Infectious Diseases and Therapy最新文献

Introduction: Broad-spectrum antimicrobials are commonly administered for community-acquired pneumonia (CAP); however, unnecessary administration may cause adverse events and poor outcomes. This study aimed to understand the impact of broad-spectrum anti-pseudomonal β-lactam use on clinical outcomes and healthcare resource utilization (HCRU) in inpatients with CAP and a low risk of drug-resistant pathogens (DRPs).

Methods: This historical cohort study reviewed Japan's hospital claims database (January to December of 2018) and included inpatients aged ≥ 20 years who received intravenous antimicrobial therapy for CAP. Those with high DRP risk were excluded. According to the initial antimicrobial regimen, patients were divided into broad-spectrum (anti-pseudomonal β-lactam therapy) and narrow-spectrum (non-anti-pseudomonal β-lactam therapy) groups. This study evaluated 30-day hospital mortality as a primary outcome using inverse probability of treatment weighting (IPTW) to adjust for differences between both groups and HCRU as an exploratory analysis.

Results: A total of 15,617 patients were analyzed (2627 in the broad-spectrum group and 12,990 in the narrow-spectrum group). In the broad-spectrum group, the 30-day mortality rate was 10.6%, which was higher than that in the narrow-spectrum group (5.3%). Furthermore, it was associated with an increased 30-day mortality compared with the narrow-spectrum group after IPTW (adjusted odds ratio, 1.77; 95% confidence interval, 1.52-2.06; p < 0.001). The mean inpatient cost was USD 6139 and USD 5184 for the broad- and narrow-spectrum groups, respectively.

Conclusions: The initial use of anti-pseudomonal β-lactams for CAP with low DRP risk is associated with poor outcomes, including death and high HCRU. Thus, initial antimicrobials should be judiciously selected for CAP management.

Introduction: Since May 2024, Israel has been experiencing a large West Nile virus (WNV) outbreak. We aimed to compare the clinical characteristics and outcomes of hospitalized cases to previous years and identify predictors of poor outcomes.

Methods: A retrospective study. We compared WNV infection cases hospitalized during the 2024 outbreak (from 29 May to 29 July) to cases hospitalized during 2018-2023. For the entire cohort, risk factors for poor outcomes were investigated using multivariable analyses. The primary outcomes were death and a composite outcome of 30-day all-cause mortality, prolonged hospitalization (≥ 28 days), or discharge to an institution.

Results: We included 134 patients, 103 admitted during 2024 and 31 during 2018-2023. The majority (109/134, 81%) had neuroinvasive disease, mostly encephalitis. In 2024, patients were older, with a lower functional state, and a higher proportion were severely immunocompromised. Mortality was numerically higher in 2024 (15/103, 15% versus 2/31, 6%). Altogether, nearly 40% of patients had poor outcomes, including 13% (17/134) mortality and 25% (34/134) discharged to institutions. Nearly 30% of patients who were severely immunocompromised died; all had B-cell depletion. Age was the only significant predictor of poor outcomes in multivariable analysis; however, patients with B-cell depletion had > 3 times higher odds for mortality (odds ratio 3.26, 95% confidence interval 0.73-13.07).

Conclusions: The large 2024 outbreak of WNV was associated with considerable mortality and functional impairment among hospitalized patients that was higher compared with previous years. Poor outcomes were particularly observed in older adults and patients with B-cell depletion. The observation of severe disease and poor outcomes in patients with B-cell depletion, as well as possible therapeutic implications, should be further investigated.

Introduction: Gender inequity in medical academic forums persists despite attempts to ensure better gender equality. In this study, we aimed to assess the proportion of female award and grant winners in both the ESCMID global and IDWeek conferences.

Methods: Female award and grant winners in infectious diseases conferences (2009-2023) were evaluated. Data were collected from the conferences' program book and websites. Gender for each award or grant recipient was assessed using Genderize.io or, if inconclusive, manually. We summarized proportions of women award/grant winners by society and over time.

Results: Between 2009 and 2023, 39% (34/88) of ESCMID award winners and 57% (858/1504) of grant winners were women; For IDWeek, 32% (39/122) of award winners and 68% (17/25) of grant winners were women. For both societies there was a clear increase in women's representation from 2009 to 2014, with stabilization thereafter.

Conclusions: Representation of women in conferences has vastly improved over the years, though additional policies and programs are needed to reduce the remaining gender disparities.

Introduction: Ceftazidime-avibactam (CZA) is recommended to treat infections caused by carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa with difficult-to-treat resistance. The selective pressure of CZA results in the isolation of multidrug-resistant Gram-negative bacteria (MDR-GNB), causing superinfection or hospital-wide spread. We aimed to study the clinical characteristics of patients who acquired GNB during CZA treatment.

Methods: Adult patients treated with CZA for ≥ 5 days for proven or suspected MDR-GNB were retrospectively enrolled at Taipei Veterans General Hospital between December 2019 and June 2021. GNB acquisition was defined as new GNB species resulting in infection or colonization isolated during the period from 5 days after the initiation of CZA until the end of treatment. Clinical features were compared between patients who acquired GNB from clinical specimen and those who did not. Multivariable analysis was used to explore risk factors for acquisition of GNB and 28-day mortality in patients who acquired GNB.

Results: Among 321 patients treated with CZA, 68 GNB were identified in 55 patients (17.1%). Elizabethkingia species (n = 15) was the most common GNB, followed by Acinetobacter species (n = 13) and Burkholderia cenocepacia (n = 11). The presence of diabetes mellitus, and mechanical ventilation were independent risk factors for GNB acquisition. There was a statistically nonsignificant trend toward increased 28-day mortality in patients with GNB acquisition compared to those without (38.2% vs. 27.8%, P = 0.105). Cerebrovascular disease and acquired GNB resulting in infection were associated with 28-day mortality in patients who acquired GNB.

Conclusions: Elizabethkingia species, Acinetobacter species, and B. cenocepacia were the major GNB acquired during CZA treatment. A trend toward increased mortality was observed in patients with GNB acquisition during CZA treatment. Further studies on optimal treatments for these patients were warranted.

Introduction: This first-time-in-human study describes the pharmacokinetics, drug-drug interaction potential, and safety of VH4011499 (VH-499), a new HIV-1 capsid inhibitor.

Methods: This double-blind, randomized, placebo-controlled, phase 1 study evaluated VH-499 in adults without HIV administered orally as single ascending doses as powder-in-bottle (PiB; part 1) and tablet (part 3) formulations and as multiple ascending doses as PiB formulation dosed once daily for 14 days (part 2). Midazolam was used to evaluate the effect of VH-499 on cytochrome P450 3A (CYP3A) activity (part 2).

Results: Overall, 73 participants were included (VH-499, n = 56; placebo, n = 17). VH-499 plasma exposures were less than dose-proportional, with median time to maximum observed concentration of 8.0-12.0 h for the PiB formulation and 24.0 h for the tablet formulation. Geometric mean terminal half-life was 51.2-66.5 h (2-3 days). The tablet formulation resulted in 45-63% lower exposures compared with PiB. Concomitant midazolam administration after single and multiple VH-499 doses did not lead to clinically significant changes in midazolam or 1-hydroxymidazolam exposures; therefore, VH-499 is not expected to inhibit or induce CYP3A4. VH-499 was well tolerated. Adverse event (AE) frequency was comparable between placebo and VH-499 groups. VH-499-related AEs were predominantly grade 1. No serious AEs across VH-499 groups, AEs leading to withdrawal from drug/study, or deaths occurred. There were no trends in vital signs, electrocardiograms, or laboratory hematology parameters and no clinically relevant changes in chemistry parameters.

Conclusion: First-time-in-human data further characterize the pharmacokinetics of orally administered VH-499 and provide support for development of VH-499 as part of a complete long-acting regimen for HIV-1 treatment and prevention.

Clinical trial registration: ClinicalTrials.gov, NCT05393271.

Introduction: Many countries recommend vaccination against Neisseria meningitidis serogroups A, C, W, and Y in infants and young children to prevent invasive meningococcal disease. We evaluated the immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT) booster in children primed with the same meningococcal vaccine 5 years earlier. Immune persistence following priming vaccination was also evaluated, and the study is ongoing to generate 10 years' post-priming data.

Methods: Healthy children, vaccinated with MenACYW-TT 5 years earlier as toddlers, were enrolled. Participants were randomized to receive MenACYW-TT booster (group 1) or no booster (group 2), stratified by country and meningococcal serogroup C (MenC) vaccination status (primed at age ≤ 1 year vs. naive). Antibodies against each serogroup were measured by serum bactericidal assay using human complement (hSBA). Seroresponse sufficiency at 30 days post-booster was demonstrated if the lower limit of the one-sided 97.5% confidence interval (CI) of the seroresponse rate (proportion of participants with post-vaccination titers ≥ 1:16 when baseline titers were < 1:8 or with a ≥ fourfold increase when baseline titers were ≥ 1:8) was > 75% for each serogroup. Seroprotection rates (proportion with hSBA titers ≥ 1:8) and geometric mean titers (GMTs) for each serogroup were also assessed.

Results: A total of 209 participants were enrolled across 26 sites in Finland, Germany, Hungary, and Spain (group 1, n = 93; group 2, n = 116). Five years post-priming, GMTs, and seroprotection rates were higher than those observed before priming vaccination in both groups, indicating long-term persistence. Booster seroresponse rates in group 1 for all serogroups ranged from 93.2% to 98.9%, with seroresponse sufficiency demonstrated (lower limit of one-sided 97.5% CIs for the seroresponse rates ranging from 85.7% to 93.8%). Seroprotection rates and GMTs post-booster increased across all serogroups, with nearly all participants seroprotected, suggesting adequate booster response. Seroresponse was comparable between MenC-primed and MenC-naive participants. No new safety concerns were identified.

Conclusions: MenACYW-TT provides long-term immune persistence and a robust immune response when administered as a booster in children primed 5 years earlier.

Trial registrations: Clinicaltrials.gov, NCT04936685; EudraCT: 2021-000104-38; WHO: U1111-1255-4941. Graphical abstract available for this article.

Introduction: Multidrug resistance (MDR) has been identified in wound bacterial isolates from Ukrainian war victims treated in Ukraine and across Europe. ILP100, a drug candidate for the treatment of skin wounds, is composed of a Limosilactobacillus reuteri expressing human chemokine CXCL12. In this study, the antimicrobial effects of ILP100 were tested on MDR bacteria isolated from wounds of Ukrainian war victims.

Methods: ILP100 was co-cultured with one of the wound pathogens (Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter cloacae, Klebsiella pneumoniae, Proteus mirabilis, Staphylococcus aureus; 12 non-MDR and 12 MDR isolates) in broth media for 12 h with subsequent survival recovery on agar plates. Additionally, agar plates were precoated with ILP100 at clinical doses (3 vs. 24 h, 1 × 10⁷ CFU/cm²) followed by co-culture with pathogens inoculated in soft agar (1 × 10⁴ CFU/cm²). To compare ILP100 with relevant antibiotics, MDR-inoculated soft agar was applied to plates with standardized ILP100 drops and antibiotic-loaded discs, followed by 18-20 h aerobic incubation at 37 °C.

Results: Dose-dependent growth inhibition of all pathogens was demonstrated, as 1000:1 and 100:1 (ILP100/isolate) inhibited pathogenic growth up to log 6.4 and log 4.3 CFU/ml, respectively. Potent antimicrobial effects were demonstrated after precoating with ILP100, as pathogen recovery was only demonstrated after 3 h of precoating, only for 10/18 isolates and then only partially. Benchmarking to relevant antibiotic discs resulted in large cleared zones surrounding the ILP100 spots but not the antibiotic discs, demonstrating potent bacterial killing by ILP100-secreted factors. Interestingly, the MDR pathogens were significantly more sensitive to the ILP100 released factors than the non-MDR isolates.

Conclusion: ILP100 effectively eliminates MDR wound pathogens, which reveals a promising strategy for the development of new classes of urgently needed antimicrobials.

Introduction: Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) is a recommended first-line antiretroviral (ART) regimen. Croatia has centralized care for people living with HIV (PLWH) in a single center, with a same-day ART initiation model whenever suitable. This retrospective cohort study aimed to determine whether same-day BIC/FTC/TAF initiation in a real-life setting is an effective regimen for achieving viral suppression.

Methods: We identified 107 ART-naïve PLWH who started BIC/FTC/TAF between May 2019 and December 2022. BIC/FTC/TAF was initiated within 24 h of the first clinical visit. To emulate a prospective clinical trial, we present our efficacy results for the whole population (intention-to-treat, ITT) and those evaluated (on treatment, OT).

Results: A total of 107 PLWH were included; the mean age was 38.5 years, 103 (96.3%) were male, and all PLWH were white. The mean CD4 count was 343.8 cells/μl (26.2% had a CD4 count < 200 cells/μl), and the HIV-1 RNA was 4.9 log10 copies/ml (43.9% had > 100,000 copies/ml). Acute/recent infection was diagnosed in 32 (29.9%) PLWH, and 4 (3.7%) were HBsAg positive. At 12 months (range 9-15), the efficacy (HIV-1 RNA < 50 copies/ml) in the ITT analysis was 78.5%, and the OT efficacy was 91.3%. Among the 15 PLWH who did not have viral load (VL) measurements at 12 months, nine had a subsequent undetectable VL, three were lost to follow-up, two moved, and one died. No discontinuations of BIC/FTC/TAF were observed.

Conclusions: In our real-life clinical setting, same-day treatment with BIC/FTC/TAF was an efficacious and feasible option for achieving viral suppression in treatment-naïve PLWH.