Enhancement of NETosis by ACE2-cross-reactive anti-SARS-CoV-2 RBD antibodies in patients with COVID-19.

BACKGROUND: High levels of neutrophil extracellular trap (NET) formation or NETosis and autoantibodies are related to poor prognosis and disease severity of COVID-19 patients. Human angiotensin-converting enzyme 2 (ACE2) cross-reactive anti-severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain (SARS-CoV-2 RBD) antibodies (CR Abs) have been reported as one of the sources of anti-ACE2 autoantibodies. However, the pathological implications of CR Abs in NET formation remain unknown. METHODS: In this study, we first assessed the presence of CR Abs in the sera of COVID-19 patients with different severity by serological analysis. Sera and purified IgG from CR Abs positive COVID-19 patients as well as a mouse monoclonal Ab (mAb 127) that can recognize both ACE2 and the RBD were tested for their influence on NETosis and the possible mechanisms involved were studied. RESULTS: An association between CR Abs levels and the severity of COVID-19 in 120 patients was found. The CR Abs-positive sera and IgG from severe COVID-19 patients and mAb 127 significantly activated human leukocytes and triggered NETosis, in the presence of RBD. This NETosis, triggered by the coexistence of CR Abs and RBD, activated thrombus-related cells but was abolished when the interaction between CR Abs and ACE2 or Fc receptors was disrupted. We also revealed that CR Abs-induced NETosis was suppressed in the presence of recombinant ACE2 or the Src family kinase inhibitor, dasatinib. Furthermore, we found that COVID-19 vaccination not only reduced COVID-19 severity but also prevented the production of CR Abs after SARS-CoV-2 infection. CONCLUSIONS: Our findings provide possible pathogenic effects of CR Abs in exacerbating COVID-19 by enhancing NETosis, highlighting ACE2 and dasatinib as potential treatments, and supporting the benefit of vaccination in reducing disease severity and CR Abs production in COVID-19 patients.

Prompt antimicrobial therapy and source control on survival and defervescence of adults with bacteraemia in the emergency department: the faster, the better.

BACKGROUND: Bacteraemia is a critical condition that generally leads to substantial morbidity and mortality. It is unclear whether delayed antimicrobial therapy (and/or source control) has a prognostic or defervescence effect on patients with source-control-required (ScR) or unrequired (ScU) bacteraemia. METHODS: The multicenter cohort included treatment-naïve adults with bacteraemia in the emergency department. Clinical information was retrospectively obtained and etiologic pathogens were prospectively restored to accurately determine the time-to-appropriate antibiotic (TtAa). The association between TtAa or time-to-source control (TtSc, for ScR bacteraemia) and 30-day crude mortality or delayed defervescence were respectively studied by adjusting independent determinants of mortality or delayed defervescence, recognised by a logistic regression model. RESULTS: Of the total 5477 patients, each hour of TtAa delay was associated with an average increase of 0.2% (adjusted odds ratio [AOR], 1.002; P < 0.001) and 0.3% (AOR 1.003; P < 0.001) in mortality rates for patients having ScU (3953 patients) and ScR (1524) bacteraemia, respectively. Notably, these AORs were augmented to 0.4% and 0.5% for critically ill individuals. For patients experiencing ScR bacteraemia, each hour of TtSc delay was significantly associated with an average increase of 0.31% and 0.33% in mortality rates for overall and critically ill individuals, respectively. For febrile patients, each additional hour of TtAa was significantly associated with an average 0.2% and 0.3% increase in the proportion of delayed defervescence for ScU (3085 patients) and ScR (1266) bacteraemia, respectively, and 0.5% and 0.9% for critically ill individuals. For 1266 febrile patients with ScR bacteraemia, each hour of TtSc delay respectively was significantly associated with an average increase of 0.3% and 0.4% in mortality rates for the overall population and those with critical illness. CONCLUSIONS: Regardless of the need for source control in cases of bacteraemia, there seems to be a significant association between the prompt administration of appropriate antimicrobials and both a favourable prognosis and rapid defervescence, particularly among critically ill patients. For ScR bacteraemia, delayed source control has been identified as a determinant of unfavourable prognosis and delayed defervescence. Moreover, this association with patient survival and the speed of defervescence appears to be augmented among critically ill patients.

Incidence and co-infection with COVID-19 of dengue during the COVID-19 pandemic.

The co-infection of dengue and COVID-19 has been regarded as a public health issue for dengue-endemic countries during the COVID-19 pandemic. Travel restrictions might decrease the chance of mosquitoes biting and, thus, reduce the risk of dengue transmission. However, the spread of dengue was reported to increase with the policies of lockdowns and social distancing in specific areas due to delayed interventions in dengue transmission. Of cases experiencing dengue and COVID-19 co-infection, most recovered after receiving supportive care and/or steroid therapy. However, some episodes of severe or fatal diseases in specific individuals, such as pregnant women, have been reported, and the clinical course of this co-infection is unrecognized or unpredictable. Accordingly, it is crucial to promptly identify predictors of developing severe viral diseases among co-infection patients.

Predictive models for short-term mortality and length of hospital stay among adults with community-onset bacteraemia before and during the COVID-19 pandemic: application of early data dynamics.

BACKGROUND: The development of scoring systems to predict the short-term mortality and the length of hospital stay (LOS) in patients with bacteraemia is essential to improve the quality of care and reduce the occupancy variance in the hospital bed. METHODS: Adults hospitalised with community-onset bacteraemia in the coronavirus disease 2019 (COVID-19) and pre-COVID-19 eras were captured as the validation and derivation cohorts in the multicentre study, respectively. Model I incorporated all variables available on day 0, Model II incorporated all variables available on day 3, and Models III, IV, and V incorporated the variables that changed from day 0 to day 3. This study adopted the statistical and machine learning (ML) methods to jointly determine the prediction performance of these models in two study cohorts. RESULTS: A total of 3,639 (81.4%) and 834 (18.6%) patients were included in the derivation and validation cohorts, respectively. Model IV achieved the best performance in predicting 30-day mortality in both cohorts. The most frequently identified variables incorporated into Model IV were deteriorated consciousness from day 0 to day 3 and deteriorated respiration from day 0 to day 3. Model V achieved the best performance in predicting LOS in both cohorts. The most frequently identified variables in Model V were deteriorated consciousness from day 0 to day 3, a body temperature ≤ 36.0 °C or ≥ 39.0 °C on day 3, and a diagnosis of complicated bacteraemia. CONCLUSIONS: For hospitalised adults with community-onset bacteraemia, clinical variables that dynamically changed from day 0 to day 3 were crucial in predicting the short-term mortality and LOS.

Reappraisal of the clinical role of metronidazole therapy for Clostridioides difficile infection in Taiwan: A multicenter prospective study.

BACKGROUND/PURPOSE: Although metronidazole is not recommended to treat Clostridioides difficile infection (CDI) in Western countries, it was still to be recommended for the treatment of non-severe CDI among Taiwanese adults in 2020. This controversy in the clinical role of metronidazole therapy for CDI was examined in a prospective clinical study. METHODS: The study was conducted from January 2015 to December 2016 in three hospitals in Taiwan. Metronidazole treatment failure (MTF) was defined as the persistence of diarrhea after six days of treatment, medication modification (shifting to oral vancomycin), or death after five days of therapy. RESULTS: Overall, 325 patients receiving metronidazole for CDI were included. The overall MTF rate was 48.6% (158 patients). Leukocyte counts of >15,000 cells/mL in peripheral blood (odd ratio [OR] 1.81; P = 0.04) and congestive heart failure (OR 3.26; P = 0.02) were independently associated with MTF. The MTF rate for patients with leukocyte counts of ≤15,000 cells/mL and no congestive heart failure, leukocyte counts of >15,000 cells/mL and no congestive heart failure, leukocyte counts of ≤15,000 cells/mL and congestive heart failure, and leukocyte counts of >15,000 cells/mL and congestive heart failure were 44.2%, 51.8%, 73.3%, and 66.7%, respectively. Of note, patients who experienced MTF had a higher recurrence rate of CDI than those with metronidazole treatment success (13.9% vs. 6.0%, P = 0.02). CONCLUSION: For Taiwanese adults with CDI, the failure rate of metronidazole therapy approached 50%, which suggests the reappraisal of the therapeutic role of metronidazole therapy, especially for patients with leukocytosis or underlying congestive heart failure.

Clostridioides difficile spores stimulate inflammatory cytokine responses and induce cytotoxicity in macrophages.

Clostridioides difficile is a gram-positive, spore-forming anaerobic bacterium, and the leading cause of antibiotic-associated diarrhea worldwide. During C. difficile infection, spores germinate in the presence of bile acids into vegetative cells that subsequently colonize the large intestine and produce toxins. In this study, we demonstrated that C. difficile spores can universally adhere to, and be phagocytosed by, murine macrophages. Only spores from toxigenic strains were able to significantly stimulate the production of inflammatory cytokines by macrophages and subsequently induce significant cytotoxicity. Spores from the isogenic TcdA and TcdB double mutant induced significantly lower inflammatory cytokines and cytotoxicity in macrophages, and these activities were restored by pre-exposure of the spores to either toxins. These findings suggest that during sporulation, spores might be coated with C. difficile toxins from the environment, which could affect C. difficile pathogenesis in vivo.

Clinical Benefit of Appropriate Empirical Fluoroquinolone Therapy for Adults with Community-Onset Bacteremia in Comparison with Third-Generation-Cephalosporin Therapy.

Both fluoroquinolones (FQs) and third-generation cephalosporins (3rd-GCs) are commonly prescribed to treat bloodstream infections, but comparative efficacies between them were rarely studied. Demographics and clinical characteristics of 733 adults with polymicrobial or monomicrobial community-onset bacteremia empirically treated by an appropriate FQ (n = 87) or 3rd-GC (n = 646) were compared. A critical illness (respectively, 8.0% versus 19.0%; P = 0.01), an initial syndrome with severe sepsis (33.3% versus 50.3%; P = 0.003), or a fatal outcome at 28 days (4.6% versus 10.5%; P = 0.08) was less common in the FQ group. A total of 645 (88.0%) patients were febrile at initial presentation, and the FQ group with (FQ group versus 3rd-GC group, respectively, 7.6 days versus 12.0 days; P = 0.04) and without (3.8 days versus 5.4 days; P = 0.001) a critical illness had a shorter time to defervescence than the 3rd-GC group. By the propensity scores, 87 patients with appropriate FQ therapy were matched with 435 treated by 3rd-GC therapy at a ratio of 1:5, and there were no significant differences in terms of bacteremia severity, comorbidity severity, major comorbidities, causative microorganisms, and bacteremia sources between groups. Moreover, crude mortality rates at 28 days (FQ group versus 3rd-GC group, respectively, 4.6% versus 7.8%; P = 0.29) did not differ significantly. However, the time to defervescence was shorter in the FQ group (4.2 ± 3.6 versus 6.2 ± 7.6 days; P < 0.001). Conclusively in the adults with community-onset bacteremia, appropriate empirical FQ therapy was related to shorter time to defervescence than with 3rd-GC therapy, at least for those without a critical illness.

Age-Related Trends in Adults with Community-Onset Bacteremia.

To understand the epidemiological variation in bacteremia characteristics among differently aged populations, adults with community-onset bacteremia during a 6-year period were studied in a retrospective cohort. A total of 2,349 bacteremic patients were stratified into four age categories: young adults (18 to 44 years old; 196 patients; 8.3%), adults (45 to 64 years old; 707 patients; 30.1%), the elderly (65 to 84 years old; 1,098 patients; 46.7%), and the oldest old (≥85 years old; 348 patients; 14.8%). Age-related trends in critical illness (a Pitt bacteremia score of ≥4) at bacteremia onset, antibiotic-resistant pathogens (extended-spectrum ß-lactamase [ESBL]-producing Escherichia coli, Klebsiella species, and Proteus mirabilis [EKP]; methicillin-resistant Staphylococcus aureus [MRSA]; and levofloxacin nonsusceptible EKP), inappropriate empirical antibiotic therapy (EAT), and 4-week mortality rate were observed. Using a multivariate regression model, critical illness at bacteremia onset (adjusted odds ratio [AOR], 9.03; P < 0.001) and inappropriate EAT (AOR, 2.67; P < 0.001) were the two leading predictors of 4-week mortality. Moreover, ESBL-producing EKP (AOR, 12.94; P < 0.001), MRSA (AOR, 8.66; P < 0.001), and levofloxacin-nonsusceptible EKP (AOR, 4.27; P < 0.001) were linked to inappropriate EAT. In conclusion, among adults with community onset bacteremia, significant positive age-related trends were noted in antibiotic-resistant pathogens and bacteremia severity, which were related to the increasing incidence of inappropriate EAT and 4-week mortality with age. Thus, different empirical antimicrobial regimens should be considered for distinct age groups.

Role of cytokine changes in clozapine-induced fever: A cohort prospective study.

AIM: Clozapine-associated fever is common but the specific cytokine changes and treatment durations that may cause fever remain unknown. We investigated the association between inflammatory cytokine changes and clozapine-induced fever in patients who were treated with clozapine. METHODS: Forty-three patients with schizophrenia or schizoaffective disorder, diagnosed by using the Chinese Version of the Mini International Neuropsychiatric Interview, were treated with clozapine for the first time (first-time use group, n = 22) or for more than 6 months (long-term use group, n = 21). The Positive and Negative Syndrome Scale, tympanic temperature, and levels of tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), interleukin-2 (IL-2), and interleukin-6 (IL-6) were determined at baseline and weeks 1, 2, 3, 4, and 6. A multiple linear regression with generalized estimating equation methods was used to analyze the association between the changes in the cytokine levels and clozapine-induced fever in the different groups. RESULTS: The IL-6 level changes were significantly different between the two groups (P = 0.04). In the first-time use group, the fever rate was increased (47.1%) compared with the long-term use group (5.6%, P = 0.005). Moreover, in these patients, the TNF-α, INF-γ, IL-2, and IL-6 levels were significantly (P < 0.001) different from patients who did not develop a fever. An interaction effect with the different treatment duration groups and fever development was only significant for IL-6 (P < 0.001). CONCLUSION: Patients who were treated with clozapine for the first time have an increased rate of developing a fever, and IL-6 might have a specific role in the interaction effect between treatment duration and fever development.

Zoonotic potential of the Clostridium difficile RT078 family in Taiwan.

Clostridium difficile is the major cause of nosocomial diarrhea. We have previously demonstrated that in southern Taiwan, severe C. difficile-associated diarrhea (CDAD) cases were due to the C. difficile RT 126 strain infection, indicating the arrival of an epidemic C. difficile clone in southern Taiwan. RT126 has a close genetic relationship with RT078. However, the RT078 family is the predominant strain of C. difficile in animals worldwide, particularly in swine. In this study, we surveyed C. difficile strains isolated from swine at several farms in Taiwan from August 2011 to March 2015. We found that all swine strains, namely RT078 (32.5%, 37 of 114), RT126 (28.9%, 33 of 114) and RT127 (37.7%, 43 of 114), belonged to the toxigenic RT078 family. All strains had high gyrA mutation rate (57.9%, 66/114), which was linked to quinolone resistance. Notably, Rep-PCR revealed that 3 RT078 animal strains had the same fingerprint as human RT078 clinical isolates; their phylogenic relationship was closely related to the whole gene sequences of tcdB, thus suggesting zoonotic potential for C. difficile infection in Taiwan.

Proton-Pump Inhibitor Exposure Aggravates Clostridium difficile-Associated Colitis: Evidence From a Mouse Model.

BACKGROUND: Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients. In addition to the infection due to toxigenic C. difficile in the gastrointestinal tract of susceptible hosts, other predisposing factors for C. difficile infection (CDI) are identified, including advanced age, a prolonged hospital stay, and use of acid-suppressive drugs. Of note, exposure to gastric acid-reducing agents, such as H2 blockers and proton pump inhibitors (PPIs), remains a controversial risk factor, and has been associated with CDI in some studies but not in others. A mouse model of antibiotic-associated clostridial colitis was established to examine the role of PPIs for CDI. MATERIALS AND METHODS: A mouse model of antibiotic-associated clostridial colitis was set up. NF-κB reporter mice were used to address the in vivo spatial and temporal inflammatory patterns of C. difficile-associated colitis. Serum levels of lipopolysaccharide and dextran-FITC were measured to reflect the barrier permeability of affected intestines. RESULTS: Mice with CDI that were exposed to PPI exhibited greater losses of stool consistency and body and cecal weights than those that were not exposed to PPI. Further, more neutrophilic infiltrations, epithelial damage, and inflammatory cytokine expression were noted in colon specimens of the mice with PPI exposure. More-evident inflammatory responses were detected by in vivo imaging of NF-κB reporter mice with CDI that were exposed to PPI. Gut barrier permeability was increased to a greater extent, as reflected by higher serum levels of lipopolysaccharide and dextran-FITC in mice with CDI that were exposed to PPI. CONCLUSIONS: Our mouse model demonstrates that PPI exposure increases the severity of intestinal inflammation in mice with C. difficile-associated colitis.

Vancomycin-resistant Clostridium innocuum bacteremia following oral vancomycin for Clostridium difficile infection.

An 85 year-old male initially admitted for septic shock due to urinary tract infection experienced Clostridium difficile-associated diarrhea during hospitalization and was treated by oral vancomycin. His clinical course was complicated by cytomegalovirus colitis and then vancomycin-resistant Clostridium innocuum bacteremia, which was cured by uneventfully parenteral piperacillin-tazobactam therapy.

Clostridium difficile ribotype 126 in southern Taiwan: a cluster of three symptomatic cases.

INTRODUCTION: Several virulent Clostridium difficile clones, designated as polymerase chain reaction (PCR) ribotypes 017, 027, or 078, are well recognized in western countries. However, the ribotype distribution of clinical C. difficile isolates in Taiwan remains unclear. METHOD: Between 2010 and 2012, we identified three patients with C. difficile-associated diarrhea (CDAD) at a hospital in southern Taiwan. The C. difficile strains isolated from these patients were further characterized by PCR detection of tcdA, tcdB, tcdC, cdtA, and cdtB, toxinotyping, multilocus sequence typing, ribotyping and repetitive-based PCR. RESULTS: Three C. difficile strains harbored tcdCΔ39 and belonged to multilocus sequence typing 11 (ST11), toxinotype V, and ribotype 126 (a ribotype 078-like clone). Notably, one patient developed pseudomembranous colitis and recurrent CDAD. These three isolates were noted between January 2012 and June 2012 and were identical, as evidenced by repetitive sequence-based PCR, suggestive of case clustering. CONCLUSION: A hypervirulent C. difficile clone, ribotype 126, causing pseudomembranous colitis and recurrent CDAD, is present in southern Taiwan.

Phage transcriptional regulator X (PtrX)-mediated augmentation of toxin production and virulence in Clostridioides difficile strain R20291.

Clostridioides difficile is a Gram-positive, anaerobic, and spore-forming bacterial member of the human gut microbiome. The primary virulence factors of C. difficile are toxin A and toxin B. These toxins damage the cell cytoskeleton and cause various diseases, from diarrhea to severe pseudomembranous colitis. Evidence suggests that bacteriophages can regulate the expression of the pathogenicity locus (PaLoc) genes of C. difficile. We previously demonstrated that the genome of the C. difficile RT027 strain NCKUH-21 contains a prophage-like DNA sequence, which was found to be markedly similar to that of the φCD38-2 phage. In the present study, we investigated the mechanisms underlying the φNCKUH-21-mediated regulation of the pathogenicity and the PaLoc genes expression in the lysogenized C. difficile strain R20291. The carriage of φNCKUH-21 in R20291 cells substantially enhanced toxin production, bacterial motility, biofilm formation, and spore germination in vitro. Subsequent mouse studies revealed that the lysogenized R20291 strain caused a more severe infection than the wild-type strain. We screened three φNCKUH-21 genes encoding DNA-binding proteins to check their effects on PaLoc genes expression. The overexpression of NCKUH-21_03890, annotated as a transcriptional regulator (phage transcriptional regulator X, PtrX), considerably enhanced toxin production, biofilm formation, and bacterial motility of R20291. Transcriptome analysis further confirmed that the overexpression of ptrX led to the upregulation of the expression of toxin genes, flagellar genes, and csrA. In the ptrX-overexpressing R20291 strain, PtrX influenced the expression of flagellar genes and the sigma factor gene sigD, possibly through an increased flagellar phase ON configuration ratio.

Association of Single Nucleotide Polymorphisms in Nucleotide-Binding Domain Leucine-Rich Repeat Protein 1 with Clostridioides difficile Colonization or Infection.

Introduction: Nucleotide-binding domain leucine-rich repeat protein (NLRP) is critical in the inflammasome-activation pathway, which is important for host survival and the clearance of Clostridioides difficile. Therefore, the influence of NLRP1 polymorphisms on C. difficile colonization (CdC) or infection (CDI) was analyzed. Materials and Methods: A prospective cohort study consisted of hospitalized adults was conducted from January 2011 to January 2013. Single nucleotide polymorphisms (SNPs) of NLRP1, including rs12150220, rs2670660, rs6502867, rs878329, rs8182352, rs3744717, and rs11078571, were incorporating in analyses. The episodes of CdC and CDI were the primary and secondary outcome, respectively. Results: Of the total of 509 eligible patients, 376 (73.9%) had neither CdC nor CDI, 104 (21.8%) had CdC without developing CDI, and 29 (4.3%) developed CDI during the study period. Through multivariate analyses, comorbid diabetes mellitus (adjusted odds ratio [AOR] 1.59, P=0.04) and CC genotype in NLRP1 rs3744717 (AOR 1.70, P=0.02) were recognized as the risk factor of CdC. After adjusting the independent predictors of CDI, in terms of comorbid diabetes mellitus (AOR 3.18, P=0.005) and prior exposure to ceftazidime/ceftriaxone (AOR 2.87, P=0.04) or proton pump inhibitors (AOR 3.86, P=0.001), patients with CC+GC genotype in NLRP1, rs878329 (AOR 2.39, P=0.03) remained a higher risk of CDI. Conclusion: For hospitalized adults, the association of CC genotype in NLRP1 rs3744717 and CdC as well as the CC+GC genotype in NLRP1 rs878329 and CDI was respectively evidenced. We believed the prompt identification of patients having specific genotype in NLRP1 would prevent and improve the quality of care in CDI.

COVID-19-associated candidiasis and the emerging concern of Candida auris infections.

The incidence of COVID-19-associated candidiasis (CAC) is increasing, resulting in a grave outcome among hospitalized patients with COVID-19. The most alarming condition is the increasing incidence of multi-drug resistant Candida auris infections among patients with COVID-19 worldwide. The therapeutic strategy towards CAC caused by common Candida species, such as Candida albicans, Candida tropicalis, and Candida glabrata, is similar to the pre-pandemic era. For non-critically ill patients or those with a low risk of azole resistance, fluconazole remains the drug of choice for candidemia. For critically ill patients, those with a history of recent azole exposure or with a high risk of fluconazole resistance, echinocandins are recommended as the first-line therapy. Several novel therapeutic agents alone or in combination with traditional antifungal agents for candidiasis are potential options in the future. However, for multidrug-resistant C. auris infection, only echinocandins are effective. Infection prevention and control policies, including strict isolation of the patients carrying C. auris and regular screening of non-affected patients, are suggested to prevent the spread of C. auris among patients with COVID-19. Whole-genome sequencing may be used to understand the epidemiology of healthcare-associated candidiasis and to better control and prevent these infections.

Effects of Inappropriate Administration of Empirical Antibiotics on Mortality in Adults With Bacteraemia: Systematic Review and Meta-Analysis.

Introduction: Bloodstream infections are associated with high mortality rates and contribute substantially to healthcare costs, but a consensus on the prognostic benefits of appropriate empirical antimicrobial therapy (EAT) for bacteraemia is lacking. Methods: We performed a systematic search of the PubMed, Cochrane Library, and Embase databases through July 2021. Studies comparing the mortality rates of patients receiving appropriate and inappropriate EAT were considered eligible. The quality of the included studies was assessed using Joanna Briggs Institute checklists. Results: We ultimately assessed 198 studies of 89,962 total patients. The pooled odds ratio (OR) for the prognostic impacts of inappropriate EAT was 2.06 (P < 0.001), and the funnel plot was symmetrically distributed. Among subgroups without between-study heterogeneity (I 2 = 0%), those of patients with severe sepsis and septic shock (OR, 2.14), Pitt bacteraemia scores of ≥4 (OR, 1.88), cirrhosis (OR, 2.56), older age (OR, 1.78), and community-onset/acquired Enterobacteriaceae bacteraemia infection (OR, 2.53) indicated a significant effect of inappropriate EAT on mortality. The pooled adjusted OR of 125 studies using multivariable analyses for the effects of inappropriate EAT on mortality was 2.02 (P < 0.001), and the subgroups with low heterogeneity (I 2 < 25%) exhibiting significant effects of inappropriate EAT were those of patients with vascular catheter infections (adjusted OR, 2.40), pneumonia (adjusted OR, 2.72), or Enterobacteriaceae bacteraemia (adjusted OR, 4.35). Notably, the pooled univariable and multivariable analyses were consistent in revealing the negligible impacts of inappropriate EAT on the subgroups of patients with urinary tract infections and Enterobacter bacteraemia. Conclusion: Although the current evidence is insufficient to demonstrate the benefits of prompt EAT in specific bacteraemic populations, we indicated that inappropriate EAT is associated with unfavorable mortality outcomes overall and in numerous subgroups. Prospective studies designed to test these specific populations are needed to ensure reliable conclusions. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42021270274.

Oral Nirmatrelvir/Ritonavir Therapy for COVID-19: The Dawn in the Dark?

Nirmatrelvir/ritonavir (Paxlovid™) is an effective and safe antiviral drug that inhibits the main protease (Mpro), 3CL protease, of SARS-CoV-2. A reduction in COVID-19-related hospitalization or death was observed in patients treated with nirmatrelvir/ritonavir within five days of symptom onset. Moreover, good oral availability enables the usage of nirmatrelvir/ritonavir, not only in hospitalized patients, but also among outpatients. Nirmatrelvir (PF-07321332) has been demonstrated to stop the spread of COVID-19 in animal models. Despite frequent mutations in the viral genomes of SARS-CoV-2, nirmatrelvir shows an effective antiviral effect against recent coronavirus mutants. Despite the promising antiviral effect of nirmatrelvir, there are several unresolved concerns. First, the final results of large-scale clinical trials for early therapy of mild cases of COVID-19 are not yet published. Second, the effectiveness of nirmatrelvir against upcoming variants in the coming years requires close monitoring. Considering the promising preliminary results of the EPIC-HR trial, nirmatrelvir/ritonavir in conjunction with vaccines and non-pharmacological interventions, may represent the dawn in the dark of the COVID-19 pandemic.

Neutrophil Ratio of White Blood Cells as a Prognostic Predictor of Clostridioides difficile Infection.

Introduction: A leukocyte count ≥15,000 cells/mL and serum creatinine of >1.5 mg/dL have been reported as two important predictors of severe CDI. However, the association of the differential ratios of blood leukocytes, and the prognosis of Clostridioides difficile infection (CDI) is not clear. Materials and Methods: A clinical study was conducted at medical wards of Tainan Hospital, Ministry of Health and Welfare in southern Taiwan between January 2013 and April 2020. Hospitalized adults (aged ≥20 years) with hospital-onset CDI (ie, symptom onset after at least 48 hours of admission) were included. Results: A total of 235 adults with an average age of 75.7 years and female predominance (51.5%), including 146 (62%) adults with non-severe CDI and 87 (38%) severe CDI, were included for analysis. Patients with severe CDI had a higher crude in-hospital mortality rate than patients with non-severe CDI (35.6% vs 18.5%, P = 0.005). Multivariate analysis revealed no association between a leukocyte count >15,000 cell/mL at the onset of CDI and in-hospital mortality (odds ratio [OR] 1.66, P = 0.21). In contrast, a neutrophil ratio >75% (OR 2.65, P = 0.02), serum creatinine >1.5 mg/L (OR 3.42, P = 0.03), and CDI caused by isolates harboring the tcdC gene (OR 3.54, P = 0.02) were independently associated with in-hospital mortality. Patients with a neutrophil ratio >85%, 80-85%, or 75-80% of serum leukocytes had a higher mortality rate (34.8%, 30.3%, or 34.4%, respectively) than patients with a neutrophil ratio of 70-75% or ≤75% (12.5% or 13.9%, respectively). Conclusion: Serum creatinine >1.5 mg/L, a high neutrophil ratio of blood leukocytes (>75%), and the causative C. difficile harboring the tcdC gene was independent prognostic predictors in hospitalized adults with CDI.