Infectious Diseases and Therapy最新文献

Introduction: Pseudomonas aeruginosa is a leading cause of bloodstream infections (BSI) in hospitalized patients. Although it is regarded as an aerobic microorganism, under certain conditions it can switch to anaerobic respiration using other terminal electron acceptors other than oxygen. The study aims to evaluate the clinical and microbiological factors associated with P. aeruginosa isolation in anaerobic blood culture bottles and determine whether anaerobic growth is an independent risk factor for septic shock and 30-day mortality in patients with P. aeruginosa BSI.

Methods: This was a retrospective unicentric study analyzing 734 episodes of P. aeruginosa BSI at a university hospital from 2010 to 2019. Clinical presentation, comorbidities, source of infection, microbiologic data, and outcomes were collected. Anaerobic growth was defined as the isolation of P. aeruginosa in at least one anaerobic blood culture bottle. Multivariate logistic regression models were used to identify factors associated with septic shock and 30-day mortality.

Results: P. aeruginosa was isolated in anaerobic bottles in 19.1% of cases, though it was never exclusively isolated in anaerobic bottles. While median time to positivity (TTP) in anaerobic bottles was significantly longer than in aerobic ones (16.5 h vs. 14.8 h, p < 0.01), TTP in aerobic bottles was shorter when P. aeruginosa was also isolated in anaerobic bottles (12.5 h vs. 15.5 h, p < 0.01). Factors significantly associated with anaerobic growth included chronic kidney disease, longer time of admission, active antibiotic treatment, and several sources of bacteremia (catheter-related, respiratory, and primary bacteremia). Anaerobic growth was independently associated with higher odds of septic shock (OR 2.8, p < 0.01) and increased 30-day mortality (OR 2.3, p < 0.01). Moreover, septic shock and mortality rates were higher when P. aeruginosa grew in both anaerobic bottles.

Conclusions: Anaerobic growth of P. aeruginosa in blood cultures is an independent predictor of septic shock and 30-day mortality in patients with P. aeruginosa BSI. The potential relationship between higher bacterial load and biofilm formation in the source of infection with anaerobic growth of P. aeruginosa may contribute to the observed poorer outcomes.

Introduction: Patient-reported outcomes (PROs) provide important insights into individuals' health and well-being. We report PROs from six observational cohort studies in treatment-experienced people with HIV switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in routine clinical practice.

Methods: Data were pooled from the BICtegravir Single Tablet Regimen (BICSTaR) cohort studies (Asia/Canada/EU/Israel/Japan) and a similarly designed Chinese cohort study (GS-CN-380-5759). Quality of life (QoL; mental/physical health) and HIV treatment satisfaction were self-reported by participants using the generic (non-HIV-specific) 36-item Short Form Health Survey questionnaire and HIV Treatment Satisfaction Questionnaire (HIVTSQ; status [s]/change), respectively. Descriptive statistics and linear mixed models adjusted for potential confounders and interactions, with bootstrapped confidence intervals, were used to analyse PROs through 24 months (12 months for treatment satisfaction).

Results: Of 3724 treatment-experienced participants included, 64.2% were Asian, 89.0% male; median age was 41 years. Baseline Mental Component Summary (MCS) scores were below the population average despite receiving antiretroviral therapy, whereas Physical Component Summary (PCS) scores were above average. At 24 months, observed median MCS score improved from baseline (+ 0.6 [interquartile range [IQR] - 4.3 to + 5.9; p = 0.018]) and median PCS score remained stable (- 0.1 [IQR - 3.3 to + 3.3; p = 0.998]). In all key populations, predicted adjusted MCS/PCS scores showed small improvements or remained stable over time. Treatment satisfaction was high at baseline (median HIVTSQs score 55 [IQR 49-60]), with participants reporting improved treatment satisfaction following the switch to B/F/TAF compared with their previous regimen (+ 27 [19-30] at 12 months). Similar improvements were observed across all key populations.

Conclusion: In this large cohort of people with HIV who switched to B/F/TAF in routine clinical practice, mental and physical health scores improved or remained stable over time and treatment satisfaction improved. Further studies are required to elucidate the clinical relevance of PRO tools and how they relate to QoL in people with HIV. Video abstract available for this article.

Trial registration: ClinicalTrials.gov identifiers NCT03580668 (Canada study) and NCT04009057 (Israel study); EudraCT trial identifier, EUPAS22185 (Europe study). Video abstract available for this article. Quality of life and treatment satisfaction in people with HIV switching to bictegravir/emtricitabine/tenofovir alafenamide: Pooled analysis from observational cohort studies - a video abstract.

Introduction: Adherence to antiretroviral therapy (ART) is crucial for people with HIV (PWH) to maintain health. The Medicare program insures a substantial proportion of PWH in the United States; however, few studies have evaluated ART treatment patterns in this population. This study described treatment persistence and switch patterns among Medicare-insured PWH with low ART adherence or significant treatment gaps prior to re-initiating ART.

Methods: A retrospective cohort study was conducted using data from Medicare Fee-For-Service and Medicare Advantage from January 2017 to December 2022. PWH aged ≥ 18 years with documented treatment experience receiving an index ART regimen of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), dolutegravir/lamivudine (DTG/3TC), dolutegravir/abacavir/lamivudine (DTG/ABC/3TC), or multi-tablet regimens (MTRs; dolutegravir + emtricitabine/tenofovir alafenamide [DTG + F/TAF] or dolutegravir + emtricitabine/tenofovir disoproxil fumarate [DTG + F/TDF]) were included. Study groups of interest included PWH with low adherence (defined as a proportion of days covered [PDC] < 85%) and PWH who had initiated index ART after a ≥ 90-day gap. Treatment nonpersistence (discontinuation or switch) and switch outcomes were evaluated using Kaplan-Meier curves and Cox proportional hazards models.

Results: Of 30,205 treatment-experienced PWH, 6140 had low adherence on the index regimen and 7227 had significant treatment gaps prior to re-initiating ART. In both groups, risk of treatment nonpersistence was significantly lower for PWH indexed on B/F/TAF versus DTG/ABC/3TC and MTRs but similar for DTG/3TC. Risk of treatment switch was lower for those indexed on B/F/TAF versus all other ART regimens evaluated (P < 0.01).

Conclusions: Among Medicare-insured PWH with low adherence or significant gaps in care, those receiving B/F/TAF had a lower risk of switch compared with other ART regimens. Optimizing ART selection to improve persistence and reduce treatment switching remains an important consideration.

Introduction: Aztreonam-avibactam was approved for adults with limited treatment options for multiple infections due to aerobic Gram-negative organisms in the European Union and for complicated intra-abdominal infection in the US, following the phase 3 REVISIT and ASSEMBLE trials. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) assigned minimum inhibitory concentration (MIC) breakpoints for aztreonam-avibactam against Enterobacterales of susceptible ≤ 4 mg/l and resistant > 4 mg/l.

Methods: A comprehensive synthesis of data supporting MIC breakpoint determination is summarized, including: joint probability of pharmacokinetic/pharmacodynamic target attainment (JPTA) analyses (based on population pharmacokinetic modeling) for aztreonam-avibactam dose selection; MIC distributions of target pathogens; clinical and microbiological efficacy outcomes; and exposure-response analyses.

Results: Among 100,228 Enterobacterales isolates, including 2449 metallo-β-lactamase-positive isolates from global surveillance studies (2017-2021), 99% had aztreonam-avibactam MICs of ≤ 8 mg/l. At MIC = 8 mg/l, the predicted JPTA at steady state was 89% to > 99% across subgroups of varying renal function, based on approved doses for aztreonam-avibactam. Clinical trial isolates fell within the same MIC distribution as surveillance studies. There was no evidence of decreased favorable microbiological responses with increasing aztreonam-avibactam MICs in clinical trials; however, in the clinical dataset, there were few Enterobacterales isolates with aztreonam-avibactam MICs of > 4 mg/l.

Conclusions: MIC distributions and JPTA simulations supported a susceptible MIC breakpoint for aztreonam-avibactam against Enterobacterales of ≤ 8 mg/l. However, limited clinical outcomes data for Enterobacterales with aztreonam-avibactam MIC ≥ 4 mg/l justified the more conservative breakpoints established by EUCAST.

Clinical trial registration: ClinicalTrials.gov, NCT03329092 and NCT03580044. Studies/analyses sponsored by Pfizer.

In the phase 3 CONVERT trial, amikacin liposome inhalation suspension (ALIS) plus guideline-based therapy (GBT) achieved greater culture conversion than GBT alone in the treatment of refractory Mycobacterium avium complex pulmonary disease (MAC-PD). In the original analysis of safety data in CONVERT, the rate of hypersensitivity pneumonitis, a prespecified group of adverse events of special interest, was higher in patients receiving ALIS plus GBT (3.1%; n = 7) versus GBT alone (0.9%; n = 1), with half of the cases reported in Japanese patients. We present a summary of serious adverse events of hypersensitivity pneumonitis that investigators deemed related to ALIS treatment in Japanese patients enrolled in CONVERT (n = 3) and its extension study (INS-312; n = 1). Patients were women older than 65 years diagnosed with pneumonitis (n = 3) or interstitial lung disease (n = 1) after initiation of ALIS (range 3-189 days). Following ALIS discontinuation and medical intervention, all four patients recovered from pneumonitis. Additional investigator-collected imaging and serum Krebs von den Lungen 6 (KL-6) data were available for two of these patients, permitting assessment of KL-6 and the potential diagnostic role of radiographic findings. At the time of diagnosis, one patient had ground-glass opacity, and the other patient had consolidation in the right lower lobe of the lung; both patients had serum KL-6 levels > 600 U/mL. Changes in chest radiography and KL-6 levels at the onset of respiratory symptoms during ALIS treatment suggest that these assessments may help guide management strategies for potential hypersensitivity pneumonitis in patients taking ALIS.Clinical Trial Registration: NCT02344004 (CONVERT) and NCT02628600 (INS-312).

Introduction: Aztreonam-avibactam (ATM-AVI) is the first β-lactam/β-lactamase inhibitor antibiotic for treating serious infections caused by multidrug-resistant Gram-negative bacteria, including metallo-β-lactamases (MBL)-Enterobacterales. The objective of this analysis was to analyze the efficiency of ATM-AVI versus colistin + meropenem (COL+MER) in adult patients with complicated intra-abdominal infections (cIAI) or hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP) based on the REVISIT study.

Methods: A model combining a decision tree and a Markov model has been adapted to the Spanish National Healthcare System perspective, considering a lifetime horizon. Patients' characteristics, clinical (probabilities of resistance, cure, mortality, recurrence, nephrotoxicity), utility, and economic inputs (direct medical costs) have been obtained from the REVISIT study and published evidence.

Results: It was found that ATM-AVI is a cost-effective alternative compared to COL+MER with an incremental cost-utility ratio (ICUR) of €3116.2 per quality-adjusted life year (QALY) gained, derived of an incremental gain of 0.6 QALYs and an additional cost of €1875.9. For each indication, an ICUR of €1284.1/QALY-gained for cIAI and €4198.6/QALY-gained for HAP/VAP were obtained. Moreover, sensitivity analysis showed that ATM-AVI would be dominant in 14.5% of cases.

Conclusions: ATM-AVI is a highly cost-effective antibiotic versus COL+MER in the management of patients with serious infections caused by MBL-Enterobacterales.

Introduction: Despite Clostridioides difficile infection (CDI) being a leading healthcare-associated infection with high morbimortality, there is little evidence on specific antimicrobial stewardship program (ASP) interventions for CDI. The objective of this study was to assess the clinical impact of implementing a specific clinical pathway for CDI management at two Spanish hospitals.

Methods: This was a quasi-experimental pre-post intervention study, and three periods were evaluated: historical (2014-2017), educational-ASP (2018-2020), and intervention (2021-2023), after implementation of a CDI-specific measures bundle. Key measures included: (1) updated local CDI guidelines; (2) 24/7 diagnostic testing and real-time positive results notification to ASP-CDI team; (3) systematic evaluation of new cases; (4) optimizing CDI antibiotic treatment and overall management; and (5) structured follow-up until 8 weeks post-treatment. Primary outcome was first CDI recurrence, and secondary outcomes were readmissions during recurrent CDI episodes and 30-day all-cause mortality.

Results: In total, there were 1435 patients with CDI included: 370 in the historical period (2014-2017), 537 in the educational-ASP period (2018-2020), and 528 in the CDI-specific clinical pathway period (2021-2023). First CDI recurrence rates significantly declined across periods in high-risk groups: immunocompromised patients, 29% in 2014-2017, 22% in 2018-2020, and 15% in 2021-2023 (p = 0.038); those with severe/fulminant initial CDI, from 38% to 34% to 24% (p = 0.027); and patients aged 65-79 years, from 29% to 31% to 13% (p = 0.003). Hospitalization during recurrent CDI episodes and mortality were significantly reduced in the CDI-specific clinical pathway period: readmissions, 11% (2014-2017), 13% (2018-2020), and 6% (2021-2023) (p = 0.017); mortality, 7%, 6%, and 4% (p = 0.023).

Conclusions: The implementation of a structured, multifaceted clinical pathway specifically designed for CDI management had significant clinical benefits, including a reduction of recurrences in high-risk groups, readmissions, and mortality.

Trial registration: ClinicalTrials.gov identifier NCT04801862.

Introduction: Carbapenem-resistant Enterobacterales (CRE) pose a major threat to immunocompromised pediatric oncology patients. However, the routes of resistance spread in this vulnerable population remain poorly understood, despite their importance for guiding infection control.

Methods: We analyzed 189 CRE bloodstream isolates (106 Escherichia coli, 72 Klebsiella pneumoniae, and 11 other Enterobacterales) collected at the Children's Cancer Hospital Egypt 57357 (August 2021-October 2022). Whole genome sequencing was used to assess sequence types, resistance genes, virulence factors, plasmid content, and transmission dynamics.

Results: Carbapenem resistance was primarily mediated by blaNDM-5, carried on species-specific plasmids: IncFIA/IncFII in E. coli and IncFIB/IncHIB megaplasmids in K. pneumoniae, frequently co-harboring additional aminoglycoside, sulfonamide, and fluoroquinolone resistance genes. The most common sequence types were ST361, ST167, and ST405 in E. coli, and ST11, ST383, and ST147 in K. pneumoniae. Clonal clustering was observed in 62.5% of K. pneumoniae but only 17% of E. coli. Plasmid phylogenetics and patient movement data indicated extensive horizontal plasmid transfer across unrelated lineages and patients, including ICU cases. A nonfunctional rmpA variant was found in 30 K. pneumoniae isolates, but no hypermucoviscous phenotype was observed.

Conclusion: CRE bloodstream infections in pediatric oncology patients are driven by both clonal expansion and plasmid-mediated dissemination, with plasmids playing a dominant role, especially in E. coli. These findings highlight the limitations of strain-based surveillance and the need for integrated genomic and plasmid-level monitoring to inform infection control in high-risk hospital settings. A Graphical Abstract is available for this article.