Burden of respiratory syncytial virus in older adults in Taiwan: An expert perspective on knowledge gaps.

The burden of respiratory syncytial virus (RSV) infection among older adults in Taiwan is not well understood due to a scarcity of published epidemiological data. Nonetheless, the increasing proportion of older adults is anticipated to translate to increased burden of RSV infection, presenting a challenge to the healthcare system. Thus, an expert meeting was convened among a panel of infectious disease specialists from Taiwan to evaluate the existing local evidence and data gaps related to RSV infection in older adults (aged ≥50 years), and propose steps to generating evidence on disease burden among this population. Overall, there are few studies on the clinical and economic burden of RSV infection in Taiwan, and existing data are limited by small sample sizes and highly selected populations. Inconsistent RSV testing practices among older adults contribute to under-diagnosis and under-reporting, driven by limitations to reimbursement policies that discourage proactive RSV testing in older adults, and the lack of appropriate, targeted RSV treatment. Crucially, the paucity of epidemiological data may perpetuate a lack of awareness of RSV among clinicians and the public, hinder investments into RSV testing at a policymaker level, and thereby impede implementation of consistent diagnostic practices, precluding a deeper understanding of RSV. To overcome these challenges, it is imperative to prioritize generation of epidemiological data to establish the burden of RSV infection among older adults in Taiwan. Such data would also support a multi-stakeholder group in assessing the impact of future RSV-related interventions, such as educational initiatives and preventative strategies including vaccines.

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.

Comparison of ERIC carbapenem-resistant Enterobacteriaceae test, BD Phoenix CPO detect panel, and NG-test CARBA 5 for the detection of main carbapenemase types of carbapenem-resistant Enterobacterales.

BACKGROUND: This study aimed to assess the performance of three commercial panels, the ERIC Carbapenem-Resistant Enterobacteriaceae Test (ERIC CRE test), the NG-Test CARBA 5 (NG CARBA 5), and the BD Phoenix CPO Detect Panel (CPO panel), for the detection of main types of carbapenemases among carbapenem-resistant Enterobacterales (CRE). METHODS: We collected 502 isolates of carbapenem-resistant Enterobacterales (CRE) demonstrating intermediate or resistant profiles to at least one carbapenem antibiotic (ertapenem, imipenem, meropenem, or doripenem). Carbapenemase genes and their specific types were identified through multiplex PCR and sequencing methods. Subsequently, the ERIC CRE test, CPO panel, and NG CARBA 5 assay were conducted on these isolates, and the results were compared with those obtained from multiplex PCR. RESULTS: The results indicated that the ERIC CRE test exhibited an overall sensitivity and specificity of 98.1% and 93.6%, respectively, which were comparable to 99.1% and 90.6% for the NG CARBA 5. However, the CPO panel demonstrated a sensitivity of only 56.2% in identifying Ambler classes, exhibiting the poorest sensitivity for class A. Moreover, while the ERIC CRE test outperformed the NG CARBA 5 in identifying multi-gene isolates with multiple carbapenemase-encoding genes, the CPO panel failed to accurately classify these isolates. CONCLUSIONS: Our findings support the utilization of the ERIC CRE test as one of the methods for detecting carbapenemases in clinical laboratories. Nonetheless, further optimization is imperative for the CPO panel to enhance its accuracy in determining carbapenemase classification and address limitations in detecting multi-gene isolates.

Global epidemiology and antimicrobial resistance of Enterobacterales harbouring genes encoding OXA-48-like carbapenemases: insights from the results of the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme 2018-2021.

OBJECTIVES: The recent emergence of carbapenem-resistant Enterobacterales poses a major and escalating threat to global public health. This study aimed to analyse the global distribution and antimicrobial resistance of Enterobacterales harbouring variant OXA-48-like carbapenemase-related genes. METHODS: Enterobacterales isolates were collected from the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme during 2018-2021. Comprehensive antimicrobial susceptibility testing and ß-lactamase gene detection were also conducted, along with statistical analysis of the collected data. RESULTS: Among the 72 244 isolates, 1934 Enterobacterales isolates were identified to harbour blaOXA-48-like genes, predominantly Klebsiella spp. (86.9%). High rates of multidrug resistance were observed, with only ceftazidime/avibactam and tigecycline showing favourable susceptibility. A discrepancy between the genotype and phenotype of carbapenem resistance was evident: 16.8% (233 out of 1384) of the Enterobacterales isolates with blaOXA-48-like genes exhibited susceptibility to meropenem. Specifically, 37.4% (64/95) of Escherichia coli strains with blaOXA-48-like genes displayed meropenem susceptibility, while the corresponding percentages for Klebsiella pneumoniae and Enterobacter cloacae complex were 25.2% (160/1184) and 0% (0/36), respectively (P < 0.05). Geographical analysis revealed that the highest prevalence of blaOXA-48-like genes occurred in Asia, the Middle East and Eastern Europe. The proportion of K. pneumoniae isolates harbouring blaOXA-232 increased from 23.9% in 2018 to 56.0% in 2021. By contrast, the proportion of blaOXA-48 decreased among K. pneumoniae isolates during 2018-2021. CONCLUSIONS: This study underscores the widespread and increasing prevalence of blaOXA-48-like genes in Enterobacterales and emphasizes the need for enhanced surveillance, improved diagnostic methods and tailored antibiotic stewardship to combat the spread of these resistant pathogens.

Disease burden and macrolide resistance of Mycoplasma pneumoniae infection in adults in the Asia-Pacific region.

OBJECTIVES: In the Asia-Pacific region, Mycoplasma pneumoniae (MP) could be a notable pathogen responsible for adult community-acquired pneumonia (CAP), with varying prevalence rates. This comprehensive review aimed to explore the epidemiology, clinical manifestations, macrolide resistance, and molecular characteristics of MP in adults across several countries in Asia. METHODS: PubMed, Embase, and Google Scholar were searched for relevant articles from 2010-2023 based on the following keywords: adult and Mycoplasma pneumoniae. RESULTS: The prevalence of MP in CAP patients in these countries ranged from 2.1% in Korea to 25.5% in Japan. Macrolide resistance was prominent, particularly in China, with rates ranging 26.9-100%. Clinical manifestations of MP infection included protean extrapulmonary manifestations, and complications such as rhabdomyolysis and thrombocytopenia. Molecular characteristics, especially the multiple locus variable-number tandem-repeat analysis type 4/5/7/2, remained predominant across various countries, emphasising the importance of ongoing surveillance. CONCLUSIONS: This review highlights the urgent need for continued monitoring of MP infections, macrolide resistance, and molecular characteristics to inform effective prevention and treatment strategies in the Asia-Pacific region.

Antimicrobial susceptibility and resistome of Actinobacillus pleuropneumoniae in Taiwan: a next-generation sequencing analysis.

Actinobacillus pleuropneumoniae infection causes a high mortality rate in porcine animals. Antimicrobial resistance poses global threats to public health. The current study aimed to determine the antimicrobial susceptibilities and probe the resistome of A. pleuropneumoniae in Taiwan. Herein, 133 isolates were retrospectively collected; upon initial screening, 38 samples were subjected to next-generation sequencing (NGS). Over the period 2017-2022, the lowest frequencies of resistant isolates were found for ceftiofur, cephalexin, cephalothin, and enrofloxacin, while the highest frequencies of resistant isolates were found for oxytetracycline, streptomycin, doxycycline, ampicillin, amoxicillin, kanamycin, and florfenicol. Furthermore, most isolates (71.4%) showed multiple drug resistance. NGS-based resistome analysis revealed aminoglycoside- and tetracycline-related genes at the highest prevalence, followed by genes related to beta-lactam, sulfamethoxazole, florphenicol, and macrolide. A plasmid replicon (repUS47) and insertion sequences (IS10R and ISVAp11) were identified in resistant isolates. Notably, the multiple resistance roles of the insertion sequence IS10R were widely proposed in human medicine; however, this is the first time IS10R has been reported in veterinary medicine. Concordance analysis revealed a high consistency of phenotypic and genotypic susceptibility to florphenicol, tilmicosin, doxycycline, and oxytetracycline. The current study reports the antimicrobial characterization of A. pleuropneumoniae for the first time in Taiwan using NGS.

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.

Antimicrobial resistance profile in Salmonella enterica serovar Choleraesuis isolates from diseased pigs in Taiwan.

This study investigated antimicrobial resistance in Salmonella enterica serovar Choleraesuis (S. Choleraesuis) isolates from diseased pigs in Taiwan (2015-2020). Among 272 isolates, florfenicol (96.7%), enrofloxacin (96.3%), doxycycline (91.2%), gentamicin (84.6%), and tiamulin (80.5%) exhibited high resistance. 99.3% of the isolates were resistant to at least one antibiotic, and 97.8% of the isolates were multidrug resistant. This study illustrated that S. Choleraesuis isolates exhibited high resistance to antimicrobials currently used in the Taiwanese swine industry.

Impact of the implementation of the Intelligent Antimicrobial System (iAMS) on clinical outcomes among patients with bacteraemia caused by methicillin-resistant Staphylococcus aureus.

OBJECTIVES: This study aimed to investigate the clinical impact of the Intelligent Antimicrobial System (iAMS) on patients with bacteraemia due to methicillin-resistant (MRSA) and methicillin-susceptible Staphylococcus aureus (MSSA). METHODS: A total of 1008 patients with suspected SA infection were enrolled before and after the implementation of iAMS. Among them, 252 with bacteraemia caused by SA, including 118 in the iAMS and 134 in the non-iAMS groups, were evaluated. RESULTS: The iAMS group exhibited a 5.2% (from 55.2% to 50.0%; P = 0.96) increase in the 1-year survival rate. For patients with MRSA and MSSA compared to the non-iAMS group, the 1-year survival rate increased by 17.6% (from 70.9% to 53.3%; P = 0.41) and 7.0% (from 52.3% to 45.3%; P = 0.57), respectively, both surpassing the rate of the non-iAMS group. The iAMS intervention resulted in a higher long-term survival rate (from 70.9% to 52.3%; P = 0.984) for MRSA patients than for MSSA patients. MRSA patients experienced a reduced length of hospital stay (from 23.3% to 35.6%; P = 0.038), and the 45-day discharge rate increased by 20.4% (P = 0.064). Furthermore, the intervention resulted in a significant 97.3% relative decrease in near miss medication incidents reported by pharmacists (P = 0.013). CONCLUSIONS: Implementation of iAMS platform improved long-term survival rates, discharge rates, hospitalization days, and medical cost (although no significant differences were observed) among patients with MRSA bacteraemia. Additionally, it demonstrated significant benefits in ensuring drug safety.

Temporal changes in biomarkers of neutrophil extracellular traps and NET-promoting autoantibodies following adenovirus-vectored, mRNA, and recombinant protein COVID-19 vaccination.

Neutrophil extracellular traps (NETs) play a role in innate pathogen defense and also trigger B-cell response by providing antigens. NETs have been linked to vaccine-induced thrombotic thrombocytopenia. We postulated a potential link between NET biomarkers, NET-promoting autoantibodies, and adverse events (AEs) after COVID-19 vaccine boosters. Healthy donors (HDs) who received ChAdOx1-S (A), mRNA-1273 (M), or recombinant protein (MVC-COV1901) vaccines at the National Taiwan University Hospital between 2021 and 2022 were recruited. We measured serial NET-associated biomarkers, citrullinated-histone3 (citH3), and myeloperoxidase (MPO)-DNA. Serum citH3 and MPO-DNA were significantly or numerically higher in HDs who reported AEs (n = 100, booster Day 0/Day 30, p = 0.01/p = 0.03 and p = 0.30/p = 0.35, respectively). We also observed a positive correlation between rash occurrence in online diaries and elevated citH3. A linear mixed model also revealed significantly higher citH3 levels in mRNA-1273/ChAdOx1-S recipients than MVC-COV1901 recipients. Significant positive correlations were observed between the ratios of anti-heparin platelet factor 4 and citH3 levels on Booster Day 0 and naïve and between the ratios of anti-NET IgM and citH3 on Booster Day 30/Day 0 in the AA-M and MM-M group, respectively. The increased levels of citH3/MPO-DNA accompanied by NET-promoting autoantibodies suggest a potential connection between mRNA-1273/ChAdOx1-S vaccines and cardiovascular complications. These findings provide insights for risk assessments of future vaccines.

Application of a multiplex molecular pneumonia panel and real-world impact on antimicrobial stewardship among patients with hospital-acquired and ventilator-associated pneumonia in intensive care units.

BACKGROUND: The optimal timing for applying the BioFire FilmArray Pneumonia Panel (FAPP) in intensive care unit (ICU) patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) remains undefined, and there are limited data on its impact on antimicrobial stewardship. METHODS: This retrospective study was conducted at a referral hospital in Taiwan from November 2019 to October 2022. Adult ICU patients with HAP/VAP who underwent FAPP testing were enrolled. Patient data, FAPP results, conventional microbiological testing results, and the real-world impact of FAPP results on antimicrobial therapy adjustments were assessed. Logistic regression was used to determine the predictive factors for bacterial detection by FAPP. RESULTS: Among 592 respiratory specimens, including 564 (95.3%) endotracheal aspirate specimens, 19 (3.2%) expectorated sputum specimens and 9 (1.5%) bronchoalveolar lavage specimens, from 467 patients with HAP/VAP, FAPP testing yielded 368 (62.2%) positive results. Independent predictors for positive bacterial detection by FAPP included prolonged hospital stay (odds ratio [OR], 3.14), recent admissions (OR, 1.59), elevated C-reactive protein levels (OR, 1.85), Acute Physiology and Chronic Health Evaluation II scores (OR, 1.58), and septic shock (OR, 1.79). Approximately 50% of antimicrobial therapy for infections caused by Gram-negative bacteria and 58.4% for Gram-positive bacteria were adjusted or confirmed after obtaining FAPP results. CONCLUSIONS: This study identified several factors predicting bacterial detection by FAPP in critically ill patients with HAP/VAP. More than 50% real-world clinical practices were adjusted or confirmed based on the FAPP results. Clinical algorithms for the use of FAPP and antimicrobial stewardship guidelines may further enhance its benefits.

High ceftazidime-avibactam resistance among carbapenem-resistant Enterobacter species: Data from the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme, 2014-2021.

OBJECTIVES: Trends in the susceptibility to ceftazidime-avibactam (CZA) and tigecycline (TGC) among Enterobacter species from different geographic areas are unknown.This study aimed to analyse the trends in CZA and TGC susceptibility changes across different continents from 2014 to 2021 utilizing Antimicrobial Testing Leadership and Surveillance (ATLAS) data. METHODS: A total of 23 669 isolates of Enterobacter species were collected over an 8-y period. RESULTS: The overall non-susceptibility rate of Enterobacter isolates to both CZA and TGC was 3.2%. India (16.5%), Guatemala (15.4%), and the Philippines (13.1%) exhibited the highest resistance to CZA. The increase in CZA resistance rates was particularly evident in Asia, with an increase from 4.0% to 8.3%, and in Latin America, from 1.5% to 5%. The non-susceptibility rate for TGC mildly increased in Africa/Middle East but decreased in other continents during the study period. The overall rate of carbapenem resistance increased from 2.9% in 2014-2017 to 4.3% in 2018-2021. Among carbapenem-resistant Enterobacter isolates, the CZA resistance rate was highest in Asia (87.4%), followed by Europe (69.2%) and Africa/Middle East (60.8%). Among the 380 Enterobacter isolates resistant to CZA and carbapenem, the most common genotype of carbapenemase genes was blaNDM (59.2%), followed by blaVIM (24.2%), blaOXA (4.2%), blaIMP (1.1%), and blaKPC (1.1%). The susceptibility of carbapenem-resistant Enterobacter to TGC remained high, with an overall susceptibility rate of 90%. CONCLUSIONS: The heterogeneous distribution of CZA resistance rates among different geographical regions highlights the divergent therapeutic options for drug-resistant Enterobacter species.

Global trends in nonsusceptibility rates of Escherichia coli isolates to meropenem and ceftazidime/avibactam: Data from the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme, 2014-21.

OBJECTIVE: To understand the global changes in the nonsusceptibility rates of Escherichia coli to meropenem and ceftazidime-avibactam (CZA), we conducted a study using the Antimicrobial Testing Leadership and Surveillance database. METHODS: A total of 49 394 E. coli isolates were collected during the 8-year study period. RESULT: The countries with the highest nonsusceptible rates for meropenem were India (16.6%), followed by Pakistan (6.7%), Ukraine (5.4%), Qatar (5.3%), and Guatemala (3.2%). For CZA, the nonsusceptible rate was highest in India (15.6%), followed by Qatar (4.0%), Guatemala (3.9%), China (2.6%), and Thailand (2.5%). During the study period, the nonsusceptible rates of meropenem and CZA in E. coli increased in Asia, Latin America, and Africa/Middle East. Isolates from the medical ICU (odds ratio [OR], 4.62) and surgical ICU (OR, 3.98) were associated with a higher risk of CZA nonsusceptible rates. Compared to intestinal specimens, respiratory and genitourinary specimens had the highest OR (2.32 and 2.17) associated with CZA resistance. Further analysis of carbapenemase distribution showed an increase in the percentage of blaNDM-positive isolates and a decrease in blaKPC-positive isolates worldwide, especially in Latin America. Additionally, we observed a gradual decline in the prevalence of blaOXA-positive E. coli without concomitant carriage of metallo-ß-lactamase genes in the worldwide surveillance. CONCLUSIONS: Further surveillance is necessary to determine whether blaNDM -positive E. coli (i.e., CZA-resistant isolates) is increasing and leading to more superbugs spreading worldwide.

Clinical characteristics and treatment outcomes among the hospitalized elderly patients with COVID-19 during the late pandemic phase in central Taiwan.

BACKGROUND: There is a lack of information regarding outcomes of elderly patients hospitalized with COVID-19 following the widespread use of COVID-19 vaccines and antiviral agents. METHODS: A retrospective study was conducted between January and August 2022, enrolling patients aged 65 years or older. Patients were categorized into two groups: 'old' (65-79 years) and 'oldest-old' (80 years or more). Multivariate regression was employed to identify independent prognostic factors for in-hospital mortality. RESULTS: A total of 797 patients were enrolled, including 428 old and 369 oldest-old patients. In each subgroup, 66.6 % and 59.6 % of patients received at least one dose of the COVID-19 vaccine, respectively. Approximately 40 % of the patients received oral antiviral agents either before or upon hospital admission. A greater percentage of the oldest-old patients received remdesivir (53.4 % versus 39.7 %, p < 0.001), dexamethasone (49.3 % versus 36.7 %, p < 0.001), and tocilizumab (10.0 % versus 6.8 %, p < 0.001) than old patients. The mortality rate was comparable between the two age subgroups (14 % versus 15.2 %). Independent predictors of in-hospital mortality included disease severity and comorbidities such as end-stage renal disease (ESRD), cirrhosis, solid tumours, and haematologic malignancies. Ageing was not correlated with increased in-hospital mortality across all comorbidity subgroups. CONCLUSIONS: In the later stages of the pandemic, with widespread vaccination and advancements in COVID-19 treatments, outcomes for hospitalized elderly and oldest-old patients with COVID-19 have improved. The influence of age on in-hospital mortality has diminished, while comorbidities such as ESRD, cirrhosis, solid tumours, and hematologic malignancies have been associated with mortality.

Minimum inhibitory concentrations of antifungals against invasive isolates of Cryptococcus species worldwide: Global antifungal antimicrobial testing leadership and surveillance program, 2010-2020.

This study examined the geographic distribution of minimum inhibitory concentrations (MICs) of antifungals against Cryptococcus isolates. Data were collected on the MICs of specific antifungals (amphotericin B, 5-flucytosine, fluconazole, voriconazole, posaconazole, and isavuconazole) against various Cryptococcus species for the period 2010 to 2020 from the Antimicrobial Testing Leadership and Surveillance database. Cryptococcus isolates were collected from samples of blood and cerebrospinal fluid (CSF) from patients hospitalized in different regions worldwide. We applied the epidemiological cutoff values (ECVs) of antifungals against various Cryptococcus species to distinguish wild-type (WT) from non-WT Cryptococcus isolates. A total of 395 isolates of Cryptococcus species cultured from blood (n = 201) or CSF (n = 194) were analyzed. C. grubii (n = 270), C. neoformans (n = 111), and C. gattii (n = 11) were the three predominant species causing bloodstream infections (BSI) or meningitis/meningoencephalitis (MME). The proportion of MICs above the ECV (1 mg/L) for amphotericin B among C. neoformans isolates was significantly lower than that among C. gattii isolates (MICs >0.5 mg/L; P < 0.001), as evaluated using the chi-square test. For most isolates of the three predominant Cryptococcus species, the MICs of new triazoles were ≤0.25 mg/L. The MICs of fluconazole and amphotericin B in the BSI/MME-causing Cryptococcus isolates collected from patients hospitalized in the Asia-Western Pacific region and Europe were significantly lower (i.e., the distributions were more leftward) than those in North America and Latin America. Ongoing monitoring of MIC data for important antifungals against cryptococcosis is crucial.

The difference in all-cause mortality between COVID-19 patients treated with standard of care plus placebo and those treated with standard of care alone: a network meta-analysis of randomised controlled trials of immunomodulatory kinase inhibitors.

OBJECTIVES: The aim of this network meta-analysis (NMA) was to assess whether participants assigned to a placebo and standard of care (SoC) group had different major coronavirus disease 2019 (COVID-19)-related outcomes than those assigned to SoC alone. DESIGN: Frequentist model-based NMA. SETTING: We searched for randomised controlled trials (RCTs) of Janus kinase/Bruton tyrosine kinase inhibitors for the management of COVID-19. PARTICIPANTS: Patients with COVID-19 infection. MAIN OUTCOME MEASURES: The primary outcome was the 28-day all-cause mortality, and secondary outcomes were: (1) use of mechanical ventilation; (2) secondary bacterial infection; (3) acceptability (i.e. drop-out rate); and (4) safety (i.e. serious adverse events). We conducted an NMA using the frequentist model. Effect sizes were estimated using odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: We identified 14 eligible RCTs enrolling a total of 13,568 participants with COVID-19. Participants assigned to placebo plus SoC had a significantly higher risk of 28-day all-cause mortality than those receiving SoC alone (OR = 1.39, 95% CI = 1.07-1.79). This finding did not change substantially by subgroup analysis stratified by epidemiology factor, pandemic history progression and statistical methodologic consideration. In addition, none of the treatments investigated were associated with a significantly different risk of secondary bacterial infection, acceptability or safety compared with the SoC group. CONCLUSIONS: This NMA suggested a higher all-cause mortality in patients treated with placebo plus SoC compared with those treated with SoC alone. However, caution is advised in interpreting these results due to the absence of a direct head-to-head comparison. Future research should critically evaluate the necessity of placebo administration in COVID-19 RCTs and consider alternative study designs to minimise potential biases.Trial registration: The current study was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (TSGHIRB No. B-109-29) and registered in PROSPERO (CRD42022376217).

Effect of pre-hospitalization use of oral antiviral agents on reducing critical illness and mortality for patients with COVID-19 pneumonia.

OBJECTIVES: This study aimed to evaluate the effect of administering nirmatrelvir/ritonavir and molnupiravir before hospitalisation on subsequent critical illness among patients with COVID-19 pneumonia. METHODS: This retrospective cohort study included patients with COVID-19 pneumonia who required hospitalisation between 1 January 1 2022 and 31 August 2022. The primary outcomes were the development of critical illness, including intensive care unit admission, use of mechanical ventilation, or mortality. A multivariate logistic regression analysis was conducted to assess the varying risks of critical illness and mortality. A total of 1,011 COVID-19 patients were analysed. Among them, 304 (30.1%) received molnupiravir and 131 (13.0%) received nirmatrelvir/ritonavir before hospitalisation. RESULTS: There were significant reductions for critical illness (adjusted odds ratio 0.29, 95% confidence interval 0.21-0.39, P < 0.001) and mortality (adjusted odds ratio 0.40, 95% confidence interval 0.27-0.59, P < 0.001) in patients receiving oral antivirals compared with those who did not. No significant differences in critical illness were observed between molnupiravir and nirmatrelvir/ritonavir. The combination of COVID-19 vaccines and oral antivirals can further reduce the risk of critical illness in high-risk populations. CONCLUSION: Administering molnupiravir and nirmatrelvir/ritonavir before hospitalisation reduced the risk of COVID-19 patients with moderate to severe pneumonia progressing to critical illness and mortality.

Clinical significance of mutations in dihydropteroate synthase in Pneumocystis jirovecii pneumonia among non-HIV-infected patients.

BACKGROUND: Dihydropteroate synthase (DHPS) mutations may be associated with trimethoprim-sulfamethoxazole resistance in Pneumocystis jirovecii pneumonia (PCP) and worse clinical outcomes. However, the clinical significance of DHPS mutations in PCP among non-human immunodeficiency virus (HIV)-infected patients remains unclear. METHODS: Patients with PCP in three tertiary referral hospitals in Taiwan between 2016 and 2020 were retrospectively enrolled. Two point mutations, Thr55Ala and Pro57Ser, in the DHPS protein were analysed. Patients with invalid DHPS mutations in the respiratory specimen, chronic respiratory failure, receiving endotracheal intubation for surgical intervention, HIV infection, Pneumocystis jirovecii colonisation, and no lactate dehydrogenase (LDH) data were excluded. The primary outcome was 30-day survival. RESULTS: A total of 215 patients were analysed. Mutants inside DHPS were found in 78 patients (36.3%) and 68 patients (31.6%) died within 30 days. A total of 214 patients (99.5%) received trimethoprim-sulfamethoxazole as the first-line treatment. The rates of mechanical ventilation, 30-day, and in-hospital mortality were similar between wild-type and mutant DHPS PCP. After adjusting for important confounders, LDH > 500 µ/L (adjusted hazard ratio [aHR] = 2.448, P = 0.001), pneumonia severity index > 135 mg/dL (aHR = 1.689, P = 0.049), and having solid tumours (aHR = 1.832, P = 0.034) were independently associated with higher mortality. In subgroup analysis, mutant DHPS PCP patients had less 30-day mortality among patients aged > 65 years (P = 0.049), with lymphopenia (P = 0.040), and those without solid tumour (P = 0.045). CONCLUSIONS: In non-HIV-infected PCP, point mutants inside DHPS may not be associated with trimethoprim-sulfamethoxazole treatment outcomes. Further prospective large-scale studies are warranted.