Infectious Diseases and Therapy最新文献

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.

Sexually transmitted infections (STIs) remain a major global health burden, with rising incidence of Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum. Doxycycline post-exposure prophylaxis (DoxyPEP), consisting of a single 200 mg dose within 72 h after condomless sex, has emerged as a promising intervention. Randomized controlled trials demonstrate consistent efficacy in reducing chlamydia and syphilis, while protection against gonorrhea is variable, being strongly influenced by baseline tetracycline resistance and anatomical site. Surveillance data from San Francisco and King County confirm that high-frequency use can drive rapid increases in gonococcal tetracycline resistance. Although no cephalosporin resistance has yet been linked to DoxyPEP, genomic correlations raise concern for co-selection of multidrug-resistant strains, particularly FC428-like clones with mosaic penA alleles. C. trachomatis remains uniformly susceptible, with resistance limited to theoretical horizontal transfer from C. suis. T. pallidum shows no evidence of resistance, supported by genomic constraints and experimental studies. Mycoplasma genitalium demonstrates low intrinsic susceptibility to doxycycline, but no acquired tetracycline resistance has been confirmed. Beyond target pathogens, DoxyPEP alters the functional resistome of the human microbiome, amplifying tetracycline resistance gene expression in gut, skin, and oropharyngeal flora, and selecting for resistant Staphylococcus aureus and commensal Neisseria. These ecological shifts underscore the importance of molecular surveillance to monitor resistance spillover. Overall, DoxyPEP provides substantial benefit in controlling chlamydia and syphilis and conditional utility against gonorrhea in low-resistance settings. Its deployment should be coupled with antimicrobial stewardship, local resistance data, and strengthened genomic surveillance to balance individual protection with population-level risks.

Introduction: Tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy regimens remain one of the first-line treatments in many countries. We assessed the changes of bone mineral density (BMD) in people with HIV (PWH) who had early switch from TDF-based regimens to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF).

Methods: This 48-week, multicenter, randomized, open-label clinical trial recruited adult PWH on TDF-based regimens with virological suppression for at least 24 weeks. Participants were randomly assigned (1:1) to immediately switch to B/F/TAF (immediate switch group) or switch after 24 weeks (deferred switch group). The primary endpoint was the median percentage change [interquartile range (IQR)] in BMD from baseline to week 48.

Results: Between December 17, 2021 and February 21, 2023, 150 PWH were randomly assigned to immediate switch group (n = 75) or deferred switch group (n = 75). At week 48, no significant difference in BMD changes of the spine was observed at week 48 [3.30% (IQR 1.19, 5.47) vs. 2.84% (0.51, 5.00); P = 0.199]. The increase in hip BMD was greater in the immediate switch group than deferred switch group [median percentage change, 2.05% (0.20, 4.12) vs. 0.88% (- 0.52, 3.15); P = 0.035]. Viral suppression at week 48 was noted in 71 (94.6%) participants assigned to the immediate switch group and in 67 (89.3%) assigned to the deferred switch group. Similar rates and severity of adverse events were observed in both groups, with no serious adverse events reported.

Conclusions: While both immediate and deferred switch from TDF-based regimens to B/F/TAF maintained virological suppression, early switch resulted in better improvement of BMD in the hip joint.

Clinical trials registration: ClinicalTrials.gov (NCT05122754).

Introduction: Optimal minocycline dosing for Acinetobacter baumannii group pneumonia remains unclear. We assessed the clinical impact of high-dose (HD) versus standard-dose (SD) minocycline and explored the predictive value of susceptibility breakpoints.

Methods: In this multicenter retrospective cohort study, hospitalized adults with AB group pneumonia treated with minocycline were classified into HD (200 mg IV q12h) or SD (100 mg IV q12h or 200 mg IV q24h) groups. Inverse probability of treatment weighting (IPTW) and multivariate logistic regression were applied to adjust for baseline differences. Kaplan-Meier survival and subgroup analyses were performed to evaluate dose-response effects and the utility of different minimum inhibitory concentration (MIC) breakpoints.

Results: Among 106 patients (HD: 46; SD: 60), HD therapy was associated with significantly lower in-hospital mortality (28.6% vs. 48.3%; p = 0.046). HD minocycline remained a protective factor in multivariate and IPTW-adjusted models. Long-term (150-day) survival favored HD therapy (log-rank test, p = 0.028). In 28 patients infected with MIC-confirmed isolates, HD therapy consistently trended toward lower mortality across MIC strata. Notably, the pharmacokinetic/pharmacodynamic (PK/PD)-informed breakpoint (≤ 1 µg/ml) better discriminated survival benefit from HD therapy, whereas the Clinical and Laboratory Standards Institute (CLSI) 2024 breakpoint (≤ 4 µg/ml) did not. These findings support dose optimization and align with the revision of CLSI breakpoints in 2025, lowering the minocycline susceptibility breakpoint for Acinetobacter spp. to ≤ 1 µg/ml.

Conclusions: High-dose minocycline significantly improved in-hospital survival for A. baumannii group pneumonia. PK/PD-informed breakpoint may offer greater clinical relevance for guiding minocycline therapy compared to CLSI 2024 breakpoint.

Pertussis or whooping cough, caused by the bacteria Bordetella pertussis, is a highly contagious respiratory disease. Over the past century, whole-cell pertussis (wP) and acellular pertussis (aP) vaccines were developed and widely adopted, leading to a substantial reduction in the number of pertussis cases. Currently, various strategies are employed to protect different segments of the population, including primary immunization, toddler and school-age boosters, adult boosters, and vaccination in pregnancy (ViP). Nonetheless, pertussis remains a global health challenge with periodic outbreaks occurring every 2-5 years. The non-pharmacological measures implemented during the COVID-19 pandemic resulted in a drastic reduction in the circulation of B. pertussis. However, post-pandemic, there has been a resurgence in pertussis cases. This review aims to explore the post-pandemic global pertussis outbreaks and identify underlying trends to gain insights into the potential contributing factors. As of June 2025, pertussis outbreaks with diverse epidemiological patterns have been reported in at least 42 countries, including 30 aP and 12 wP vaccine-using countries. Some common observations among these countries include low infant immunization rates and an absence of vaccination programs for specific populations such as school-aged children, adults, and pregnant individuals. Additionally, in countries with extensive immunization schedules and high vaccination uptake, outbreaks have occurred in regions with low vaccination coverage rates (VCRs). Multiple interrelated factors may have contributed to the post-pandemic pertussis outbreaks, such as the cyclic epidemiology of pertussis, low VCR, waning vaccine-derived immunity, low uptake of boosters, and lack of lifelong protection through regular boosters. To effectively mitigate the incidence of pertussis outbreaks, it is crucial to administer regular booster vaccinations throughout an individual's lifetime, with particular emphasis on at-risk populations and pregnant individuals. A Graphical Abstract is available for this article.