Introduction Ventilator-associated pneumonia (VAP) is the most frequent healthcare-associated infection in intensive care units and is associated with high morbidity and mortality. Current diagnostic criteria lack specificity, leading to misclassification and unnecessary antibiotic use. Identifying patient subgroups with a common pathophysiological basis (pneumoclusters) may distinguish true VAP of varying aetiology and severity from non-infectious mimics, enabling more targeted therapy and improved antimicrobial stewardship.Methods and analysis ClusterVAP is an exploratory, observational, prospective, multicentre cross-sectional study conducted in intensive care units across Sweden, France, Portugal, Denmark and the UK. Mechanically ventilated patients aged 18 years or older with newly developed clinical signs of lower respiratory tract infection will undergo bronchoalveolar lavage (BAL) or mini BAL sampling on clinical indication. Proteomic profiling using liquid chromatography tandem mass spectrometry will be performed on BAL supernatants. Unsupervised consensus clustering will define pneumoclusters, which will be characterised using clinical, microbiological and radiological data. 30-day outcomes, including mortality, ventilator-free days, antibiotic-free days, intensive care unit-free days and hospital-free days, will be compared across clusters to describe clinical trajectories. Candidate protein biomarkers for pragmatic cluster assignment will be derived using differential expression analysis.Ethics and dissemination Ethical approval will be obtained at all participating sites. Deferred consent will be used where permitted, with subsequent patient or proxy consent according to local regulations. Results will be disseminated through peer-reviewed publications and scientific conferences.Trial registration number NCT07245888.

Background Sex is a major cause of heterogeneity in the epidemiology, management, response to treatment, and outcome of infectious and respiratory diseases. We aimed to describe differences between males and females in characteristics, management, and mortality among patients affected by ventilator-associated pneumonia (VAP). Methods We performed a post hoc exploratory analysis of the EUVAP/CAP cohort, a prospective multinational cohort study of patients requiring mechanical ventilation in 27 intensive care units from nine countries. Sexes were compared with respect to baseline characteristics, interventions, and outcomes in univariate and adjusted analyses. Results Among the 2436 intubated adult patients in the cohort, 450 (18.5%) developed VAP; of these VAP cases, 293 (65.1%) were male, and the median age was 64 years. Compared with females, males had more comorbidities, and underwent bronchoscopy more frequently (20.5% vs. 11.5%, P=0.016) and triple antibiotic therapy (33.1% vs. 22.3%, P=0.016)., Intensive care unit mortality was 41.3% vs. 45.2% (P=0.422). In multivariate analysis, age in years (adjusted odds ratio [aOR]=1.02, 95%confidence interval [CI]: 1.00 to 1.04), septic shock (aOR=1.72, 95%CI: 1.02 to 2.91), McCabe score (life expectancy 1–5 years vs. >5 years: aOR=1.53, 95%CI: 0.81 to 2.54; 〈1 year vs. 〉 5 years: aOR=7.67, 95%CI: 2.41 to 24.39; P=0.002), and infection with high risk bacteria for multidrug resistance (aOR=1.86, 95%CI: 1.12 to 3.09; P=0.016) were independently associated with mortality, but not sex (aOR for males vs. females=0.92, 95%CI 0.56 to 1.49; P=0.722). The relation between sex and mortality was not affected by age <50 years. Conclusions The risk of mortality did not differ between sexes in patients affected by VAP. Affected males had more comorbidities, heavy alcohol use, and underwent bronchoscopy and triple antibiotic therapy more frequently.

Clostridioides difficile infection (CDI) are the most frequent healthcare-associated diarrhoeal disease in the intensive care unit (ICU). Critically ill patients face multiple risk factors—including broad-spectrum antibiotic exposure, disrupted gut microbiota, invasive procedures, and immunological dysfunction—that amplify both CDI incidence and severity. This opinion paper reviews recent advances in CDI diagnosis and management specifically in the ICU setting, with a focus on immunosenescence—the age-related progressive decline in innate and adaptive immune function with systemic inflammation (inflammaging). We argue that aging-related immune dysfunction alters the host response to Clostridioides difficile, reduces toxin neutralization ability, attenuates classical clinical severity markers (fever and leukocytosis), and negatively affects treatment outcomes. These immunological changes are not adequately captured in current CDI severity scores, notably the ATLAS score, which was derived and validated in younger, non-ICU populations. We emphasize that understanding the interaction between immunosenescence and CDI pathogenesis is essential to improve risk stratification, optimize treatment selection, and develop meaningful prevention strategies for an increasingly elderly ICU population. This includes prioritizing early and effective CDI treatment in elderly patients to avoid ICU progression, establishing dedicated randomized controlled trials for fulminant disease, and designing severity assessment tools and vaccine strategies that account for immune senescence.

AimOur objective was to increase our understanding of the effects of the time course of metabolic alterations on the risk of hospital-acquired pneumonia (HAP) and response to treatment in critically ill patients.MethodsWe first studied the blood metabolome at day 1, day 3-4 and day 6-7 of patients from a prospective, observational cohort of brain-injured patients in two French centres. We classified the metabolic response by unsupervised longitudinal consensus clustering. To evaluate the robustness of metabolic patterns, a Fast-and-Frugal Tree trained on the discovery cohort was applied to a replication dataset from the PREV-HAP randomised clinical trial testing interferon gamma-1b for the prevention of HAP in critically ill patients. The primary outcome was the association of metabolic response patterns with HAP.FindingsOf the 128 patients analysed (330 samples), 57 (45%) had developed HAP and 21 (16%) acute respiratory distress syndrome (ARDS). Based on metabolites involved in fatty acid metabolism, we identified three metabolic response patterns associated with the risks of HAP (24%, 60% and 78% of HAP, respectively) and ARDS (6%, 16% and 43%, respectively). In a replication dataset (315 samples from 105 patients), we found similarities regarding blood metabolite temporal courses and associations with HAP (18%, 28% and 40% of HAP, respectively). Moreover, the probability of being discharged alive from the ICU with interferon gamma-1b was decreased in patients with low-risk metabolic response patterns and increased in patients with high-risk metabolic response patterns.ConclusionsLongitudinal clustering classified metabolic response patterns into low-, moderate-, and high-risk groups for HAP and can help identify responders and non-responders to interferon gamma-1b after a single treatment injection.Trial registrationNumber clinicaltrial.gov NCT02003196 and NCT04793568

Background/Objectives: Fosfomycin is an old antimicrobial agent historically used in its oral formulation for uncomplicated urinary tract infections. In the current context of rising antimicrobial resistance and limited antimicrobial options, fosfomycin has attracted renewed interest. Methods: A comprehensive review on the IV fosfomycin use focusing on critically ill patients and/or severe infections due to difficult-to-treat (DTR) Gram-negative bacilli (GNB). Results: Fosfomycin's IV formulation is now being used more widely, particularly in critically ill patients with multidrug-resistant (MDR) or DTR-GNB infections. It offers several attractive features: a unique mechanism of action that minimizes cross-resistance; a broad spectrum of activity, covering both Gram-negative and Gram-positive pathogens; and consistent synergy with multiple pivotal antimicrobials. Its pharmacokinetic/pharmacodynamic (PK/PD) profile is favorable, with extensive tissue penetration, including the central nervous system. The ratio of area under the concentration-time curve to the minimum inhibitory concentration of the pathogen (AUC/MIC) is considered the optimal PK/PD target for fosfomycin. The adverse events are mainly non-serious (most frequently, hypernatremia and hypokalemia), although safety data for higher dosing regimens remain limited. Growing clinical evidence supports IV fosfomycin as an effective and well-tolerated component of combination therapy for severe infections in critically ill patients, including those infections caused by extended-spectrum beta-lactamases-, carbapenemase-producing Enterobacterales, and DTR non-fermentative GNB. Nevertheless, as with many rediscovered antimicrobials, its expanded role requires confirmation through rigorously designed clinical trials to better define its efficacy, optimal use, and safety profile in the treatment of severe DTR-GNB infections.

Ventilator-associated pneumonia (VAP) remains the most frequent ICU-acquired infection and a major driver of antimicrobial exposure. Historically, clinicians treated patients for 10-14 days or longer, particularly when multidrug-resistant organisms were suspected. Current evidence from randomized trials and meta-analyses now supports shorter-course therapy (~7 days) for most immunocompetent patients with VAP who demonstrate clinical improvement. Mortality and treatment failure are not increased when compared with longer regimes. The REGARD-VAP trial demonstrated the non-inferiority of individualized ≤7-day therapy compared with conventional longer courses. This remained true even in cohorts rich in non-fermenting Gram-negative bacilli (NF-GNB) and carbapenem-resistant organisms while markedly reducing antibiotic-related toxicity. North American and European guidelines recommend 7-8 days as the default duration, with individualized extension for slow clinical response, bacteremia, uncontrolled foci, or profound immunosuppression. Additionally, biomarker-guided discontinuation, particularly serial procalcitonin (PCT), may reduce antibiotic days when used to enrich clinical assessment. This narrative review synthesizes guideline recommendations, trial evidence, biomarker-guided stewardship, and pathogen- and patient-specific scenarios to provide a practical framework for intensivists: treat until infection is controlled and the patient is improving, usually about 1 week, and extend therapy only with clear justification.

Objectives: Vancomycin is crucial for treating severe Gram-positive infections, but its narrow therapeutic index complicates dosing. Trough monitoring may inadequately reflect exposure, while AUC-guided dosing, although recommended, is often impractical. Alternative metrics such as the time in therapeutic range (TIR) and volatility index may reflect exposure dynamics. Augmented renal clearance (ARC) further challenges vancomycin therapy in Intensive Care Unit (ICU) settings. This study evaluated trough-based exposure metrics and their associations with ICU mortality and acute kidney injury (AKI). Methods: We retrospectively analyzed 109 ICU patients with sepsis receiving vancomycin. Exposure was assessed using mean trough concentrations, TIR (proportion of troughs within predefined ranges), and the volatility index, defined as the intra-individual standard deviation divided by the mean trough concentration (SD/mean). Outcomes were ICU mortality and AKI. Associations were evaluated using multivariable regression, bootstrap resampling, and restricted cubic splines. Results: TIR >15 was independently associated with higher mortality (adjusted OR 3.88; p = 0.0326) and AKI stage II-III (adjusted OR 5.63; p = 0.0068). Higher mean troughs correlated with AKI stage II-III, whereas higher volatility showed an inverse association (adjusted OR 0.15; p = 0.0240). ARC (4.6%) occurred exclusively in younger patients and predicted subtherapeutic exposure (TIR <10, p = 0.0485). Conclusions: Sustained troughs >15 mg/L were associated with mortality and nephrotoxicity, while the most favorable outcomes were descriptively observed at mean trough levels of approximately 8-12 mg/L, suggesting a possible narrow exposure range that requires prospective validation. These findings highlight the limitations of trough-based monitoring alone; the trough-derived metrics should be regarded as exploratory rather than validated decision-making tools.

Background: Advanced cirrhosis induces profound CD4+ T-cell depletion through splenic sequestration and immune dysregulation. Pneumocystis jirovecii pneumonia risk thresholds remain undefined in non-HIV immunocompromised populations, necessitating investigation in cirrhotic patients. Objectives: To investigate the potential association between peripheral CD4+ T-cell counts and opportunistic infections (OI)—specifically Pneumocystis jirovecii (PJ)—in hospitalized patients with liver disease, and to characterize clinical outcomes across immunological risk strata. Methods: We retrospectively analyzed 455 adults hospitalized in a single institution with hepatic disorders. CD4+ T-cell counts were available in 227/455 patients. Among these, 22 patients met predefined immunological risk criteria (CD4+ < 500/µL and/or HIV positivity) and were classified into three immunological risk clusters (IRCs): IRC-A (HIV−, CD4+ < 200/µL; n = 9), IRC-B (HIV+, CD4+ < 200/µL; n = 7), and IRC-C (HIV−, CD4+ 200–499/µL; n = 6). PJ PCR testing was evaluated when available. Results: Among 455 patients, in-hospital mortality was 103/455 (22.6%). Of the 22 immunologically at risk patients, 15/22 had cirrhosis. PJ PCR was performed in 8/22 patients (IRC-A: 2; IRC-B: 4; IRC-C: 2), with 3/8 positive (37.5%): IRC-A (1/2), IRC-B (1/4), IRC-C (1/2). Ct values ranged from 27.0 to 31.7. Two PJ-PCR–positive cirrhotic patients (IRC-A: n = 1; IRC-C: n = 1) survived without specific anti-PJ therapy; one HIV-positive patient (IRC-B) received trimethoprim-sulfamethoxazole and survived. In-hospital mortality was 5/9 (55.6%) in IRC-A, 2/7 (28.6%) in IRC-B, and 3/6 (50.0%) in IRC-C; none of the deaths were attributable to PJ pneumonia. Conclusions: Severe CD4+ T-cell depletion (<200/µL) was common among cirrhotic patients and associated with PJ detection (3/8 tested), but not with PJ-related mortality (0/3). Mortality was primarily driven by hepatic decompensation and bacterial infections. CD4+ assessment may improve risk stratification in cirrhosis; however, prospective, multicenter studies are warranted to validate these findings and to evaluate CD4-guided strategies for the prevention of opportunistic infections.

Host-respiratory microbiome interplay is vital to lung homeostasis. Systemic inflammatory response syndrome (SIRS) is an intense alteration in host status that necessitates rapid microbiome adaptation to avoid respiratory complications. Using longitudinal multi-omic data from patients with SIRS, we confirm that the respiratory microbiome, blood metabolome, and immune cells form a dynamic metasystem and define a metacluster with distinct T/B cell trafficking, anaerobic bacteria, high tyrosine metabolism, and low fatty acid biosynthesis. This metacluster status can serve to classify the severity of alterations in host-lung microbiome interactions as moderate or severe and to predict pneumonia and mortality. We demonstrate the robustness of these findings in an independent, randomized controlled trial and propose that interferon-γ treatment may benefit patients with severe metacluster alterations but harm those with moderate alterations. Our study supports the concept of the host-respiratory microbiome as a dynamic metasystem, in which specific alterations are associated with pneumonia and responses to interferon-γ treatment.

Antimicrobial resistance (AMR) poses a significant global health challenge, and antimicrobial stewardship (AMS) initiatives are acknowledged as vital measures to enhance antibiotic utilization in healthcare facilities. Nevertheless, the effective execution of AMS programs continues to be exceptionally difficult across various healthcare environments. This opinion paper consolidates findings globally to pinpoint the primary obstacles and emerging viewpoints related to the implementation of hospital-based AMS. The analysis indicates that the challenges are complex, encompassing organizational, structural, cultural, educational, and behavioural aspects. Deficiencies in leadership and governance at various institutional tiers create a lack of accountability and commitment, while insufficient human and financial resources—including a shortage of infectious disease specialists, clinical pharmacists, and microbiologists—compromise the sustainability of these programs. Deeply rooted professional hierarchies and power dynamics among healthcare disciplines hinder interprofessional collaboration and diminish the acceptance of stewardship recommendations. Knowledge deficits and a lack of AMS-specific training across all professional categories further limit implementation, as do inadequate diagnostic laboratory capabilities and restricted health information technology. A persistent gap between national policies and local implementation realities leads to guidelines that are poorly suited to institutional contexts, while mandatory strategies may result in unintended outcomes such as regulatory evasion and decreased motivation among healthcare workers. These challenges are intensified in low- and middle-income countries but remain significant even in well-resourced environments. Promising strategies encompass multidisciplinary team approaches, governmentled accountability frameworks, contextualized implementation plans, and expanded roles for healthcare professionals.

Background. Ventilator-associated tracheobronchitis (VAT) and pneumonia (VAP) are the most frequent nosocomial infections in the critical care setting and are associated with increased morbidity. At the same time, VAP is also associated with attributable mortality, especially when caused by difficult-to-treat (DTR) Gram-negative bacteria (GNB) that have limited treatment options. Studies have assessed the impact of nebulized aminoglycosides or colistin to improve VAT and VAP outcomes or as an adjunct to intravenous antimicrobial treatment or as a preventive approach. Objective. This overview aimed to assess systematic reviews that examine the efficacy and safety of antimicrobial nebulization for preventing and treating ventilator-associated infections in the critically ill. Methods. Systematic reviews, meta-analyses, and original randomized controlled trials and prospective observational studies were included. Searches were conducted in MEDLINE (via PubMed), the Cochrane, Epistemonikos, and PROSPERO. The methodological quality assessment was performed using standardized tools. Results. Regarding VAP treatment, the included systematic reviews presented critically low quality. The clinical response effect size to amikacin and colistin nebulization were RR 1.23 (95% CI 1.13–1.34), I2 = 47% and OR 1.39 (0.87–2.20), I2 = 56%. The main safety concern was bronchospasm with RR 2.55 (1.40–4.66), I2 = 0% and OR 5.19 (1.05–25.52), I2 = 0%. The certainty of evidence was usually very low. For VAT treatment, limited evidence showed a better clinical response and less emergence of resistant bacteria. Regarding VAP prevention, data are limited to two trials; however, only the larger one presented a low risk of bias and resulted in a reduced VAP rate. Conclusions. Delivery via nebulization might be considered in addition to IV antimicrobial treatment of GNB ventilator-associated infections. The available evidence is weak, and more studies focused on infections due to DTR-GNBs should be prioritized.

Effective sepsis treatment requires not only the timely administration of appropriate antimicrobials but also precise dosing to maximize patient survival in intensive care units (ICUs). However, the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics in critically ill patients differ significantly from those in the general population. Understanding these pathophysiological changes is essential for optimizing antibiotic therapy. In this context, adequate dosing refers to strategies that achieve therapeutic drug concentrations at the infection site, ensuring both clinical and microbiological effectiveness while minimizing the risk of antibiotic-related toxicity. Additionally, optimizing the mode of antibiotic administration-particularly for beta-lactams-through continuous infusion has shown benefits, including improved achievement of PK/PD targets, higher clinical cure rates, and better microbiological eradication. To ensure proper antimicrobial dosing, therapeutic drug monitoring (TDM) is the preferred approach. However, TDM is not universally available in all ICUs or for all antimicrobial agents. In its absence, clinicians must rely on factors such as the patient's clinical condition, the identified pathogen, the impact of organ dysfunction requiring extracorporeal therapies, and the physicochemical properties of antimicrobials to guide dosing decisions. The pharmacokinetics of antimicrobials can vary widely between critically ill patients and even within the same patient throughout their ICU stay, emphasizing the need for individualized dosing strategies and dynamic reassessments. This review aims to outline the key pathophysiological changes observed in critically ill patients and their influence on antimicrobial dosing decisions, while also providing practical considerations to help clinicians optimize antimicrobial therapy in this patient population. Finally, the outstanding challenges in delivering optimal antimicrobial therapy to critically ill patients will be explored, highlighting areas for future research.

PURPOSE OF REVIEW:To provide an updated overview of optimal antibiotic duration in ventilator-associated pneumonia (VAP), integrating guideline recommendations, clinical evidence, and expert opinion. RECENT FINDINGS:A randomized controlled trial, retrospective studies and meta-analyses support shorter (≤7-8-day) regimens for immunocompetent patients with VAP, reducing toxicity and, potentially, resistance development without compromising outcomes. However, while short-course regimens are increasingly supported, recent trials of newer agents often report durations >7 days, reflecting real-world challenges in resistant pathogens and trial design. SUMMARY:VAP remains the leading healthcare-associated infection in intensive care units (ICUs), related to worse outcomes and contributing substantially to antimicrobial use. Historically, prolonged antibiotic courses (≥10-14) were standard, particularly for cases involving multidrug-resistant (MDR) or extensively drug-resistant (XDR) organisms. This review synthesizes current evidence supporting shorter course therapy for VAP (≤7-8 days), emphasizing the importance of clinical response and individualization. While guideline convergence on 7-8 days has grown, exceptions apply for specific pathogens (e.g., nonfermenters, MDR or XDR organisms), bacteremia, slow response, or structural lung disease. Biomarkers like procalcitonin may assist in select cases but lack VAP-specific validation. Regular reassessment is essential to balance efficacy with stewardship. Evidence gaps remain for immunocompromised patients and ultra-short regimens.

OBJECTIVE:To assess the relationship between body mass index (BMI, i.e., kg/m2) and mortality in ICU patients with intra-abdominal infection or sepsis. METHODS:This is a secondary analysis from AbSeS, an international, observational cohort study including patients with intra-abdominal infection (n = 2588). Patients were classified as underweight (BMI < 18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25-29.9), or obese (BMI ≥ 30). Independent relationships with mortality were assessed by logistic and Cox regression. Results reported as odds ratios (OR) or hazard ratios (HR) 95 % and confidence interval (CI). Sensitivity analyses were performed for age (<65 or ≥ 65 years), sex, and sepsis or septic shock. RESULTS:Overall mortality was 29.1 %. Logistic regression showed underweight to be associated with increased mortality (OR 1.76, 95 % CI 1.12-2.78), while obesity was independently associated with a decreased mortality risk compared to normal weight patients (OR 0.75, 95 % CI 0.58-0.97). Mortality in overweight patients was not different from patients with a normal weight. In patients < 65 years, the association with underweight remained, while obesity was no longer associated with decreased mortality. All significant relationships between BMI and mortality disappeared when only considering patients ≥ 65 years. Underweight was associated with increased mortality in patients with sepsis, but not in septic shock. In Cox regression, underweight remained an independent risk factor for death (HR 1.72, 95 % CI 1.25-2.35), whereas obesity was no longer associated with a decreased mortality risk. CONCLUSION:In the context of intra-abdominal infection in ICU patients, underweight is independently associated with increased mortality. The possible association of obesity with decreased mortality risk is less robust. IMPLICATIONS FOR CLINICAL PRACTICE:Nutritional screening should be part of preoperative evaluation in elective abdominal surgery. If undernutrition is identified, targeted nutritional support should be initiated early to improve postoperative resilience and potentially reduce mortality risk in case of critical illness.

Pneumonia remains a significant global health concern, particularly among those requiring admission to the intensive care unit (ICU). Despite the availability of international guidelines, there remains heterogeneity in clinical management. The D-PRISM study aimed to develop a global overview of how pneumonias (i.e., community-acquired (CAP), hospital-acquired (HAP), and Ventilator-associated pneumonia (VAP)) are diagnosed and treated in the ICU and compare differences in clinical practice worldwide. The D-PRISM study was a multinational, survey-based investigation to assess the diagnosis and treatment of pneumonia in the ICU. A self-administered online questionnaire was distributed to intensive care clinicians from 72 countries between September to November 2022. The questionnaire included sections on professional profiles, current clinical practice in diagnosing and managing CAP, HAP, and VAP, and the availability of microbiology diagnostic tests. Multivariable analysis using multiple regression analysis was used to assess the relationship between reported antibiotic duration and organisational variables collected in the study. A total of 1296 valid responses were collected from ICU clinicians, spread between low-and-middle income (LMIC) and high-income countries (HIC), with LMIC respondents comprising 51

AIMS:To explore differences between sexes in the prognosis of severe community-acquired pneumonia. METHODS:We analysed consecutive patients admitted to 27 intensive care units (ICU) from nine European countries and included in the EU-VAP/CAP cohort. All were mechanically ventilated for severe CAP. Sex was obtained from the medical records. Sexes were compared according to age, severity of illness, chronic health condition, co-morbidities, use of diagnostic procedures, length of mechanical ventilation, stay in the ICU, initial antibiotic treatment, and pathogens. The primary outcome was ICU mortality. We tested in a multivariate logistic regression the association of sex with mortality. RESULTS:We included 257 patients (32 % women; mean age 60.5 years). Mean SAPS II score was 48.6 and 125 patients (50.6 %) were in septic shock, without difference between sexes. Women had more frequently a McCabe score of 0 (61 % vs. 51 % of men, p = 0.13). Bronchoscopy was performed in 39 % of men and 26 % of women (p = 0.04). Antibiotic treatment did not differ between sexes. A pathogen was identified in 47 % of patients. 101 patients (39.3 %) died: 35 % of men and 48 % of women (OR 0.59, 95 % CI 0.34-1.00). Male sex was associated with lower mortality (OR 0.42, 95 % CI 0.21-0.84) after adjusting for age, SAPS II score, McCabe score, and use of bronchoscopy. CONCLUSION:Women mechanically ventilated at the ICU for severe CAP had higher mortality despite similar severity of disease and better chronic health. Bronchoscopy was performed more frequently in men suggesting differences in management between sexes.