Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) is currently a serious global concern. Antimicrobial stewardship programs (ASPs) are one of the key strategies to overcome this resistance. However, evidence about the long-term clinical and ecological impacts of ASPs is scarce. A multidisciplinary team conducted a multifaceted intervention in a CR-Kp endemic hospital over a 6-year period. We assessed the monthly long-term impacts of ASPs on carbapenem use, incidence density (ID), and crude death rates of hospital-acquired CR-Kp infections. Other variables potentially related to CR-Kp incidence and healthcare activity indicators were monitored. Carbapenem use showed a sustained reduction over the long term, with a difference of −66.19% (95% CI −87.03 to −45.34) between the expected pre-intervention trend consumption value and that obtained six years after starting the program. The ID of CR-Kp also decreased significantly and was maintained over the long term, with a relative reduction of −88.14% (95% CI; −100.4 to −75.85) at the end of the study period. The crude death rate of CR-Kp at 14 and 28 days decreased significantly after the intervention and remained steady after six years. Infection control indicator trends remained stable. This mixed ASP contributed to reducing the high incidence of infections and mortality rates of CR-Kp, achieving a sustained ecological and clinical effect.

The standard prophylaxis treatment for cytomegalovirus (CMV) disease in CMV-seropositive lung transplant recipients is six months of prophylaxis with valganciclovir followed by six months of pre-emptive therapy. This protocol is associated with adverse events and risk of resistance. We have previously shown that prophylaxis can be suspended in CMV-seropositive kidney transplant recipients receiving thymoglobulin without increasing the risk of CMV disease and reducing the incidence of neutropenia. The objective of the current study is to demonstrate that immunoguided prophylaxis is effective and safe in seropositive lung transplant recipients. A phase III, multicentre, randomised, open-label, noninferiority clinical trial was conducted in adult lung transplant recipients. Patients were randomised (1:1) to two groups: (1) immunoguided prophylaxis (IP), consisting of 3 months of universal prophylaxis followed by CMV-specific cell-mediated immunity-guided discontinuation, or (2) standard prophylaxis (SP), consisting of 6 months of prophylaxis followed by pre-emptive therapy, both for a total of 12 months. The noninferiority margin was 7%. The primary and secondary efficacy endpoints were CMV disease and asymptomatic CMV replication at month 18. The primary and secondary safety endpoints were incidence of neutropenia (defined as neutrophil count <1500 cells/μL), incidence of rejection and number of days of valganciclovir prophylaxis. This trial was registered in EudraCT (2018-003300-39) and ClinicalTrials.gov (NCT03699254). This trial has been completed. Patients were recruited between April 2019 and December 2021 in seven Spanish centres. A total of 150 patients were randomised (75 patients per group). Incidence of CMV disease at month 18 did not differ among groups (18·7% [14 patients] vs. 16·0% [12 patients]; risk difference [RD] −0·03 [95% CI −0·15% to 0·06%]; P = 0·620) but occurred earlier in the IP group compared to the SP group. The proportion of patients who developed CMV disease at ≤180 days after transplant was higher in the IP group compared with the SP group (8% [6 patients] vs. 0% [0 patients]; RD −0·08 [95% CI −0·14 to −0·02; P = 0·009]). Asymptomatic CMV replication was reduced in the IP group vs. the SP group (4·0% [3 patients] vs. 16·0% [12 patients]; adjusted RD 0·12 [95% CI 0·03–0·21; P = 0·009]). A total of 30 patients (40%) in the IP group did not require prophylaxis from month 4 to 12. No significant difference was observed in the proportion of patients with neutropenia during months 4 to 7 (14·7% [11 patients] vs. 25·3% [19 patients]; RD 0·11 [95% CI −0·02 to 0·23]; P = 0·090) or rejection (33·3% [25 patients] vs. 30·7% [23 patients]; RD −0·03 [95% CI −0·18 to 0·12; P = 0·690]). The median days of valganciclovir was lower in the IP group than in the SP group (137 [92–266] vs. 198 [173–281]; P < 0.001). Immunoguided prophylaxis was noninferior to the standard of care in preventing CMV disease in lung transplant recipients. It could be considered for implementing in clinical practice in CMV-seropositive lung transplant recipients upon considering the study limitations. 10.13039/501100004587 Carlos III Health Institute , the SATOT Research Grant, the 10.13039/100006301 CIBER (Biomedical Network Research Centre Consortium), the 10.13039/501100004837 Ministry of Science and Innovation , and the 10.13039/501100000780 European Union .

The cutoff value of the commercial interferon (IFN)-γ release assay (QuantiFERON-CMV) proposed by the manufacturer is assumed to be predictive. We aimed to determine the optimal cutoff value for protection against clinically significant cytomegalovirus (CMV) infection within 30 days. We analyzed two different cohorts: adult CMV seropositive kidney transplant (KT) recipients with antithymocyte globulin (ATG) induction from the TIMOVAL study and seropositive lung transplant (LT) patients from the CYTOCOR study. The optimal cutoff value was established using Youden’s index. We estimated the predictive capacity of the cutoff value through the AUROC and assessed the diagnostic accuracy of the assay at the different cutoff values. We finally evaluated clinical variables that could improve the predictive ability of the assay on a predictive score. Four hundred-four samples from 130 transplant recipients were analyzed. The optimal cutoff value was ≥2.2 IU/mL for both populations, with a positive predictive value of 99% and 99.5% (95% CI, 98–100%) for KT and LT recipients, respectively. The AUROC of the predictive score was 0.85 (95% CI, 0.73–0.97). Using the proposed cutoff value and the Quanti-CMV score may allow the individualization of preventive strategies and serve as an objective tool to support clinical decision-making.

Introduction Cytomegalovirus (CMV) infection is a common complication in patients undergoing haematopoietic stem cell transplantation (SCT). Letermovir (LTV) prophylaxis during the first 100 days post-SCT is effective and safe in preventing this infection, although it may be associated with a delay in CMV-specific immune reconstitution. Hence, a study is needed to evaluate whether the absence of CMV-specific immune reconstitution at the end of LTV prophylaxis is associated with the development of late infection. This could facilitate the individualisation of CMV prophylaxis duration in these patients. Methods and analysis INMUNOEND is a multicentre, prospective, observational, non-interventional study including CMV seropositive patients undergoing allo-SCT who receive LTV prophylaxis during the first 100 days post SCT. Immunological and virological monitoring will be conducted until day+200 post-SCT. The primary outcome is the percentage of patients who develop clinically significant CMV infection up to day+200 post-SCT after completing LTV prophylaxis. Data collected will include baseline characteristics of the haematological diseases and comorbidities, variables related to SCT (ie, engrafment, graft-versus-host disease, use of LTV and CMV replication) and variables related to CMV-specific immune reconstitution. Ethics and dissemination Ethical approval has been obtained from the institutional review board (Comité de Ética de la Investigación de Córdoba; SICEIA-2024–0 01 762). The results of this study will be published in peer-reviewed journals and disseminated at national and international conferences. Trial registration number NCT06814301.

Infections caused by KPC-producing Klebsiella pneumoniae (KPC-KP) represent a persistent public health challenge. This prospective study examines ten-year trends, clinical features, and genomic epidemiology of hospital-onset (HOI) and non-hospital-onset (non-HOI, including healthcare-associated [HcAI] and community-acquired [CA]) KPC-KP infections following a 2012 outbreak. We evaluated the impacts of a 2014 antimicrobial stewardship program (ASP) and COVID-19-related infection prevention and control (IPC) measures, with emphasis on hospital-to-community dissemination. We analysed a prospective, longitudinal cohort of patients (2012–2022) in a tertiary referral hospital. Interrupted time series and ARIMA models assessed ASP and IPC impacts on incidence density (ID). Cross-correlation analysis explored temporal associations between HOI and non-HOI trends. Whole-genome sequencing and PERMANOVA evaluated the genomic structure of ST512/KPC-3 isolates. Multivariable regression analysed the association between infection type and clinical outcomes. Among 467 patients, 33.2% had non-HOI (ID 0.53/1,000 admissions/month) and 66.8% HOI (ID 0.30, p = 0.39). Urinary tract infections predominated in non-HOI (52.9%), while bloodstream and respiratory infections were more common in HOI. Incidence density of HOI and non-HOI infections declined significantly following ASP implementation, with a 4-month lag suggesting sequential transmission dynamics. These reductions were maintained during the pandemic. Genomic data confirmed ST512/KPC-3 dominance and hospital-to-community spread, with temporal factors—rather than acquisition type—explaining genetic variation. Adjusted analyses showed similar 30-day mortality and treatment responses across HOI and non-HOI. ASP and COVID-19 IPC measures contributed to maintaining low KPC-KP incidence. Genomic evidence underscores the role of temporal dynamics and clonal expansion in ST512/KPC-3 dissemination. Non-HOI infections are clinically significant and require targeted, system-wide surveillance and control strategies.

Invasive fungal infections (IFIs) are of major concern in lung transplant recipients. Although Aspergillus fumigatus is the predominant pathogen, non-A fumigatus mould infections (NAFMIs) also account for a substantial proportion of IFIs. We aimed to describe the epidemiology, clinical spectrum, risk factors, and outcomes of NAFMIs after lung transplantation. We performed a retrospective, international, multicentre, case-control study across nine tertiary care centres in Canada and Europe. We included adult (aged ≥18 years) lung transplant recipients. Cases were defined as individuals with proven or probable IFIs caused by a mould other than A fumigatus (NAFMI group). Exclusion criteria were a concomitant infection with A fumigatus and a non-A-fumigatus mould and isolated positivity of galactomannan in serum or bronchoalveolar lavage. Two controls per case were included: one with IFI due to A fumigatus (A fumigatus control group) and one free of any IFI (IFI-free control group). 1:1:1 matching was done according to centre and time after transplantation (for IFI-free controls). We reviewed medical records to assess the clinical and radiological presentation and clinical outcomes (including 12-week therapeutic response, 12-month survival, development of chronic lung allograft dysfunction [CLAD] and post-transplant lymphoroliferative disorder) and used logistic regression models to assess risk factors for IFIs. The primary outcomes were the description of the microbial aetiologies of NAFMI, survival and CLAD 12-month post-IFI, and identification of factors associated with NAFMI. Between Jan 1, 2010, and Jan 1, 2020, we included 120 individuals in the NAFMI group and 240 individuals in the control groups (n=120 in each control group). Median age at transplantation was 56 years (IQR 44-63); 170 (47%) of 360 participants were female and 190 (53%) were male. Only eight (7%) of 120 individuals in the NAFMI group had a polyfungal or mixed infection. Aspergillus flavus (26 [22%] of 120) and Aspergillus niger (24 [20%]) were the most common pathogens in the NAFMI group, followed by Scedosporium apiospermum (9[8%]). Respiratory symptoms predominated in individuals with IFI, and clinical presentations were similar in individuals with NAFMI and A fumigatus IFI. 12-month mortality was comparable across groups (NAFMI: 37/118 [31%], A fumigatus: 36/117 [31%], p=1; IFI-free controls: 25/120 [21%], p=0·11 compared with NAFMI). CLAD at 12-month post-IFI occurred at similar frequencies in cases and controls (NAFMI: 13/108 [12%], A fumigatus 17/111 [15%], p=0·69; IFI-free controls: 8/110 [7%], p=0·36 compared with NAFMI). Pre-transplant immunosuppression (adjusted odds ratio 3·82, 95% CI 1·55-9·38; p=0·0039) and pre-transplant intensive care unit stay (3·07, 1·01-9·34; p=0·048) were independently associated with NAFMI occurrence, when compared with IFI-free controls. NAFMIs mostly involve non-fumigatus Aspergillus spp. Diagnostic features of NAFMIs are similar to those of A fumigatus infections; pre-transplant immunosuppression can increase the risk of NAFMI onset. These findings reinforce the importance of a thorough investigation when a mould is isolated from the airways after lung transplantation. None.