacter baumannii isolates and its implications for combined antibiotic treatment.

BACKGROUND: We investigated the presence of heteroresistance against both tigecycline and colistin in Acinetobacter baumannii and then evaluated the effectiveness of combined antibiotic treatment given the existence of discrete tigecycline- and colistin-resistant subpopulations. METHODS: We performed population analysis profiling (PAP) to evaluate the degree of composite heteroresistance in A. baumannii isolates, with the extent of this resistance quantified using subsequent antibiotic susceptibility testing. We then evaluated the amino acid sequence of PmrBAC and the relative mRNA expression levels of pmrB. Finally, we investigated the combined antibiotic efficacy of tigecycline and colistin in multiple-heteroresistant isolates using dual PAP and in vitro time-killing assays. RESULTS: All tigecycline-heteroresistant A. baumannii isolates, with the exception of one colistin-resistant isolate, were also heteroresistant to colistin. Evaluations of the colistin-resistant subpopulations revealed amino acid alterations in PmrA and PmrB and increased expression of pmrB. All tigecycline-resistant subpopulations were susceptible to colistin, and all colistin-resistant subpopulations were susceptible to tigecycline. Dual PAP analysis using tigecycline and colistin showed no heteroresistance, and in vitro time-killing assays revealed that a combination of these two antibiotics effectively eliminated the bacterial cells. CONCLUSION: Our results suggest that multiple heteroresistance to tigecycline and colistin is highly prevalent among A. baumannii clinical isolates and that these resistant subpopulations exist independently in single multiple heteroresistant isolates. Therefore, our findings may explain the success of combined antibiotic therapies in these infections.

First Case of Pseudoclavibacter alba Bacteremia in a Patient with Cholangitis.

BACKGROUND: Pseudoclavibacter alba isolated from human urine in culture collection was introduced as a new species, but since then, no other reports on P. alba isolated from the environment or organisms have been published. We thus present the first case report of P. alba bacteremia. METHODS: An 85-year-old female patient was admitted with intermittent abdominal pain and chills that had persisted for one week. She was diagnosed cholangitis with common bile duct stones. RESULTS: Gram-positive bacteria were detected in her peripheral blood culture and identified Pseudoclavibacter species by matrix-assisted laser desorption-ionization-time of flight mass spectrometry. Pseudoclavibacter alba was identified by performing the 16S ribosomal RNA gene sequence. CONCLUSIONS: This is the first case report of P. alba bacteremia in a patient with cholangitis.

Carbapenem Use in the Last Days of Life: A Nationwide Korean Study.

The appropriate use of carbapenem is a critical concern for patient safety and public health, and is a national priority. We investigated the nationwide status of carbapenem prescription in patients within their last 14 days of life to guide judicious-use protocols from the previous study comprised of 1350 decedents. Carbapenem use was universally controlled through computerised authorisation system at all centres during the study period. Carbapenem prescribing patterns and their optimality were evaluated. A total of 1201 patients received antimicrobial agents within the last two weeks of their lives, of whom 533 (44.4%) received at least one carbapenem. The median carbapenem treatment duration was seven days. Of the 533 patients receiving carbapenems, 510 (95.7%) patients had microbiological samples drawn and 196 (36.8%) yielded carbapenem-resistant pathogens. A total of 200 (37.5%) patients were referred to infectious disease (ID) specialists. Of the 333 patients (62.5%) who did not have ID consultations, 194 (58.2%) were assessed as "not optimal", 79 (23.7%) required escalation, 100 (30.0%) required de-escalation, and 15 (4.5%) were discontinued. Notwithstanding the existing antibiotic restriction program system, carbapenems are commonly prescribed to patients in their last days of life.

Effectiveness of regdanvimab treatment for SARS-CoV-2 delta variant, which exhibited decreased in vitro activity: a nationwide real-world multicenter cohort study.

Background: Immune-evading severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are emerging continuously. The clinical effectiveness of monoclonal antibody agents that exhibit decreased in vitro activity against SARS-CoV-2 variants needs to be elucidated. Methods: A nationwide, multicenter, retrospective cohort study was designed to evaluate the effectiveness of regdanvimab, an anti-SARS-CoV-2 monoclonal antibody agent. Regdanvimab was prescribed in South Korea before and after the emergence of the delta variant, against which the in vitro activity of regdanvimab was decreased but present. Mild to moderate coronavirus 2019 (COVID-19) patients with risk factors for disease progression who were admitted within seven days of symptom onset were screened in four designated hospitals between December 2020 and September 2021. The primary outcomes, O2 requirements and progression to severe disease within 21 days of admission, were compared between the regdanvimab and supportive care groups, with a subgroup analysis of delta variant-confirmed patients. Results: A total of 2,214 mild to moderate COVID-19 patients were included, of whom 1,095 (49.5%) received regdanvimab treatment. In the analysis of the total cohort, significantly fewer patients in the regdanvimab group than the supportive care group required O2 support (18.4% vs. 27.1%, P < 0.001) and progressed to severe disease (4.0% vs. 8.0%, P < 0.001). In the multivariable analysis, regdanvimab was significantly associated with a decreased risk for O2 support (HR 0.677, 95% CI 0.561-0.816) and progression to severe disease (HR 0.489, 95% CI 0.337-0.709). Among the 939 delta-confirmed patients, O2 support (21.5% vs. 23.5%, P = 0.526) and progression to severe disease (4.2% vs. 7.3%, P = 0.055) did not differ significantly between the regdanvimab and supportive care groups. In the multivariable analyses, regdanvimab treatment was not significantly associated with a decreased risk for O2 support (HR 0.963, 95% CI 0.697-1.329) or progression to severe disease (HR 0.665, 95% CI 0.349-1.268) in delta-confirmed group. Conclusions: Regdanvimab treatment effectively reduced progression to severe disease in the overall study population, but did not show significant effectiveness in the delta-confirmed patients. The effectiveness of dose increment of monoclonal antibody agents should be evaluated for variant strains exhibiting reduced susceptibility.

Species identification, antibiotic resistance, and virulence in Enterobacter cloacae complex clinical isolates from South Korea.

This study aimed to identify the species of Enterobacter cloacae complex (ECC) isolates and compare the genotype, antibiotic resistance, and virulence among them. A total of 183 ECC isolates were collected from patients in eight hospitals in South Korea. Based on partial sequences of hsp60 and phylogenetic analysis, all ECC isolates were identified as nine species and six subspecies. Enterobacter hormaechei was the predominant species (47.0%), followed by Enterobacter kobei, Enterobacter asburiae, Enterobacter ludiwigii, and Enterobacter roggenkampii. Multilocus sequence typing analysis revealed that dissemination was not limited to a few clones, but E. hormaechei subsp. xiangfangensis, E. hormaechei subsp. steigerwaltii, and E. ludwigii formed large clonal complexes. Antibiotic resistance rates were different between the ECC species. In particular, E. asburiae, E. kobei, E. roggenkampii, and E. cloacae isolates were highly resistant to colistin, whereas most E. hormaechei and E. ludwigii isolates were susceptible to colistin. Virulence was evaluated through serum bactericidal assay and the Galleria mellonella larvae infection model. Consistency in the results between the serum resistance and the G. mellonella larvae infection assay was observed. Serum bactericidal assay showed that E. hormaechei, E. kobei, and E. ludwigii were significantly more virulent than E. asburiae and E. roggenkampii. In this study, we identified the predominant ECC species in South Korea and observed the differences in antibiotic resistance and virulence between the species. Our findings suggest that correct species identification, as well as continuous monitoring is crucial in clinical settings.