Layer-by-layer assembly of quercetin-loaded zein/γPGA/low-molecular-weight chitosan/fucoidan nanosystem for targeting inflamed blood vessels.

Chitosan acts as a versatile carrier in polymeric nanoparticle (NP) for diverse drug administration routes. Delivery of antioxidants, such as quercetin (Qu) showcases potent antioxidant and anti-inflammatory properties for reduction of various cardiovascular diseases, but low water solubility limits uptake. To address this, we developed a novel layer-by-layer zein/gamma-polyglutamic acid (γPGA)/low-molecular-weight chitosan (LC)/fucoidan NP for encapsulating Qu and targeting inflamed vessel endothelial cells. We used zein (Z) and γPGA (r) to encapsulate Qu (Qu-Zr NP) exhibited notably higher encapsulation efficiency compared to zein alone. Qu-Zr NP coated with LC (Qu-ZrLC2 NP) shows a lower particle size (193.2 ± 2.9 nm), and a higher zeta potential value (35.2 ± 0.4 mV) by zeta potential and transmission electron microscopy analysis. After coating Qu-ZrLC2 NP with fucoidan, Qu-ZrLC2Fa NP presented particle size (225.16 ± 0.92 nm), zeta potential (-25.66 ± 0.51 mV) and maintained antioxidant activity. Further analysis revealed that Qu-ZrLC2Fa NP were targeted and taken up by HUVEC cells and EA.hy926 endothelial cells. Notably, we observed Qu-ZrLC2Fa NP targeting zebrafish vessels and isoproterenol-induced inflamed vessels of rat. Our layer-by-layer formulated zein/γPGA/LC/fucoidan NP show promise as a targeted delivery system for water-insoluble drugs. Qu-ZrLC2Fa NP exhibit potential as an anti-inflammatory therapeutic for blood vessels.

Epidemiology and antimicrobial susceptibility profiles of Enterobacterales causing bloodstream infections before and during COVID-19 pandemic: Results of the Study for Monitoring Antimicrobial Resistance Trends (SMART) in Taiwan, 2018-2021.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has contributed to the spread of antimicrobial resistance, including carbapenem-resistant Enterobacterales. METHODS: This study utilized data from the Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program in Taiwan. Enterobacterales from patients with bloodstream infections (BSIs) were collected and subjected to antimicrobial susceptibility testing and ß-lactamase gene detection using a multiplex PCR assay. Statistical analysis was conducted to compare susceptibility rates and resistance genes between time periods before (2018-2019) and during the COVID-19 pandemic (2020-2021). RESULTS: A total of 1231 Enterobacterales isolates were collected, predominantly Escherichia coli (55.6%) and Klebsiella pneumoniae (29.2%). The proportion of nosocomial BSIs increased during the COVID-19 pandemic (55.5% vs. 61.7%, p < 0.05). Overall, susceptibility rates for most antimicrobial agents decreased, with Enterobacterales from nosocomial BSIs showing significantly lower susceptibility rates than those from community-acquired BSIs. Among 123 Enterobacterales isolates that underwent molecular resistance mechanism detection, ESBL, AmpC ß-lactamase, and carbapenemase genes were detected in 43.1%, 48.8% and 16.3% of the tested isolates, respectively. The prevalence of carbapenemase genes among carbapenem-resistant Enterobacterales increased during the pandemic, although the difference was not statistically significant. Two novel ß-lactamase inhibitor combinations, imipenem-relebactam and meropenem-vaborbactam, preserved good efficacy against Enterobacterales. However, imipenem-relebactam showed lower in vitro activity against imipenem-non-susceptible Enterobacterales than that of meropenem-vaborbactam. CONCLUSIONS: The COVID-19 pandemic appears to be associated with a general decrease in antimicrobial susceptibility rates among Enterobacterales causing BSIs in Taiwan. Continuous surveillance is crucial to monitor antimicrobial resistance during the pandemic and in the future.

Comparative Analysis of Two Commercial Automated Systems with Agar Dilution for Oxacillin Susceptibility and Their Association with Genotypes of Invasive Staphylococcus aureus Isolates (2011-2021).

Background: Determining oxacillin susceptibility using reference methods and automated systems is crucial for treating invasive infections caused by Staphylococcus aureus. This study compares the oxacillin susceptibility results from the two automated systems with agar dilution and correlates them with genotypes of invasive S. aureus. Methods: Non-duplicate S. aureus invasive isolates were collected over an 11-year period. The oxacillin susceptibility was determined with Phoenix 100 (Jan 2011 to Aug 2018) or Vitek 2 (Sep 2018 to Dec 2021), and susceptibility for oxacillin and cefoxitin was determined with agar dilution. Methicillin-resistant S. aureus (MRSA) was confirmed with mecA existence, and the genotype was determined using SCCmec. The association between genotype and antibiotic susceptibility using two automated systems and agar dilution was evaluated. Results: A total of 842 invasive S. aureus, including 443 mecA+ MRSA and 399 mecA- MSSA, were collected. The susceptibility rates of oxacillin determined by two automated systems and agar dilution were 68.8% (76.8% for Phoenix 100 and 57.6% for Vitek 2) and 54.0%, respectively. When compared with the oxacillin susceptibility using agar dilution, the categorical agreement for Phoenix 100 and Vitek 2 were 0.46% and 0.88%, respectively (p < 0.001). One hundred and forty-three isolates were misinterpreted as oxacillin-susceptible S. aureus (OSSA) using automated systems while comparing with agar dilution, among which molecularly community-associated MRSA (CA-MRSA) outnumbered healthcare-associated MRSA (HA-MRSA) (99 vs 34, p < 0.001). There were 70 mecA+ OSSA (OS-MRSA) using agar dilution, among which 42 harbored SCCmec types were predominantly categorized as CA-MRSA (38, p < 0.001). Conclusion: The categorical agreement of Vitek 2 in determining oxacillin susceptibility and predicting mecA existence is comparable with agar dilution, whereas Phoenix 100 is not. Most of those ORSA determined by agar dilution but misinterpreted as OSSA by automated systems and OS-MRSA are categorized as CA-MRSA.

Revealing polygenic pleiotropy using genetic risk scores for asthma.

In this study we examined how genetic risk for asthma associates with different features of the disease and with other medical conditions and traits. Using summary statistics from two multi-ancestry genome-wide association studies of asthma, we modeled polygenic risk scores (PRSs) and validated their predictive performance in the UK Biobank. We then performed phenome-wide association studies of the asthma PRSs with 371 heritable traits in the UK Biobank. We identified 228 total significant associations across a variety of organ systems, including associations that varied by PRS model, sex, age of asthma onset, ancestry, and human leukocyte antigen region alleles. Our results highlight pervasive pleiotropy between asthma and numerous other traits and conditions and elucidate pathways that contribute to asthma and its comorbidities.

Emerging infections in vulnerable hosts: Stenotrophomonas maltophilia and Elizabethkingia anophelis.

PURPOSE OF REVIEW: This systematic review aimed to explore the recent trends in the epidemiology, risk factors, and antimicrobial susceptibility of two emerging opportunistic pathogens, Stenotrophomonas maltophilia and Elizabethkingia anophelis . RECENT FINDINGS: Since 2020, numerous outbreaks of S. maltophilia and E. anophelis have been reported worldwide. Most of these outbreaks have been associated with healthcare facilities, although one outbreak caused by E. anophelis in France was considered a community-associated infection. In terms of antimicrobial susceptibility, trimethoprim/sulfamethoxazole (TMP-SMZ), levofloxacin, and minocycline have exhibited good efficacy against S. maltophilia . Additionally, cefiderocol and a combination of aztreonam and avibactam have shown promising results in in vitro susceptibility testing. For E. anophelis , there is currently no consensus on the optimal treatment. Although some studies have reported good efficacy with rifampin, TMP-SMZ, piperacillin/tazobactam, and cefoperazone/sulbactam, minocycline had the most favourable in vitro susceptibility rates. Cefiderocol may serve as an alternative due to its low minimum inhibitory concentration (MIC) against E. anophelis . The role of vancomycin in treatment is still uncertain, although several successful cases with vancomycin treatment, even with high MIC values, have been reported. SUMMARY: Immunocompromised patients are particularly vulnerable to infections caused by S. maltophilia and E. anophelis , but the optimal treatment strategy remains inconclusive. Further research is necessary to determine the most effective use of conventional and novel antimicrobial agents in combatting these multidrug-resistant pathogens.

In vitro susceptibilities of Stenotrophomonas maltophilia isolates to antimicrobial agents commonly used for related infections: Results from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2004-2020.

Stenotrophomonas maltophilia is an emerging opportunistic pathogen for which there are limited therapeutic options because of intrinsic multidrug resistance. S. maltophilia isolates were collected as part of the Antimicrobial Testing Leadership and Surveillance (ATLAS) program and minimum inhibitory concentrations (MICs) were determined using broth microdilution methods. Susceptibility was interpreted according to Clinical and Laboratory Standards Institute (CLSI) breakpoints. Isolates with tigecycline MIC ≤2 mg/L were defined as susceptible, using the United States Food and Drug Administration criteria of Enterobacterales. A total of 2330 S. maltophilia isolates were collected from 47 countries worldwide in the ATLAS program from 2004 to 2020. Most patients were hospitalized (92.3%, 2151/2330) and respiratory tract infections (47.8%, 1114/2330) were the most common source of isolates. Minocycline had the highest susceptibility rate (98.8%), followed by levofloxacin (85.0%), trimethoprim-sulfamethoxazole (TMP-SMX) (84.4%), and ceftazidime (53.7%). A total of 98.3% (2290/2330) of S. maltophilia isolates had tigecycline MIC ≤2 mg/L. Among the S. maltophilia isolates exhibiting resistance to levofloxacin and ceftazidime, 89.3% (150/168) and 97.3% (692/711), respectively, were susceptible to tigecycline. Eight countries provided more than 30 isolates and were selected for comparison. Geographical difference in antimicrobial resistance was significant for levofloxacin, minocycline, and tigecycline (all P<0.05) but not for ceftazidime (P=0.467). These in vitro data demonstrated that minocycline had a higher susceptibility rate than levofloxacin and ceftazidime, and that tigecycline could be an alternative or salvage option for the treatment of S. maltophilia infections.

A new collaborative care approach toward hepatitis C elimination in marginalized populations.

BACKGROUND: Treating marginalized populations with HCV infection for elimination is faced with the challenge for the integration of HCV screening service offered for patients often moving across multiple settings. We envisaged a novel collaborative care approach to identify to what extent HCV patients overlapped between and within these multiple institutions and reported the findings of treatment coverage of these marginalized populations after HCV care cascades. METHODS: We enrolled 7765 patients residing in the Changhua County, Taiwan offered with HCV screening from correctional institutions, HIV clinics, methadone clinics, and the existing HIV surveillance program (four subgroups including police-arrested people, probationers, non-injection drug user, and high-risk behavior people) between 2019 and 2020. The collaborative care and information were integrated through a teamwork of gastroenterologists, psychologists, infectious disease specialists, and nursing coordinators under the auspices of local health authority. RESULTS: The overall participation rate in HCV screening was 92.65% (7194/7765). The prevalence rate was the highest in methadone clinics (90.17%) followed by correctional institutions (37.67%), HIV clinics (34.60%), and the surveillance program (18.14%). We found 25.41% (77/303) of methadone clinic patients, 17.65% (129/731) of HIV clinic patients, and various proportions for 44.09% (41/93) of deferred prosecuted or probationers under surveillance program were also recruited into other settings. Individuals' patient flow within setting was more frequent than that between setting. After calibrating the overlap of patient flow, a total of 1700 anti-HCV positives out of 4074 after screening were traced with available follow-up information to complete 92.52% treatment coverage of 1177 RNA-positives (77.23%) diagnosed from 1524 undergoing RNA testing with similar findings across multiple settings. CONCLUSION: A new collaborative integrated care was adopted for elucidating patient flow between and within multiple settings in order to calibrate the accurate demand for HCV care cascades and enhance HCV treatment coverage in marginalized populations.

Caring for Each Other: A Resident-Led Peer Debriefing Skills Workshop.

Background: Inadequate time and space to process critical incidents contribute to burnout. Residents do not regularly participate in emotional debriefs. An institutional needs assessment revealed only 11% of surveyed pediatrics and combined medicine-pediatrics residents had participated in a debrief. Objective: The primary objective was to increase resident comfort in participation in peer debriefs after critical incidents from 30% to 50% with implementation of a resident-led peer debriefing skills workshop. Secondary objectives included increasing resident likelihood of leading debriefs and comfort in identifying symptoms of emotional distress. Methods: Internal medicine, pediatrics, and medicine-pediatrics residents were surveyed for baseline participation in debriefs and comfort in leading peer debriefs. Two senior residents became trained debrief facilitators and led a 50-minute peer debriefing skills workshop for co-residents. Pre- and post-workshop surveys assessed participant comfort in and likelihood of leading peer debriefs. Surveys distributed 6 months post-workshop assessed resident debrief participation. We implemented the Model for Improvement from 2019 to 2022. Results: Forty-six (77%) and 44 (73%) of the 60 participants completed the pre- and post-workshop surveys. Post-workshop, residents' reported comfort in leading debriefs increased from 30% to 91%. The likelihood of leading a debrief increased from 51% to 91%. Ninety-five percent (42 of 44) agreed that formal training in debriefing is beneficial. Almost 50% (24 of 52) of surveyed residents preferred to debrief with a peer. Six months post-workshop, 22% (15 of 68) of surveyed residents had led a peer debrief. Conclusions: Many residents prefer to debrief with a peer after critical incidents that cause emotional distress. Resident-led workshops can improve resident comfort in peer debriefing.

In vitro activities of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam and other comparators against Pseudomonas aeruginosa isolates with discrepant resistance to carbapenems: Data from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2012-2021.

OBJECTIVES: This study aimed to investigate the in vitro susceptibility and ß-lactamase-encoding genes of Pseudomonas aeruginosa (P. aeruginosa) isolates with discrepant resistance to various carbapenems. METHODS: Data on P. aeruginosa isolates were obtained from the Antimicrobial Testing Leadership and Surveillance program from 2012-2021. Minimum inhibitory concentrations of P. aeruginosa isolates were determined using the broth microdilution method. ß-lactamase-encoding genes were identified using multiplex polymerase chain reaction assays. RESULTS: Among the P. aeruginosa isolates that were tested, the percentages of isolates resistant to imipenem, meropenem and doripenem were 26.9% (14 447 of 53 617), 20.5% (14 098 of 68 897) and 17.5% (3660 of 20 946), respectively. Imipenem-resistant P. aeruginosa isolates were more susceptible to all tested antimicrobial agents (except colistin) than the meropenem-resistant or doripenem-resistant P. aeruginosa isolates. Carbapenemase genes were detected in 14.3% (2020 of 14 098) of meropenem-resistant P. aeruginosa isolates. Imipenem-resistant meropenem-susceptible P. aeruginosa isolates had higher susceptibility profiles, fewer carbapenemase genes (0.3% [five of 1858] vs. 4.1% [10 of 242]; P < 0.05) and a lower risk of being classified as multidrug-resistant than the imipenem-susceptible meropenem-resistant isolates (16.1% [299 of 1858] vs. 73.6% [178 of 242]; P < 0.05). Among all ß-lactam combination agents, ceftazidime-avibactam and ceftolozane-tazobactam had higher susceptibility rates than meropenem-vaborbactam for meropenem-resistant P. aeruginosa (61.8% and 55.5% vs. 30.2%; P < 0.05). CONCLUSION: Discrepancy in the resistance of different P. aeruginosa isolates to various carbapenems suggests their different underlying resistance mechanisms. These findings can be useful for effective resistance trend monitoring and accurate antimicrobial treatment in the future.

In vitro activity of imipenem/relebactam, meropenem/vaborbactam and comparators against Enterobacterales causing urinary tract infection in Taiwan: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART), 2020.

OBJECTIVES: Antimicrobial resistance due to ß-lactamase production is a worldwide issue, and ß-lactamase inhibitors have been developed to overcome the growing problem. This study aimed to evaluate the in vitro activities of two recently introduced carbapenem/ß-lactamase inhibitor combinations - imipenem/relebactam and meropenem/vaborbactam - and their comparators against Enterobacterales from patients with urinary tract infections (UTIs). METHODS: Enterobacterales isolates from patients with UTIs in Taiwan and participating in the Study for Monitoring Antimicrobial Resistance Trends (SMART) in 2020 were included. Minimum inhibitory concentrations (MICs) for various antibiotics were determined using the broth microdilution method. Susceptibility was interpreted based on the MIC breakpoints of the Clinical and Laboratory Standards Institute 2022. Genes encoding common ß-lactamases, including extended-spectrum ß-lactamases, AmpC ß-lactamases and carbapenemases, were detected using multiplex polymerase chain reaction. RESULTS: A total of 309 Enterobacterales isolates were included, against which both imipenem/relebactam and meropenem/vaborbactam exerted excellent efficacy (275 of 309, 95% and 288 of 309, 99.3%, respectively). Among imipenem non-susceptible isolates, 17 of 43 (39.5%) and 39 of 43 (90.7%) were susceptible to imipenem/relebactam and meropenem/vaborbactam, respectively. CONCLUSION: Imipenem/relebactam and meropenem/vaborbactam may be appropriate choices for treating UTIs due to Enterobacterales resistant to commonly used antibiotics. Continuous monitoring of antimicrobial resistance is crucial.

A low-molecular-weight chitosan fluorometric-based assay for evaluating antiangiogenic drugs.

Low-molecular-weight chitosan (LMWCS) damaged cell membranes in zebrafish showed its possibility to release reporter proteins for detection. In this study, we developed a simple fluorometric-based assay for the evaluation of clinical antiangiogenic drugs using LMWCS and Tg(fli1:EGFP) transgenic zebrafish, which expressed green-fluorescence protein (GFP) in the endothelial cells of blood vessel. In vitro stable and transiently transfected cell lines was released luciferase and green fluorescent protein (GFP) for intensity evaluation upon LMWCS fluorometric-based assay. In vivo Tg(fli1:EGFP) transgenic zebrafish was also released GFP from endothelial cells of blood vessels and show an increase of fluorescent intensity upon LMWCS fluorometric-based assay. Treatment with the clinical antiangiogenic drug sorafenib and analyzed by LMWCS fluorometric-based assay showed significantly reduction of angiogenesis. Furthermore, treatment with 2 µM sorafenib showed a significant reduction in angiogenesis of the intersegmental vein (ISV) and dorsal longitudinal anastomotic vessels (DLAV) in Tg(fli1:EGFP) transgenic zebrafish. Fluorescence intensity reduction from 2 µM sorafenib was used as a factor in the LMWCS fluorescence-based assay for relative antiangiogenic evaluation. Relative angiogenesis evaluation of the clinical drugs axitinib, cabozantinib, and regorafenib showed a significant reduction. Collectively, this study provided a simple, convenient, and rapid LMWCS fluorometric-based assay for evaluating angiogenic drugs using transgenic zebrafish.

Seroprevalence of varicella-zoster virus antibody and immunogenicity of live attenuated varicella vaccine in healthcare workers in Taiwan.

BACKGROUND: Healthcare workers (HCWs) without evidence of immunity to varicella-zoster virus (VZV) are recommended to undergo varicella vaccination. Immunogenicity of live attenuated varicella vaccine has rarely been investigated among HCWs in Taiwan. METHODS: Anti-VZV immunoglobulin G (IgG) titer was checked for all HCWs at Changhua Christian Hospital from 2011 to 2017. One-dose and two-dose (separated by 4-8 weeks) vaccines were administered to HCWs with equivocal and negative anti-varicella IgG results, respectively. Follow-up anti-VZV IgG was determined at least 4 weeks after completion of vaccination. Factors associated with seroconversion to varicella vaccination were analyzed. RESULTS: Among 2406 included HCWs, the anti-VZV IgG serostatus was tested positive, equivocal and negative in 1924 (79.9%), 117 (4.9%) and 365 (15.2%), respectively. The seroprevalence had decreased from 88.0% (235/267) in 2011 to 72.2% (270/374) in 2017 (p for trend <0.05). A total of 67.8% (327/482) HCWs completed scheduled vaccination and serological follow-up. The seroconversion rates for HCWs with baseline equivocal and negative anti-VZV IgG results were 100% (80/80) and 79.4% (196/247) after one- and two-dose vaccination, respectively. In multivariate analysis, obesity (adjusted odds ratio, 0.308; 95% confidence interval [CI], 0.11-0.94, p = 0.039) was the only factor statistically significantly associated with seroconversion to vaccination. CONCLUSION: Decreasing trends of seroprevalence of VZV were observed among HCWs from 2011 to 2017. HCWs who were obese were less likely to respond to varicella vaccination.

Geographic patterns of Acinetobacter baumannii and carbapenem resistance in the Asia-Pacific Region: results from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2012-2019.

OBJECTIVES: This study aimed to investigate the geographic distribution of carbapenem-resistant Acinetobacter baumannii (CR-AB) isolates in the Asia-Pacific region. METHODS: We collected A. baumannii isolates using the Antimicrobial Testing Leadership and Surveillance program from 2012 to 2019. The minimum inhibitory concentrations (MICs) of the isolates were determined using the broth microdilution method. The major carbapenemase genes were identified using multiplex polymerase chain reaction assays for the isolates collected between 2012 and 2014. CR-AB was defined as isolates with meropenem MICs ≥8 mg/l. RESULTS: In total, 2674 A. baumannii isolates were collected from 13 countries, of which 1918 (71.7%) were CR-AB. The carbapenem resistance rates among A. baumannii isolates were as low as 2.8% and 6.5% in Japan and Australia, respectively, but as high as 88% and 87.2% in South Korea and India, respectively. Of the 232 CR-AB isolates that underwent carbapenemase gene screening, 224 (96.6%) harbored at least one carbapenemase gene. A total of 226 carbapenemase genes were detected, with blaOXA-23 (94.7%, 214/226) being the most dominant, followed by blaOXA-72 (2.7%, 6/226), blaOXA-58 (2.2%, 5/226), and blaNDM-1 (0.4%, 1/226). CR-AB isolates had >80% resistance to amikacin, ampicillin/sulbactam, cefepime, ceftazidime, ciprofloxacin, levofloxacin, and piperacillin/tazobactam. The rates of CR-AB resistance to minocycline and colistin were 7.2% (31/429) and 1.7% (23/1368). For cefoperazone/sulbactam and tigecycline, 50.2% (527/1049) and 93.3% (1789/1918) of CR-AB isolates had an MIC ≤16 mg/l and ≤2 mg/l, respectively. CONCLUSION: The prevalence of carbapenem resistance in A. baumannii showed significant differences among countries in the Asia-Pacific region, and the treatment options were limited.

Cross-protective humoral immunity to coronaviruses from SARS coronavirus 2-naïve sera of children with Kawasaki disease.

OBJECTIVES: SARS coronavirus 2 (SARS-CoV-2)-associated multi-system inflammatory syndrome in children indicates that viruses can trigger a Kawasaki disease (KD)-like hyperinflammation. A plausible hypothesis was that coronavirus-specific 'holes' in humoral immunity could cause both diseases. METHODS: To determine whether SARS-CoV-2-naïve patients with KD have inferior humoral immunity for the novel coronavirus, sera of children with KD and control children from year 2015 to 2021 were subjected to ELISA, microwestern, and neutralization assays to evaluate the capabilities in recognizing the receptor-binding domain of SARS-CoV-2, spotting spike proteins of three respiratory syndromic coronaviruses, and blocking SARS-CoV-2 from binding to angiotensin-converting enzyme 2 receptors in vitro, respectively. RESULTS: 29 patients with KD before 2019, 74 patients with KD in 2019 or 2020, 54 non-febrile controls, and 24 febrile controls were included in the study. SARS-CoV-2 was recognized on ELISA for both patients with KD in 2016 and those with KD in 2020. Microwestern demonstrated cross-reactive IgG in an all-or-none manner towards three spike proteins of syndromic coronaviruses regardless of sample year or KD status. The ratio between the sera that recognized all spike proteins and those that recognized none (51 vs. 47) was significantly higher from patients with KD than from non-febrile controls (17 vs. 32; p 0.047) but not from febrile controls (13 vs. 11; p 0.85). Most positive sera (12 of 17 controls, 5 of 8 patients with KD before 2019, and 28 of 33 patients with KD in 2019 or 2020) offered protection comparable to low-titre sera from the WHO reference panel. DISCUSSION: Humoral immunity of SARS-CoV-2-naïve children with KD was not inferior to that of controls in offering cross-protection against the novel coronavirus.

Geographic patterns of global isolates of carbapenem-resistant Klebsiella pneumoniae and the activity of ceftazidime/avibactam, meropenem/vaborbactam, and comparators against these isolates: Results from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2020.

Carbapenem-resistant Enterobacterales (CRE) are a growing threat to public health. This study was conducted to determine the prevalence of carbapenem-resistant Klebsiella pneumoniae (CR-KP) and the associated carbapenemase genes using data from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2020. Minimum inhibitory concentrations (MICs) were determined using the broth microdilution method, and carbapenemase genes were detected using multiplex polymerase chain reaction (PCR). Clinical and Laboratory Standards Institute breakpoints were used for interpretation of susceptibility. A total of 6753 K. pneumoniae isolates were collected from 57 countries in six regions worldwide. Of these, 1118 (16.6%) were CR-KP isolates. Among 1079 of the tested CR-KP isolates, 1017 (94.3%) had at least one of the class A (41.0%, 417/1017), B (39.3%, 400/1017), and D (38.8%, 395/1017) carbapenemase genes. The resistance patterns and associated genes differed significantly between the participating countries. India, Greece, and Argentina had the highest rates of carbapenem resistance. Susceptibility to the ß-lactamase inhibitor combination, ceftazidime/avibactam was greater than that to meropenem/vaborbactam in all K. pneumoniae (93.7% vs. 90.3%, P < 0.05), CR-KP (63.3% vs. 41.5%, P < 0.05), CR-KP with genes for Klebsiella pneumoniae carbapenemase-like carbapenemase (99.5% vs. 96.0%, P < 0.05), oxacillinase-like carbapenemase (98.7% vs. 4.6%, P < 0.05), and CR-KP without carbapenemase genes (93.5% vs. 79.0%, P < 0.05). CR-KP was the only exception with class B carbapenemase, with susceptibility rates of 1.4% and 9.4% to ceftazidime/avibactam and meropenem/vaborbactam, respectively (P < 0.05). Overall, surveillance results are important for guiding empirical antimicrobial therapy in different regions and for monitoring the global transmission of CR-KP with varying resistance mechanisms.

In vitro susceptibilities of isolates of potentially naturally inducible chromosomal AmpC-producing metallo-ß-lactamase-negative carbapenem-resistant Enterobacterales species to ceftazidime-avibactam: Data from the Antimicrobial Testing Leadership and Surveillance Programme, 2012-2019.

OBJECTIVES: A total of 74 570 potentially naturally inducible chromosomal AmpC-producing (PNIC-AmpC) Enterobacterales isolates included in the Antimicrobial Testing Leadership and Surveillance Programme were obtained worldwide during 2012-2019 (22 503 from 2012-2014 and 52 067 from 2015-2019). Of these isolates, 117 and 711 obtained during 2012-2014 and 2015-2019, respectively, were carbapenem-resistant Enterobacterales (PNIC-AmpC-CRE). The MICs of ceftazidime-avibactam for these isolates were determined using the broth microdilution method. METHODS: Genes encoding different Ambler classes of ß-lactamases were investigated using multiplex PCR. After 97 isolates harbouring genes encoding metallo-ß-lactamases (MßL) were excluded, 731 PNIC-AmpC MßL-negative CRE isolates (101 from 2012-2014 and 630 from 2015-2019) were included in this study. RESULTS: Enterobacter cloacae (E. cloacae) complex species, Escherichia coli (E. coli) and Citrobacter freundii (C. freundii) complex species accounted for 36.3% (n = 265), 30.4% (n = 222) and 11.8% (n = 86), respectively, followed by Providencia species (n = 72), Serratia species (n = 52) and Klebsiella aerogenes (n = 34). The resistance rates to ceftazidime-avibactam for the overall PNIC-AmpC MßL-negative CRE isolates markedly differed between the two periods (35.6% vs. 63.3%; P < 0.001). Similar trends were observed for the MßL-negative-CR-E. cloacae complex species (47.4% vs. 65.2%; P = 0.046) and MßL-negative-CR-E. coli (16.2% vs. 63.8%; P < 0.001) but not for MßL-negative-CR-C. freundii complex species (40% vs. 62%; P = 0.153). Amongst the PNIC-AmpC MßL-negative CRE isolates, resistance rates to ceftazidime-avibactam worsened. CONCLUSIONS: Caution should be taken when empirically prescribing ceftazidime-avibactam for infections caused by PNIC-AmpC-CRE before susceptibility data are available.

Carbapenemase-producing Enterobacterales infections: recent advances in diagnosis and treatment.

Increasing carbapenem resistance in Enterobacterales poses a threat to public health. In recent decades, this increase in carbapenem resistance has been caused by the global dissemination of carbapenemase-producing Enterobacterales (CPE). Carbapenemases are members of the ß-lactamases that are divided into classes A, B and D based on their molecular structures. Although certain traditionally used antibiotics, such as amikacin, polymyxins, tigecycline and fosfomycin, may remain effective against some CPE, their clinical use is limited owing to adverse effects, including renal toxicity, tissue penetration or the requirement for combination treatment. Recently, several novel agents have been approved for clinical use, such as ceftazidime/avibactam, ceftolozane/tazobactam, cefiderocol, eravacycline, omadacycline, meropenem/vaborbactam, imipenem/cilastatin/relebactam and plazomicin. However, the spectrum of antimicrobial activities and efficacies of novel agents vary depending on the mechanisms associated with carbapenem resistance in Enterobacterales. Therefore, it is of utmost importance to enable accurate and rapid diagnosis of CPE infection, including the determination of their antimicrobial resistance mechanisms. Here, recent advances in methods for the identification of CPE have been reviewed, including phenotypic methods (carbapenemase inactivation methods), biochemical methods [Carbapenemase Nordmann-Poirel (Carba NP) test and modified Carba NP test], immunochromatographic methods, proteomic methods [matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF/MS)] and molecular-based methods [nucleic acid amplification technologies, hybridisation techniques (microarray) and whole-genome sequencing]. Both precise diagnosis and adequate treatment are important to combat the emerging CPE crisis.