Infectious Diseases and Therapy最新文献

Introduction: Despite the approval of a 20-valent pneumococcal conjugate vaccine (PCV20) for pediatric use in many regions globally, integration of PCV20 into national immunization programs (NIPs) is delayed in some countries. We explored the public health and economic benefits forfeited by postponing transitions from lower-valent pneumococcal conjugate vaccines (PCVs) to PCV20.

Methods: A targeted literature review (TLR) identified modeling studies comparing the public health and economic impact of PCV20 versus 13-valent PCV (PCV13) or 15-valent PCV (PCV15) in pediatric NIPs. Only studies with accessible models underwent data extraction and analysis. Foregone public health (pneumococcal disease cases/disease-related deaths) and economic (medical/non-medical costs) outcomes, defined as the projected incremental differences between the outcomes associated with PCV20 and lower-valent PCVs, were calculated over 2 years following PCV20 implementation (per year and month). Discount rates for all outcomes were adjusted to 0% given the short time horizon and for consistency across analyses.

Results: The TLR identified models from 13 countries globally. The monthly health benefits forgone due to delayed transitions from PCV13 to PCV20 ranged between 40 (Slovakia) and 1740 (Canada) pneumococcal disease cases averted in the first year of delay across populations, increasing by between 1.5 (Sweden) and 15-16 times (Germany and Mexico) in the second year. Forgone cumulative disease-related deaths averted ranged from 18 (Spain) to 2657 (Germany) and forgone cumulative direct medical cost-savings ranged from 930 thousand Euros (Portugal) to 146 million Euros (Germany) due to delayed transitions from PCV13 to PCV20 over 2 years. Similar, but slightly reduced, benefits were forfeited with delayed transitions from PCV15 to PCV20.

Conclusion: Delays in implementing PCV20 into pediatric NIPs were projected to have substantial negative public health and economic consequences. These results underscore the necessity for national immunization technical advisory groups, policymakers, health organizations, and manufacturers to accelerate replacement of lower-valent standard-of-care PCVs with PCV20.

Introduction: Infants and young children typically have the highest age-related risk of invasive meningococcal disease. The immunogenicity and safety of a single primary dose and a booster of a meningococcal A/C/W/Y tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix^®) in infants were evaluated.

Methods: In this phase 3b, open-label, single-arm study, healthy 3-month-old infants received a single Nimenrix dose followed by a booster at age 12 months (1 + 1 series). Functional antibodies before and 1 month after each vaccination were evaluated with serum bactericidal antibody assays using rabbit (rSBA) or human (hSBA) complement for each A/C/W/Y serogroup. Primary endpoints were rSBA seroprotection (titers ≥ 1:8) rates and geometric mean titers (GMTs); supportive secondary endpoints included hSBA seroprotection (titers ≥ 1:4) rates and GMTs. Local reactions and systemic events occurring within 7 days, adverse events (AEs), serious AEs, and newly diagnosed chronic medical conditions following vaccination were assessed.

Results: Overall, 147 and 143 participants received the primary and booster Nimenrix doses, respectively. rSBA seroprotection rates across serogroups were 82.3-91.1% at 1 month after the primary dose and increased to 100% at 1 month after the booster. rSBA GMTs were considerably higher after the booster (1299.5‒2714.1) than after the primary dose (54.7‒202.4). In hSBA evaluations performed as supportive to rSBA evaluations, seroprotection rates increased from 38.8 to 95.5% after the primary dose to 100% after the booster, with corresponding GMT increases (8.8‒149.8 to 1208.4‒7299.6). Local reactions and most systemic events were mild to moderate in severity; no new safety concerns were identified.

Conclusion: Nimenrix given at ages 3 and 12 months had a favorable safety profile and elicited protective immune responses and robust anamnestic booster responses across A/C/W/Y serogroups. These results provide important support for this alternative Nimenrix 1 + 1 immunization schedule for infants < 6 months, allowing flexibility in infant meningococcal immunization.

Trial registration: ClinicalTrials.gov, NCT04819113.

Introduction: Sepsis is a serious condition that may lead to death or profoundly affect the well-being of those who survive. The aim of this systematic review was to identify and summarize evidence on the impact of all-cause sepsis on health-related quality of life (HRQoL), physical, cognitive, and psychological outcomes among sepsis survivors in the USA.

Methods: Studies assessing HRQoL, physical, cognitive, and psychological outcomes in patients who survived an episode of sepsis and published from January 1, 2010, to September 30, 2023, were systematically identified through EMBASE, MEDLINE, and MEDLINE In-Process databases, as well as through gray literature.

Results: Of 2885 records identified, 7 studies (7 publications; N = 180,592 participants) met the eligibility criteria for inclusion in this review. Studies examined the effects of sepsis on the following outcomes of interest: HRQoL (4 studies), physical functioning (5 studies), cognitive status (3 studies), and psychological well-being (3 studies). After 12 months, sepsis survivors who developed chronic critical illness (N = 63) had significantly poorer HRQoL as measured by EuroQoL 5-dimensional (EQ-5D) questionnaire mean utility index score and Short Form 36-item (SF-36) physical and mental summary scores compared with patients who rapidly recovered (N = 110). Among patients admitted to a skilled nursing facility post-sepsis (N = 66,540), 34% and 72.5% had severe or very severe cognitive impairment and dependence to perform activities of daily living, respectively. Significant increase in moderate-to-severe cognitive impairment among severe sepsis survivors (N = 623) before and after sepsis was reported (median 0.9 [IQR: 0.4, 1.4] years; 6.1% and 16.7%, respectively [P < 0.001]). Substantial depression and anxiety symptoms were frequently observed post-sepsis, but with limited evidence for increased burden as assessed by specific psychological measures.

Conclusion: These findings underscore the profound negative impacts of sepsis on patients' HRQoL, ability to perform activities of daily living, and cognitive abilities.

Introduction: Predictors of coronavirus disease 2019 (COVID-19)-related rehospitalization remain underexplored. This study aims to identify the main risk factors associated with rehospitalizations due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfections among residents of Lombardy, northern Italy.

Methods: A retrospective observational study was conducted using two linked administrative databases covering demographic data, comorbidities, hospital records, and COVID-19 data of Lombardy residents. The study population included patients hospitalized for COVID-19 between February 2020 and August 2021. Rehospitalization was defined as a second COVID-19-related hospitalization occurring at least 90 days after the first admission. The Fine-Gray subdistribution hazard model was used to identify risk factors, accounting for death as a competing risk.

Results: Out of 98,369 patients hospitalized for COVID-19 between February 1, 2020 and August 31, 2021, 72,593 were alive 90 days after admission and 610 of these (0.8%) were rehospitalized. A higher rehospitalization risk was observed in older male patients with multiple comorbidities. Renal failure, liver disease, and use of diuretics were significantly associated with rehospitalization risk, while female biological sex and the use of lipid-lowering drugs were associated with a lower risk.

Conclusions: This is the first study conducted on regional administrative databases to investigate COVID-19 rehospitalizations. Through the availability of a huge cohort, it provides a groundwork for optimizing care for individuals at higher risk for COVID-19-related rehospitalizations. It underlines the need for patient-management approaches that extend beyond the initial recovery. This stresses the importance of ongoing monitoring and personalized interventions for those at heightened risk not only of SARS-CoV-2 reinfection but also related rehospitalizations.

Introduction: Dolutegravir (DTG) + lamivudine (3TC) demonstrated high rates of virologic suppression (VS) and low rates of virologic failure (VF), discontinuation, and drug resistance in randomized trials. Real-world evidence can support treatment effectiveness, safety, and tolerability in clinical practice and aid in treatment decisions.

Methods: A systematic literature review (SLR) was conducted to identify studies using DTG + 3TC (January 2013-March 2024). Studies were screened to include observational studies reporting 48- or 96-week on-treatment VS, VF, or discontinuation outcomes; proportions of individuals with each outcome at each time point were estimated using random- and common-effects models.

Results: Of 249 SLR-identified publications, 43 reported consistently defined outcomes of interest at comparable time points, representing 1480 individuals naive to antiretroviral therapy (ART) and 12,234 individuals with prior ART experience. At weeks 48 and 96, respectively, estimated proportions (95% CIs; random-effects model) with on-treatment VS were high (naive to ART, 0.964 [0.945-0.979] and 0.902 [0.816-0.966]; prior ART, 0.966 [0.950-0.980] and 0.971 [0.946-0.990]), with low estimated proportions experiencing VF (naive to ART, 0.001 [0.000-0.013] and 0.001 [0.000-0.008]; prior ART, 0.009 [0.005-0.015] and 0.015 [0.007-0.024]) and discontinuations for any reason (naive to ART, 0.052 [0.019-0.097] and 0.130 [0.084-0.183]; prior ART, 0.067 [0.042-0.098] and 0.084 [0.047-0.130]). Across identified studies (> 44,000 unique individuals), those reporting resistance outcomes at VF/blip (regardless of emergence) detected integrase strand transfer inhibitor (INSTI) mutations in 0 of 2346 individuals naive to ART and 0.02% (4/20,060) of individuals with prior ART experience (S147G, R263K, G118R + E138K, T66A + G118R + E138K); additionally, N155H was reported in an individual using DTG + 3TC with unknown baseline ART status.

Conclusion: Overall treatment outcomes in real-world settings confirm the efficacy, tolerability, and high barrier to resistance seen in phase 3 trials across diverse populations, including those naive to ART or with prior ART experience.

Recurrent Clostridioides difficile infection (rCDI) is a major cause of increased morbidity, mortality, and healthcare costs. Fecal-microbiota-based therapies are recommended for rCDI on completion of standard-of-care (SoC) antibiotics to prevent further recurrence: these therapies include conventional fecal-microbiota transplantation and the US Food and Drug Administration-approved therapies REBYOTA® (RBL) and VOWST Oral Spores™ (VOS). As an alternative to microbiota-based therapies, bezlotoxumab, a monoclonal antibody, is used as adjuvant to SoC antibiotics to prevent rCDI. There are no head-to-head clinical trials comparing different microbiota-based therapies or bezlotoxumab for rCDI. To address this gap, we conducted a systematic literature review to identify clinical trials on rCDI treatments and assess the feasibility of using them to conduct an indirect treatment comparison (ITC). The feasibility analysis determined that trial heterogeneity, particularly relating to inclusion criteria, may significantly compromise ITC and prevent cross-trial comparisons. Our analysis underlines the need to adopt standardized protocols to ensure comparability across trials.

Introduction: We aimed to investigate risk factors for mortality among older adults (≥ 75 years) with hospital-acquired bloodstream infections (HA-BSI) in the intensive care unit (ICU).

Methods: We included patients aged ≥ 75 years with HA-BSI in ICU from the EUROBACT-2 cohort (2019-2021). Univariable and multivariable analyses were conducted to identify predictors of 28-day mortality.

Results: The cohort included 563 patients (median age 80, 39% women). Mortality at 28 day was 50%. Factors associated with mortality in multivariate analysis were admission due to COVID-19, failure to achieve source control, and higher SOFA. Among older adults with Gram-negative BSI, corticosteroid administration for septic shock was an additional factor. Among functionally independent patients, age itself was not associated with mortality.

Conclusions: HA-BSI in older adults in ICU are associated with high mortality. Inadequate source control is a significant modifiable risk factor. The use of corticosteroids in ICU management of older adults should be further investigated.

Introduction: Despite a scarcity of data, before 2022 Ukraine was already considered a high-prevalence country for carbapenemase-producing Enterobacterales (CPE), and the situation has dramatically worsened during the full-scale war with Russia. The aim of this study was to analyse CPEs isolated in Poland from victims of war in Ukraine.

Methods: The study included 65 CPE isolates from March 2022 till February 2023, recovered in 36 Polish medical centres from 57 patients arriving from Ukraine, differing largely by age and reason for hospitalisation. All isolates were sequenced by MiSeq and ten Klebsiella pneumoniae isolates also by MinION. Taxonomy, clonality and resistomes were analysed for all CPEs, whereas phylogeny, serotypes, virulomes and plasmids were characterised for K. pneumoniae, and partially for Escherichia coli ST131, using various bioinformatic tools.

Results: Multifactorial diversity of the isolates reflected the patients' clinical-epidemiological heterogeneity. The CPEs represented six species. Klebsiella pneumoniae was the most prevalent with 50 isolates and 15 sequence types (STs), mainly ST395, ST307, ST11, ST147 and ST23, producing NDM (-1/-5), OXA-48 (-48/-1242) or KPC (-2/-3)-like carbapenemases. Each of the STs produced groups of loosely related isolates, clusters of close relatives and/or unique isolates, correlating with K serotypes and carbapenemases. Many of these, especially NDM-1- and/or OXA-48-producing ST395 and ST307, were related to Russian organisms. Others, for example, NDM-1-producing ST11, clustered with those from Poland. Numerous K. pneumoniae isolates had specific virulence genes, including aerobactin iuc, largely due to spread of pNDM-MAR plasmids, showing both resistance and virulence. Two E. coli ST131 isolates belonged to clades B or C1 and produced KPC-3 or NDM-1, respectively.

Conclusions: Together with similar studies from Germany and The Netherlands, this work has documented broad dissemination of CPE in Ukraine, driven by a number of specific K. pneumoniae lineages circulating over a large territory of Eastern Europe.

Tuberculous meningitis (TBM) disables more than a third of its sufferers. Recent research has focused on optimizing the antitubercular regimen, mainly by increasing the dosage of rifampicin. However, pyrazinamide, with higher penetration into the central nervous system, is generally overlooked. We discuss the potential clinical impact of using pyrazinamide throughout antitubercular therapy in TBM, in contrast to only the intensive phase. This approach may improve the treatment outcomes and reduce disability in TBM. We summarize the available data regarding this approach from in vitro studies, clinical cohorts, toxicity data, and baseline resistance rates. Additionally, we discuss the two ongoing clinical trials evaluating this approach.

Introduction: As no standard case definitions for respiratory syncytial virus-associated lower respiratory tract disease (RSV-LRTD) in adults are available, this study analyzed definitions for severe RSV-LRTD from previously published data in hospital and community cohorts of adults with RSV-associated symptoms.

Methods: The frequency, sensitivity, and specificity of acute respiratory disease symptoms among hospitalized and community cohorts of adults with RSV were analyzed. RSV-LRTD signs/symptoms assessed included shortness of breath (dyspnea), cough and/or fever, wheezing/rales/rhonchi (abnormal lung sounds by auscultation), sputum production, tachypnea, hypoxemia, and pleuritic chest pain.

Results: Dyspnea and tachypnea provided the best differentiation between hospitalized and community RSV-positive cases. The severe RSV-LRTD case definition yielding one of the highest and best-balanced sensitivity and specificity was dyspnea paired with either abnormal lung sounds by auscultation, hypoxemia, tachypnea, cough and/or fever, sputum, or chest pain.

Conclusions: Dyspnea alone, and in combination with certain other lower respiratory tract disease signs/symptoms, was a leading symptomatic indicator for severe RSV outcomes. These results contribute to the harmonization of case definitions for RSV disease.