Emergence and Transmission of the High-Risk ST78 Clone of OXA-48-Producing Enterobacter hormaechei in a Single Hospital in Taiwan.

Carbapenem-resistant Enterobacter cloacae complex is a significant global healthcare threat, particularly carbapenemase-producing Enterobacter hormaechei (CPEH). From January 2017 to January 2021, twenty-two CPEH isolates from a regional teaching hospital in central Taiwan were identified with the carriage of carbapenemase genes blaKPC-2, blaIMP-8, and predominantly blaOXA-48. Over 80% of these CPEH strains clustered into the high-risk ST78 lineage, carrying a blaOXA-48 IncL plasmid (pOXA48-CREH), nearly identical to the endemic plasmid pOXA48-KP in ST11 Klebsiella pneumoniae. This OXA-48-producing ST78 lineage disseminated clonally from 2018 to 2021 and transferred pOXA48-CREH to ST66 and ST90 E. hormaechei. An IMP-8-producing ST78 strain harboring a blaIMP-8-carrying pIncHI2 plasmid appeared in 2018, and by late 2020, a KPC-2-producing ST78 strain was identified after acquiring a novel blaKPC-2-carrying IncFII plasmid. These findings suggest that the high-risk ST78 lineage of E. hormaechei has emerged as the primary driver behind the transmission of CPEH. ST78 has not only acquired various carbapenemase-gene-carrying plasmids but has also facilitated the transfer of pOXA48-CREH to other lineages. Continuous genomic surveillance and targeted interventions are urgently needed to control the spread of emerging CPEH clones in hospital settings.

A Phase 3, Randomized, Controlled Trial Evaluating the Efficacy and Safety of Ropeginterferon Alfa-2b in Patients with Moderate COVID-19.

INTRODUCTION: Ropeginterferon alfa-2b is a novel mono-pegylated proline-interferon. This clinical study aimed to evaluate its antiviral efficacy of ropeginterferon alfa-2b against SARS-CoV-2 infection. METHODS: This is a multicenter, randomized, open-label study. Adult patients with confirmed SARS-CoV-2 infection with initial cycle threshold (Ct) value < 30 and symptom onset within 4 days were enrolled. Eligible patients were randomized in a 2:1 ratio to receive a single 250-µg dose of ropeginterferon alfa-2b subcutaneously plus standard of care (SOC) or to receive SOC alone. The primary endpoint was the proportion of patients with a negative RT-PCR result for SARS-CoV-2 or discharged from the hospital before Day 8. Change in clinical status based on the World Health Organization (WHO) clinical progression scale and pulmonary infiltrations through chest radiograph were also evaluated. RESULTS: A total of 132 patients were enrolled and treated with study medication. Higher percentages of patients who achieved Ct ≥ 30 or were discharged from the hospital were observed on Day 8 and every other time point of assessment, i.e., Days 5, 11, 15, and 22, in the ropeginterferon alfa-2b group compared to the SOC alone group. However, the difference was statistically significant on Day 11 but not on Day 8. The primary endpoint was not met. The ropeginterferon alfa-2b group showed a higher improvement rate in lung infiltration on Day 5 (27.6% vs. 0.0%, p = 0.0087) and a higher improvement rate in WHO clinical progression scores on Day 8 (69.4% vs. 35.3%, p = 0.03) than those in the SOC group. No ropeginterferon alfa-2b-related serious adverse event was observed. CONCLUSION: Our data show that ropeginterferon alfa-2b with SOC shortened the duration of SARS-CoV-2 shedding compared with SOC alone. In addition, ropeginterferon alfa-2b as an additional therapy could be beneficial by improving lung infiltration.

Prediction by genetic MATS of 4CMenB vaccine strain coverage of invasive meningococcal serogroup B isolates circulating in Taiwan between 2003 and 2020.

Neisseria meningitidis serogroup B (NmB) strains have diverse antigens, necessitating methods for predicting meningococcal serogroup B (MenB) vaccine strain coverage. The genetic Meningococcal Antigen Typing System (gMATS), a correlate of MATS estimates, predicts strain coverage by the 4-component MenB (4CMenB) vaccine in cultivable and non-cultivable NmB isolates. In Taiwan, 134 invasive, disease-causing NmB isolates were collected in 2003-2020 (23.1%, 4.5%, 5.2%, 29.8%, and 37.3% from individuals aged ≤11 months, 12-23 months, 2-4 years, 5-29 years, and ≥30 years, respectively). NmB isolates were characterized by whole-genome sequencing and vaccine antigen genotyping, and 4CMenB strain coverage was predicted using gMATS. Analysis of phylogenetic relationships with 502 global NmB genomes showed that most isolates belonged to three global hyperinvasive clonal complexes: ST-4821 (27.6%), ST-32 (23.9%), and ST-41/44 (14.9%). Predicted strain coverage by gMATS was 62.7%, with 27.6% isolates covered, 2.2% not covered, and 66.4% unpredictable by gMATS. Age group coverage point estimates ranged from 42.9% (2-4 years) to 66.1% (≤11 months). Antigen coverage estimates and percentages predicted as covered/not covered were highly variable, with higher estimates for isolates with one or more gMATS-positive antigens than for isolates positive for one 4CMenB antigen. In conclusion, this first study on NmB strain coverage by 4CMenB in Taiwan shows 62.7% coverage by gMATS, with predictable coverage for 29.8% of isolates. These could be underestimated since the gMATS calculation does not consider synergistic mechanisms associated with simultaneous antibody binding to multiple targets elicited by multicomponent vaccines or the contributions of minor outer membrane vesicle vaccine components.IMPORTANCEMeningococcal diseases, caused by the bacterium Neisseria meningitidis (meningococcus), include meningitis and septicemia. Although rare, invasive meningococcal disease is often severe and can be fatal. Nearly all cases are caused by six meningococcal serogroups (types), including meningococcal serogroup B. Vaccines are available against meningococcal serogroup B, but the antigens targeted by these vaccines have highly variable genetic features and expression levels, so the effectiveness of vaccination may vary depending on the strains circulating in particular countries. It is therefore important to test meningococcal serogroup B strains isolated from specific populations to estimate the percentage of bacterial strains that a vaccine can protect against (vaccine strain coverage). Meningococcal isolates were collected in Taiwan between 2003 and 2020, of which 134 were identified as serogroup B. We did further investigations on these isolates, including using a method (called gMATS) to predict vaccine strain coverage by the 4-component meningococcal serogroup B vaccine (4CMenB).

Ribotypes and antimicrobial susceptibility profiles of clinical Clostridioides difficile isolates: A multicenter, laboratory-based surveillance in Taiwan, 2019-2021.

BACKGROUND: The clinical burden of Clostridioides difficile infections (CDIs) remains substantial globally. This study aimed to investigate the ribotypes (RTs) and antimicrobial susceptibility of C. difficile isolates collected in Taiwan. METHODS: C. difficile isolates were prospectively collected from four medical centers in Taiwan from 2019 to 2021. In a reference laboratory, in vitro susceptibility to clindamycin, moxifloxacin, metronidazole, vancomycin, fidaxomicin, and rifaximin were tested, and ribotyping was conducted to determine their genetic diversity. RESULTS: A total of 568 C. difficile isolates were included. Metronidazole resistance was not observed, and the susceptibility rate of vancomycin was 99.5 %. Clindamycin showed poor activity against these isolates, with a resistance rate of 74.8 %. Fidaxomicin exhibited potent activity and 97.4 % of isolates were inhibited at 0.25 µg/mL. Rifaximin MIC90 increased from 0.015 µg/mL in 2019 to 0.03 µg/mL in 2020 and 2021. Of 40 RTs identified, two predominant RTs were RT 078/126 (78, 14 %) and 014/020 (76, 13 %). RT 017, traditional harboring truncated tcdA, accounted for 3 % (20 isolates) and there was no isolate belonging to RT 027. The proportions of RT 078 increased from 11.2 % in 2019 to 17.1 % in 2021, and the predominance of RT 078/126 was more evident in central Taiwan. CONCLUSIONS: Vancomycin, fidaxomicin, and metronidazole remain in vitro effective against clinical C. difficile isolates in Taiwan. The reservoirs and genetic relatedness of two major RTs with zoonotic potentials, RT 078/126 and 014/020, warrant further investigations.

Distinct evolution of ST11 KL64 Klebsiella pneumoniae in Taiwan.

Carbapenem-resistant ST11_KL64 Klebsiella pneumoniae emerged as a significant public health concern in Taiwan, peaking between 2013 and 2015, with the majority of isolates exhibiting OXA-48 as the sole carbapenemase. In this study, we employed whole-genome sequencing to investigate the molecular underpinnings of ST11_KL64 isolates collected from 2013 to 2021. Phylogenomic analysis revealed a notable genetic divergence between the ST11_KL64 strains in Taiwan and those in China, suggesting an independent evolutionary trajectory. Our findings indicated that the ST11_KL64_Taiwan lineage originated from the ST11_KL64 lineage in Brazil, with recombination events leading to the integration of ICEKp11 and a 27-kb fragment at the tRNAASN sites, shaping its unique genomic landscape. To further elucidate this unique sublineage, we examined the plasmid contents. In contrast to ST11_KL64_Brazil strains, which predominantly carried blaKPC-2, ST11_KL64_Taiwan strains exhibited the acquisition of an epidemic blaOXA-48-carrying IncL plasmid. Additionally, ST11_KL64_Taiwan strains consistently harbored a multi-drug resistance IncC plasmid, along with a collection of gene clusters that conferred resistance to heavy metals and the phage shock protein system via various Inc-type plasmids. Although few, there were still rare ST11_KL64_Taiwan strains that have evolved into hypervirulent CRKP through the horizontal acquisition of pLVPK variants. Comprehensive characterization of the high-risk ST11_KL64 lineage in Taiwan not only sheds light on its epidemic success but also provides essential data for ongoing surveillance efforts aimed at tracking the spread and evolution of ST11_KL64 across different geographical regions. Understanding the molecular underpinnings of CRKP evolution is crucial for developing effective strategies to combat its emergence and dissemination.

National surveillance of antimicrobial susceptibilities to ceftaroline, dalbavancin, telavancin, tedizolid, eravacycline, omadacycline, and other comparator antibiotics, and genetic characteristics of bacteremic Staphylococcus aureus isolates in adults: Results from the Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART) program in 2020.

Methicillin-resistant Staphylococcus aureus (MRSA) causes invasive infections and is associated with community-acquired infections (CAIs) and hospital-associated infections (HAIs). In 2020, 315 S. aureus isolates, including 145 methicillin-susceptible S. aureus (MSSA) and 170 MRSA, mainly associated with bacteremia and mostly CAIs, were collected from 16 hospitals in different regions of Taiwan. Minimum inhibitory concentrations (MICs) were determined using the Sensititre™ complete automated AST system. Staphylococcal cassette chromosome mec (SCCmec) types were analysed using multiplex polymerase chain reaction. The median age of patients infected with MRSA was significantly higher than that of patients infected with MSSA (72.5 years vs. 67.0 years, P=0.027). MIC50/MIC90 values of eravacycline and omadacycline were 0.06/0.12, and 0.25/0.5, respectively. Of the MRSA isolates, 4.1% presented susceptible dose-dependence to ceftaroline, most of which (85.7%) were HAI- and Panton-Valentine leukocidin (PVL)-negative. Among the MRSA isolates, 7.1% were not susceptible to telavancin and tedizolid (mainly type IV, PVL-negative, and CAI), 0.6% were not susceptible to daptomycin (type III, PVL-negative, and HAI), and 1.8% were not susceptible to quinupristin/dalfopristin (three isolates were type III, IV, and VT, respectively, and all were PVL-negative), but all were susceptible to dalbavancin. In conclusion, patients with bacteremia caused by MRSA were older than those with bacteremia caused by MSSA, SCCmec type IV was more predominant in CAI than in HAI, and MRSA isolates not susceptible to novel anti-MRSA antimicrobials belonged to types II, III, or IV. Further studies that include comprehensive demographics and more detailed descriptions of other antimicrobial-resistant genes are urgently needed.

Geographic patterns of carbapenem-resistant, multi-drug-resistant and difficult-to-treat Acinetobacter baumannii in the Asia-Pacific region: results from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2020.

This study evaluated the in-vitro activity of multiple classes of antibiotics, including novel ß-lactam combination agents, tigecycline and colistin, against carbapenem-resistant (CRAB), multi-drug-resistant (MDRAB) and difficult-to-treat (DTRAB) Acinetobacter baumannii. Minimum inhibitory concentrations (MICs) were determined using the broth microdilution method. Susceptibility profiles and the distribution of selected antimicrobials among countries were illustrated and examined based on the breakpoints of the Clinical and Laboratory Standards Institute, European Committee on Antimicrobial Susceptibility Testing and the US Food and Drug Administration. In total, 847 A. baumannii isolates were evaluated, and 692 isolates were characterized as CRAB, MDRAB or DTRAB. The prevalence of drug-resistant A. baumannii was >70.0% in South Korea, India and China, while the resistance rate of tigecycline was <5.5%. The MICs of meropenem and meropenem/vaborbactam for drug-resistant A. baumannii were equal (both MIC50 and MIC90 were 32 mg/L, range 0.25-32 mg/L). The overall resistance rate remained high for multiple classes of antibiotics, including penicillins, cephalosporins, carbapenems, quinolones and aminoglycosides (>84.0%, >96.0%, >98.0%, >88.0% and >87.0%, respectively), but not colistin or tigecycline (1.1% and 4.3%, respectively). China showed the lowest susceptibility to tigecycline for drug-resistant A. baumannii isolates compared with other countries. In conclusion, the resistance rate of drug-resistant A. baumannii remains high against multiple classes of antimicrobials. Colistin was the most potent agent, followed by tigecycline. The geographic pattern of tigecycline-resistant A. baumannii varied among countries. Therefore, continuous surveillance of A. baumannii resistance profiles in different regions is required.

Mesenchymal stem cell therapy on top of triple therapy with remdesivir, dexamethasone, and tocilizumab improves PaO2/FiO2 in severe COVID-19 pneumonia.

Background: Despite patients with severe coronavirus disease (COVID-19) receiving standard triple therapy, including steroids, antiviral agents, and anticytokine therapy, health condition of certain patients continue to deteriorate. In Taiwan, the COVID-19 mortality has been high since the emergence of previous variants of this disease (such as alpha, beta, or delta). We aimed to evaluate whether adjunctive infusion of human umbilical cord mesenchymal stem cells (MSCs) (hUC-MSCs) on top of dexamethasone, remdesivir, and tocilizumab improves pulmonary oxygenation and suppresses inflammatory cytokines in patients with severe COVID-19. Methods: Hospitalized patients with severe or critical COVID-19 pneumonia under standard triple therapy were separated into adjuvant hUC-MSC and non-hUC-MSC groups to compare the changes in the arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio and biological variables. Results: Four out of eight patients with severe or critical COVID-19 received either one (n = 2) or two (n = 2) doses of intravenous infusions of hUC-MSCs using a uniform cell dose of 1.0 × 108. Both high-sensitivity C-reactive protein (hs-CRP) level and monocyte distribution width (MDW) were significantly reduced, with a reduction in the levels of interleukin (IL)-6, IL-13, IL-12p70 and vascular endothelial growth factor following hUC-MSC transplantation. The PaO2/FiO2 ratio increased from 83.68 (64.34-126.75) to 227.50 (185.25-237.50) and then 349.56 (293.03-367.92) within 7 days after hUC-MSC infusion (P < 0.001), while the change of PaO2/FiO2 ratio was insignificant in non-hUC-MSC patients (admission day: 165.00 [102.50-237.61]; day 3: 100.00 [72.00-232.68]; day 7: 250.00 [71.00-251.43], P = 0.923). Conclusion: Transplantation of hUC-MSCs as adjunctive therapy improves pulmonary oxygenation in patients with severe or critical COVID-19. The beneficial effects of hUC-MSCs were presumably mediated by the mitigation of inflammatory cytokines, characterized by the reduction in both hs-CRP and MDW.

Microevolution of CG23-I Hypervirulent Klebsiella pneumoniae during Recurrent Infections in a Single Patient.

CG23-I lineage constitutes the majority of hypervirulent Klebsiella pneumoniae. A diabetic patient suffered six episodes of infections caused by CG23-I K. pneumoniae. A total of nine isolates were collected in 2020. We performed whole-genome sequencing to elucidate the within-patient evolution of CG23-I K. pneumoniae. The maximum pairwise difference among the nine longitudinally collected isolates was five single nucleotide polymorphisms. One of the mutations was at the Asp87 position of GyrA. Four indels were identified, including an initiator tRNAfMet duplication, a tRNAArg deletion, a 7-bp insertion, and a 22-bp deletion. All 9 isolates had the genomic features of CG23-I K. pneumoniae, a chromosome-borne ICEKp10, and a large virulence plasmid. The carriage of a complete set of genes for the biosynthesis of colibactin by ICEKp10 gave the nine isolates an ability to cause DNA damage to RAW264.7 cells. Compared with the initial isolate, the last isolate with an additional copy of initiator tRNAfMet grew faster in a nutrient-limiting condition and exhibited enhanced virulence in BALB/c mice. Collectively, we characterized the within-patient microevolution of CG23-I K. pneumoniae through an in-depth comparison of genome sequences. Using the in vitro experiments and mouse models, we also demonstrated that these genomic alterations endowed the isolates with advantages to pass through in vivo selection. IMPORTANCE CG23-I is a significant lineage of hypervirulent Klebsiella pneumoniae. This study characterizes the within-patient microevolution of CG23-I K. pneumoniae. Selective pressures from continuous use of antibiotics favored point mutations contributing to bacterial resistance to antibiotics. The duplication of an initiator tRNAfMet gene helped CG23-I K. pneumoniae proliferate to reach a maximal population size during infections. For longer persistence inside a human host, the large virulence plasmid evolved with more flexible control of replication through duplication of the iteron-1 region. With the genomic alterations, the last isolate had a growth advantage over the initial isolate and exhibited enhanced virulence in BALB/c mice. This study gives us a deeper understanding of the genome evolution during the within-patient pathoadaptation of CG23-I K. pneumoniae.

Definite therapy of mixed infection alleviates refractory dilemma of adult chronic suppurative otitis media.

The characteristics, risk factors, microbial distributions and effective treatment regimens for Chronic suppurative otitis media (CSOM) patients intractable to empirical therapy were analyzed. Adult CSOM patients of China Medical University Hospital from 2018 to 2020 were included. Subjects of refractory and non-refractory groups were investigated for characteristics of age, sex, nation, comorbidities, otomycosis, and associated complications. Risk factors, microbiology distributions, and treatment regimens were analyzed. Twenty-six refractory patients (55.0 ± 17.7 years) and 66 non-refractory patients (54.1 ± 13.7 years) were studied. A significantly higher rate of otomycosis and CSOM complications was observed in refractory group than in non-refractory one (73.1% vs. 36.4%; p = 0.002; 57.7% vs. 10.6%, p < 0.001, respectively). Multivariate analysis revealed atopic diathesis (p = 0.048), otomycosis (p = 0.003) and CSOM complications (p < 0.001) were risk factors of refractory CSOM. Coagulase-negative staphylococci (CoNS) and methicillin-resistant Staphylococcus aureus (MRSA) were the prevailing pathogens. Patients of refractory group tented to have higher rates of mixed infection (42.9%% vs. 23.7%) and significantly more included fungal pathogen (19.0% vs. 2.6%; p = 0.049) than those of non-refractory cohort. Topical treatment of fungus significantly improved outcome of refractory CSOM. Atopic diathesis, otomycosis, and CSOM-associated complications were risk factors of refractory CSOM. Systemic and local treatment to possible drug-resistant pathogens, likely CoNS and fungus, possible improves recalcitrant CSOM. Correspondingly, early identification of CSOM complications, routine culture and susceptibility testing and treatment of resistant bacteria and fungus are key elements to the successful management of adult CSOM.

Demographic Features of Invasive Meningococcal Disease in Taiwan, 1993 to 2020, and Genetic Characteristics of Neisseria meningitidis Isolates, 2003 to 2020.

We present the demographic features of invasive meningococcal disease (IMD) in Taiwan between 1993 and 2020 and the genetic characteristics of Neisseria meningitidis isolates recovered from 2003 to 2020. IMD was rare in Taiwan between 1993 and 2020, with an annual incidence ranging from 0.009 to 0.204 per 100,000 people. The case fatality rate (CFR) declined from 18.1% for patients in 1993 to 2002 to 9.8% in 2003 to 2020. Infants less than 12 months were most susceptible to the disease. N. meningitidis serogroup B (NmB) was most predominant, responsible for 81.2% (134/165) of the IMD cases in 2003 to 2020. The majority of the isolates recovered from 2003 to 2020 belonged to 4 worldwide-spread hyperinvasive clonal complexes (cc), cc4821 (30.3%), cc32 (19.4%), cc41/44 (12.7%), cc23 (7.3%), and also a newly assigned clonal complex, cc3439 (10.3%). Core genome multilocus sequence typing (cgMLST) profile comparisons revealed that the cc4821 isolates with a T-to-I substitution at position 91 in gyrA were closely related to those originating from China. Of the 165 isolates, 20.0% and 53.3% were predicted to be covered by the Bexsero and Trumenba vaccines, respectively, whereas, 77.0% and 46.7% remained indeterminate. In conclusion, N. meningitidis isolates recovered in Taiwan between 2003 and 2020 were mostly highly diverse. Most IMD cases appeared sporadically and were caused by localized strains, although some patients were infected by recently introduced strains. cgMLST is a powerful tool for the rapid comparison of genetic relatedness among a large number of isolates. cgMLST profiling, based on 1,241 core genes, and strain tracking can be performed on the website of cgMLST@Taiwan (http://rdvd.cdc.gov.tw/cgMLST/). IMPORTANCE N. meningitidis can cause life-threatening invasive meningococcal disease (IMD), including meningitis and sepsis, resulting in a high CFR and long-term sequelae in survivors. Here, we report the demographic features of IMD in Taiwan over a 28-year period (1993 to 2020) and the genetic characteristics of N. meningitidis isolates recovered from patients with IMD over an 18-year period (2003 to 2020). We conducted a whole-genome sequence analysis to characterize the genetic features of the isolates and developed a cgMLST scheme for epidemiological investigation and strain tracking. The findings can be beneficial in understanding the epidemiology of IMD in Taiwan, the genetic characteristics of the bacterial strains, and the distribution of vaccine antigens for vaccine development and implementation.

Risk factors and prognoses of invasive Candida infection in surgical critical ill patients with perforated peptic ulcer.

BACKGROUND: The risk of invasive Candida infection (ICI) is high in patients with perforated peptic ulcer (PPU) who received laparotomy or laparoscopic surgery, but the risk factors and predictors of morbidity outcomes remain uncertain. This study aims to identify the risk factors of ICI in surgical critically ill PPU patients and to evaluate the impact on patient's outcomes. METHODS: This is a single-center, retrospective study, with a total of 170 surgical critically ill PPU patients. Thirty-seven patients were ICI present and 133 were ICI absent subjects. The differences in pulmonary complications according to invasive candidiasis were determined by the Mann-Whitney U test. Evaluation of predictors contributing to ICI and 90-day mortality was conducted by using multivariate logistic regression analysis. RESULTS: Candida albicans was the primary pathogen of ICI (74.29%). The infected patients had higher incidence of bacteremia (p < 0.001), longer intensive care unit (p < 0.001) and hospital (p < 0.001) stay, longer ventilator duration (p < 0.001) and increased hospital mortality (p = 0.02). In the multivariate analysis, serum lactate level measured at hospital admission was independently associated with the occurrence of ICI (p = 0.03). Liver cirrhosis (p = 0.03) and Sequential Organ Failure Assessment (SOFA) score (p = 0.007) were independently associated with the 90-day mortality. CONCLUSIONS: Blood lactate level measured at hospital admission could be a predictor of ICI and the surgical critically ill PPU patients with liver cirrhosis and higher SOFA score are associated with poor outcomes.

A nosocomial salmonellosis outbreak caused by blaOXA-48-carrying, extensively drug-resistant Salmonella enterica serovar Goldcoast in a hospital respiratory care ward in Taiwan.

OBJECTIVES: A nosocomial salmonellosis outbreak caused by Salmonella enterica serovar Goldcoast occurred in a respiratory care ward (RCW) of a hospital in central Taiwan between December 24, 2020, and January 21, 2021. Ten isolates recovered from 10 RCW residents were resistant to extended-spectrum cephalosporins. The resistance mechanism needs to be investigated. METHODS: Whole-genome sequencing and antimicrobial susceptibility testing were conducted to determine the genetic resistance determinants and the phenotypic resistance in the isolates. RESULTS: Each of the 10 outbreak isolates harbored an IncHI2 plasmid that carried 15 antimicrobial resistance genes aac(3)-IId, aadA22, aph(3')-Ia, aph(6)-Id, arr-2, blaCTX-M-55, blaLAP-2, blaTEM-1, dfrA14, floR, lnu(F), qnrS13, sul2, sul3, tet(A), an efflux pump regulatory gene ramAp and an IncL plasmid carried a blaOXA-48. The outbreak strains were expected to be resistant to numerous antimicrobials, including aminoglycosides, b-lactams /inhibitors, tetracycline, rifamycin, lincosamide, sulfonamides, trimethoprim, phenicols, fluoroquinolones, and carbapenems. Two outbreak isolates displayed higher minimum inhibitory concentrations than the other eight isolates to cefmetazole and carbapenems, which was linked to a deficiency of a major facilitator superfamily transporter in the two isolates. CONCLUSION: The carbapenem-resistant outbreak strains could have been derived from extensively drug-resistant S. enterica Goldcoast strains, which have been a major pathogen in Taiwan since 2018, through the acquisition of a blaOXA-48-carrying plasmid. Special efforts are needed in Taiwan to monitor the spread of extremely resistant strains.

Immunogenicity and safety of homologous and heterologous ChAdOx1-S and mRNA-1273 vaccinations in healthy adults in Taiwan.

BACKGROUND: In Taiwan, the vaccination program started in March 2021, with ChAdOx1-S being the first available WHO-approved COVID-19 vaccine, followed by Moderna vaccine. This study aimed to investigate the immunogenicity and safety of homologous and heterologous prime-boost regimens with ChAdOx1-S and mRNA-1273. METHODS: From March to November 2021, homologous or heterologous regimens with ChAdOx1-S and mRNA-1273 vaccination (ChAdOx1-S/ChAdOx1-S, mRNA-1273/mRNA-1273, ChAdOx1-S/mRNA-1273) were given to 945 healthy participants. Serum samples were collected at designated time points. The anti-RBD/S1 antibody titers and neutralizing ability were measured by three different immunoassays: Elecsys® Anti-SARS-CoV-2 S (Roche Diagnostics, Mannheim, Germany), AdviseDx SARS-CoV-2 IgG II (Abbott Diagnostics Division, Sligo, Ireland), and cPass™ SARS-CoV-2 Neutralization Antibody Detection Kit (GenScript, New Jersey, USA). RESULTS: We found that heterologous vaccination with ChAdOx1-S/mRNA-1273 had an acceptable safety profile and induced higher total anti-RBD/S1 antibody production (p < 0.0001), yet lower anti-RBD/S1 IgG titer (p < 0.0001) and neutralizing ability (p = 0.0101) than mRNA-1273/mRNA-1273 group. Both regimens showed higher antibody titers and superior neutralizing abilities than ChAdOx1-S/ChAdOx1-S. An age-dependent antibody response to ChAdOx1-S/mRNA-1273 was shown after both the priming and the booster doses. Younger age was associated with higher antibody production and neutralizing ability. CONCLUSIONS: Heterologous ChAdOx1-S/mRNA-1273 vaccination regimen is generally safe and induces a robust humoral immune response that is non-inferior to that of mRNA-1273/mRNA-1273.

Non-susceptibilities to antibiotics against important Gram-negative bacteria, and imipenem-relebactam, meropenem-vaborbactam against carbapenem non-susceptible Enterobacterales and Pseudomonas aeruginosa isolates implicated in complicated intra-abdominal and urinary tract infections in Taiwan, 2019.

INTRODUCTION: Susceptibility of isolates of top-ranking Enterobacterales species and Pseudomonas aeruginosa implicated in complicated intra-abdominal infections (cIAI) and urinary tract infections (cUTI) to important antibiotics, including imipenem-relebactam (IMR) and meropenem-vaborbactam (MVB), in Taiwan in 2019 were evaluated. METHODS: MICs to various antibiotics were determined using broth microdilution method. Susceptibility results were interpreted mainly based on the MIC breakpoints of the Clinical and Laboratory Standards Institute (CLSI) 2021, but susceptibilities of IMR and MVB were interpreted based on the CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2021. Resistance genes amongst carbapenem-non-susceptible (NS) Gram-negative bacteria (GNB) were investigated using multiplex polymerase chain reaction (PCR). Escherichia coli (n = 356), Klebsiella pneumoniae (n = 165) and Enterobacter cloacae complex (n = 42) isolates accounted for 85.3% of the 660 Enterobacterales isolates. RESULTS: The non-susceptibility rates of imipenem (IPM), IMR against isolates of non-Morganellaceae Enterobacterales, and meropenem (MEM), MVB against all Enterobacterales isolates were 92.2%/94.8%, 98.4-98.7%/98.4-99%, 95%/98.2% and 98.8-100%/99.4-100% for the cIAI/cUTI subgroups, respectively. Amongst the 40 IPM-NS-non-Morganellaceae Enterobacterales isolates, when the CLSI 2021 criteria were applied, 10 were NS to IMR, and four Klebsiella pneumoniae isolates (harbouring blaKPC but neither blaMBL nor blaOXA-48-like genes) were NS to IMR and MVB. Amongst the 93 Pseudomonas aeruginosa isolates under evaluation, the addition of relebactam (4 mg/L) resulted in a 4-to-16-fold reduction in the MICs of IPM in all 15 IPM-NS-Pseudomonas aeruginosa isolates (including 10 porin-deficient ones) not harbouring blaMBL/blaOXA-48-like genes. Contrastingly, the addition of vaborbactam (8 mg/L) improved the non-susceptibility to MEM in one (20%) of five IPM/MEM-NS Pseudomonas aeruginosa isolates. CONCLUSION: Continuous monitoring of susceptibility to clinically important GNB is warranted.

In vitro activity of cefiderocol, cefepime/enmetazobactam, cefepime/zidebactam, eravacycline, omadacycline, and other comparative agents against carbapenem-non-susceptible Pseudomonas aeruginosa and Acinetobacter baumannii isolates associated from bloodstream infection in Taiwan between 2018-2020.

BACKGROUND/PURPOSE: This study aimed to investigate the in vitro susceptibilities of carbapenem-non-susceptible Pseudomonas aeruginosa (CNSPA) and Acinetobacter baumannii (CNSAB) isolates to cefiderocol, novel ß-lactamase inhibitor (BLI) combinations, new tetracycline analogues, and other comparative antibiotics. METHODS: In total, 405 non-duplicate bacteremic CNSPA (n = 150) and CNSAB (n = 255) isolates were collected from 16 hospitals in Taiwan between 2018 and 2020. Minimum inhibitory concentrations (MICs) were determined using the broth microdilution method, and susceptibilities were interpreted according to the relevant guidelines or in accordance with results of previous studies and non-species-related pharmacokinetic/pharmacodynamic data. RESULTS: Among the isolates tested, cefiderocol demonstrated potent in vitro activity against CNSPA (MIC50/90, 0.25/1 mg/L; 100% of isolates were inhibited at ≤4 mg/L) and CNSAB (MIC50/90, 0.5/2 mg/L; 94.9% of isolates were inhibited at ≤4 mg/L) isolates. More than 80% of CNSPA isolates were susceptible to cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, and amikacin, based on breakpoints established by the Clinical and Laboratory Standards Institute. Activities of new BLI combinations varied significantly. Tetracycline analogues, including tigecycline (MIC50/90, 1/2 mg/L; 92.5% of CNSAB isolates were inhibited at ≤2 mg/L) and eravacycline (MIC50/90, 0.5/1 mg/L; 99.6% of CNSAB isolates were inhibited at ≤2 mg/L) exhibited more potent in vitro activity against CNSAB than omadacycline (MIC50/90, 4/8 mg/L). CONCLUSIONS: The spread of CNSPA and CNSAB poses a major challenge to global health. Significant resistance be developed even before a novel agent becomes commercially available. The development of on-site antimicrobial susceptibility tests for these novel agents is of great clinical importance.

Multicenter surveillance of antimicrobial susceptibilities and resistance mechanisms among Enterobacterales species and non-fermenting Gram-negative bacteria from different infection sources in Taiwan from 2016 to 2018.

OBJECTIVES: To explore the in vitro antimicrobial susceptibility among clinically important Gram-negative bacteria (GNB) in Taiwan. METHODS: From 2016 through 2018, a total of 5458 GNB isolates, including Escherichia coli (n = 1545), Klebsiella pneumoniae (n = 1255), Enterobacter species (n = 259), Pseudomonas aeruginosa (n = 1127), Acinetobacter baumannii complex (n = 368), and Stenotrophomonas maltophilia (n = 179), were collected. The susceptibility results were summarized by the breakpoints of minimum inhibitory concentration (MIC) of CLSI 2020, EUCAST 2020 (for colistin), or published articles (for ceftolozane/tazobactam). The resistance genes among multidrug-resistant (MDR) or extensively drug-resistant (XDR)-GNB were investigated by multiplex PCR. RESULTS: Significantly higher rates of non-susceptibility (NS) to ertapenem and carbapenemase production, predominantly KPC and OXA-48-like beta-lactamase, were observed in Enterobacterales isolates causing respiratory tract infection than those causing complicated urinary tract or intra-abdominal infection (12.7%/3.44% vs. 5.7%/0.76% or 7.7%/0.97%, respectively). Isolates of Enterobacter species showed higher rates of phenotypic extended-spectrum ß-lactamase and NS to ertapenem than E. coli or K. pneumoniae isolates. Although moderate activity (54-83%) was observed against most potential AmpC-producing Enterobacterales isolates, ceftolozane/tazobactam exhibited poor in vitro (44.7-47.4%) activity against phenotypic AmpC Enterobacter cloacae isolates. Additionally, 251 (22.3%) P. aeruginosa isolates exhibited the carbapenem-NS phenotype, and their MDR and XDR rate was 63.3% and 33.5%, respectively. Fifteen (75%) of twenty Burkholderia cenocepacia complex isolates were inhibited by ceftolozane/tazobactam at MICs of ≤4 µg/mL. CONCLUSIONS: With the increase in antibiotic resistance in Taiwan, it is imperative to periodically monitor the susceptibility profiles of clinically important GNB.

Molecular diagnosis and therapy for Plasmodium ovale infection of a returned traveler from East Africa.

Malaria is an infectious disease caused by Plasmodium parasites that are mainly transmitted through the bites of infected female Anopheles mosquitoes. The average annual number of malaria cases was less than ten in Taiwan in the last five years. Most of the cases were caused by Plasmodium vivax and Plasmodium falciparum, and were primarily diagnosed in travelers who returned from Southeast Asia and Africa. Here, we report the first case of Plasmodium ovale infection within five years that was confirmed by peripheral blood smear examination and molecular identification in a 25-year-old Asian female patient who returned from Uganda.

Multicenter surveillance of in vitro activities of cefepime-zidebactam, cefepime-enmetazobactam, omadacycline, eravacycline, and comparator antibiotics against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii complex causing bloodstream infection in Taiwan, 2020.

OBJECTIVES: To determine the in vitro activities of novel and comparator antibiotics against Gram-negative bacteria (GNB) in Taiwan. METHODS: Isolates of Escherichia coli (n = 335), Klebsiella pneumoniae (n = 316; 144 isolates with hyperviscosity characteristics), Pseudomonas aeruginosa (n = 271), Acinetobacter baumannii complex (n = 187), and non-typhoidal Salmonella species (n = 226), Shigella species (n = 13) from miscellaneous culture sources were collected in 2020 in Taiwan. The MICs of the isolates to test antibiotics were determined using the broth microdilution method. GeneXpert was used to detect genes encoding carbapenemases among the carbapenem-non-susceptible (NS) Enterobacterales isolates. RESULTS: The MIC values of the cefepime-enmetazobactam combination against extended-spectrum ß-lactamase-producing E. coli and K. pneumoniae isolates (MIC90 ≤ 0.5 mg/L), blaKPC-harboring E. coli isolates (0.25 mg/L; n = 2), and 80% of blaOXA-48-like gene-harboring K. pneumoniae isolates (≤2 mg/L) were low. The MIC ranges of the cefepime-zidebactam against carbapenemase-producing Enterobacterales isolates (irrespective of the carbapenemase type [MIC90 ≤ 4 mg/L]) and carbapenem-NS or ceftolozane-tazobactam-NS P. aeruginosa isolates (MIC90 value, 8 mg/L) were significantly lower than those of the cefepime-enmetazobactam. CONCLUSIONS: The efficacy of novel antibiotics against important drug-resistant GNB must be monitored and validated during the clinical treatment of patients.

Bacteriophages and phage-delivered CRISPR-Cas system as antibacterial therapy.

Multidrug-resistant (MDR) bacterial infections in humans are increasing worldwide. The global spread of antimicrobial resistance poses a considerable threat to human health. Phage therapy is a promising approach to combat MDR bacteria. An increasing number of reports have been published on phage therapy and the successful application of antibacterials derived using this method. Additionally, the CRISPR-Cas system has been used to develop antimicrobials with bactericidal effects in vivo. The CRISPR-Cas system can be delivered into target bacteria in various ways, with phage-based vectors being reported as an effective method. In this review, we briefly summarise the results of randomised control trials on bacteriophage therapy. Moreover, we integrated mechanisms of the CRISPR-Cas system antimicrobials in a schematic diagram and consolidated the research on phage-delivered CRISPR-Cas system antimicrobials.