Suppression of Microbial Burden to Reduce Pneumonia in Critical Illness: the SMURF Feasibility Pilot Study

Suppression of Microbial Burden to Reduce Pneumonia in Critical Illness: the SMURF Feasibility Pilot Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Suppression of Microbial Burden to Reduce Pneumonia in Critical Illness: the SMURF Feasibility Pilot Study Elizabeth Rohrs, Marlena Ornowska, Jessica Wittmann, Sean Hernandez, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8960209/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Apr, 2026 Read the published version in Critical Care → Version 1 posted 11 You are reading this latest preprint version Abstract Background: Nasal antimicrobial photodynamic therapy (aPDT) is a non-antibiotic decolonization strategy with potential to reduce ICU-acquired infections without contributing to antimicrobial resistance. We conducted a feasibility pilot to evaluate implementation of intranasal aPDT in critically ill adults and to generate preliminary estimates of microbiologic and clinical outcomes to inform a future definitive trial. Design: Prospective, single-center, non-randomized feasibility pilot study with sequential control and intervention phases. Setting: Adult mixed medical–surgical intensive care units at a tertiary academic hospital. Patients: Adults ≥19 years with an expected ICU stay >48 hours. Intervention: During the intervention phase, patients received intranasal aPDT every 48 hours until ICU discharge. Control-phase patients received standard ICU care without nasal decolonization. Nasal swabs were obtained at ICU admission and every four days. Main feasibility outcomes: Recruitment rate, protocol adherence, safety, data completeness, and ability to adjudicate pneumonia events using blinded, rule-based criteria aligned with CDC/NHSN definitions. Results: A total of 227 patients were analyzed (126 control, 101 intervention). Recruitment targets were met. Adherence to scheduled nasal swab collection was 97.7%. During the intervention phase, 57.8% of scheduled aPDT treatments were delivered in full and 12.0% partially delivered. No intervention-related serious adverse events were observed. Pneumonia adjudication was completed with high inter-system concordance and minimal missing data, supporting adequacy of data capture tools. Exploratory analyses demonstrated significantly lower early cumulative nasal pathogen burden in the intervention group (p<0.01). The incidence of adjudicated VAP/HAP was 9.0 per 1,000 ICU patient-days during the intervention phase compared with 14.9 per 1,000 ICU patient-days during the control phase (incidence rate ratio 0.61, 95% CI 0.31–1.17). A hierarchical composite endpoint incorporating pneumonia, microbiologic clearance, and cumulative pathogen burden yielded a win ratio of 1.29 (95% CI 0.74–2.31) favoring treatment. Conclusions: Implementation of nasal aPDT in the ICU was feasible and safe, with high sampling adherence and successful blinded adjudication. Exploratory signals of reduced pathogen burden and lower pneumonia incidence support progression to a multicenter randomized trial powered for clinical endpoints. Trial Registration: NCT06867458 clinicaltrials.gov, Registration date March 6, 2025 Antimicrobial photodynamic therapy Nasal decolonization Ventilator-associated pneumonia Hospital-acquired pneumonia Critical Care Infection prevention. Figures Figure 1 Figure 2 Figure 3 Key messages Healthcare-associated infections remain a major cause of morbidity and mortality in the ICU, and current nasal decolonization strategies are limited by antibiotic resistance. Nasal antimicrobial photodynamic therapy (aPDT) offers a non-antibiotic approach to reducing nasal bacterial carriage through light-activated microbial inactivation. In this pilot study, implementation of nasal aPDT was feasible, safe, and associated with reduced bacterial load and lower observed infection rates. These findings support a future multicenter randomized controlled trial to evaluate the impact of aPDT on infection prevention and antibiotic stewardship in critical care. Introduction Healthcare-associated infections (HAIs) remain a major source of morbidity and mortality among hospitalized patients, particularly those in intensive care units (ICUs). 1 – 3 Approximately 7% of Intensive Care Unit (ICU) patients develop an HAI after the second hospital day, contributing to prolonged length of stay and increased antibiotic exposure. 4 , 5 Hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and bloodstream infections (BSI) are among the most consequential HAIs, collectively accounting for an estimated 10,000 deaths and more than 3.4 million excess ICU days annually in the United States alone. 6 Most ICU-acquired infections are associated with invasive devices such as central venous catheters and endotracheal tubes. 7 Although indispensable for critical care, these devices carry inherent infection risk that is difficult to eliminate through device modification alone. In addition to device-related transmission, nasal and hand carriage of pathogenic organisms represent key sources of nosocomial spread. 8 , 9 While hand hygiene is a cornerstone of infection prevention, the nasal cavity remains an underrecognized reservoir for organisms including Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Escherichia coli. 10 – 12 Nasal decolonization strategies aim to reduce both patient self-infection and cross-transmission by suppressing this reservoir. 10 , 13 Given that approximately 20% of individuals are persistent carriers of S. aureus, universal decolonization protocols have been adopted in high-risk settings such as ICUs. 14 Topical mupirocin is effective in reducing MRSA carriage and infection rates and is included in several infection-prevention guidelines. 15 – 19 However, widespread use has driven the emergence of resistance, with some centers reporting mupirocin resistance in up to 63% of MRSA isolates. 15 , 20 These trends highlight the need for effective non-antibiotic alternatives. Antimicrobial photodynamic therapy (aPDT) is a non-antibiotic approach that uses light-activated photosensitizers to generate reactive oxygen species, resulting in rapid microbial killing without selecting for resistance. 21 The Steriwave device (Ondine Biomedical, Vancouver, Canada) applies methylene blue to the anterior nares followed by red light illumination (670 nm), producing targeted microbial inactivation. Prior studies have demonstrated reductions in surgical site infections and SARS-CoV-2 viral load with a favorable safety profile. 22 , 23 However, the feasibility and potential impact of nasal aPDT in the ICU setting have not been established. This pilot study evaluated the feasibility and preliminary efficacy of nasal aPDT for reducing nasal bacterial carriage and preventing VAP and HAP in critically ill adults. Methods Study Design and Setting We conducted a prospective, single-center, non-randomized, sequential pre-post pilot study in a mixed medical-surgical adult ICU at Royal Columbian Hospital, Fraser Health Authority, British Columbia, Canada, assessing the feasibility and preliminary efficacy of intranasal antimicrobial aPDT using the Steriwave device for preventing ICU-acquired infections. The study was conducted between March and September 2025. The Fraser Health Research Ethics Board approved the study under waiver of consent (Tri-Council Policy Statement 2 Article 3.7A), approval number 2024142. Data were collected prospectively from electronic medical records, laboratory reports, and bedside documentation using Fraser Health's validated data capture system. Participants were followed throughout ICU stay and for four days post-discharge, with in-hospital mortality recorded to 60 days post-admission. As a pilot study, no formal sample size calculation was performed. We anticipated approximately 400 participants based on 100 monthly ICU admissions. As a feasibility pilot, all analyses were prespecified and exploratory, intended to inform endpoint selection and power calculations for a subsequent multicenter cluster-randomized crossover trial rather than to support confirmatory inference. Study Phases and Intervention The four-month study comprised a two-month control phase followed by a two-month intervention phase. Control patients received standard ICU care, including chlorhexidine bathing but no nasal decolonization. Intervention patients received intranasal aPDT every 48 hours until ICU discharge. The aPDT procedure involved applying a photosensitizer compound (methylene blue dye) to both nares using pre-saturated swabs, followed by illumination with 670 nm red light to each naris for approximately two minutes. This process was repeated once for a complete treatment cycle. Trained ICU nurses performed all treatments under research team supervision. Eligibility Criteria Adults aged ≥ 19 years with expected ICU stay > 48 hours were eligible. Exclusions included pregnancy/breastfeeding, known allergy to methylene blue or chlorhexidine, nasal/facial trauma preventing nares access, or physician-determined contraindications. Co-enrollment in other studies was considered case-by-case. Nasal Surveillance and Microbiologic Assessment Nasal swabs were collected at ICU admission and every four days thereafter (immediately pre-treatment during intervention phase). Samples were collected using Copan ESwabs and transported under controlled conditions (≤ 2h room temperature or refrigerated 4–8°C, processed within 48h). Swabs were cultured for Staphylococcus aureus (MRSA/MSSA) and multidrug-resistant gram-negative organisms (collectively termed non-respiratory pathogenic bacteria). Samples were plated on sheep blood agar and ESBL chromogenic media (CHROMagar™ ESBL, Chromagar, France) for detection of resistant gram-negative organisms. Laboratory technicians performed assessments blinded to study phase. Semi-quantitative growth was reported on a 0–4 scale: 0 (no growth), 1 (scant), 2 (light), 3 (moderate), 4 (heavy). Collection days were mapped to the nearest protocol timepoint (Day 0, 4, or 8); samples within ± 2 days were assigned to the timepoint that was missed. Cumulative bacterial exposure (Days 0–8) was quantified using area under the curve (AUC) of semi-quantitative score versus time, calculated by trapezoidal rule with bucketed timepoints (0, 4, 8). AUCs were compared using Mann–Whitney U test. Pneumonia Event Adjudication Suspected VAP/HAP events were adjudicated using a structured framework aligned with CDC/NHSN pneumonia criteria. 24 We employed AI-assisted adjudication to standardize criteria application. Clinical, radiographic, microbiologic, and ventilator data were abstracted into a prespecified dataset. Two independent AI-based decision-support systems independently applied decision rules through sequential assessment of imaging, clinical signs, microbiologic evidence, timing, and ventilator exposure to classify events as VAP, HAP, or no pneumonia. Outputs included event presence, type, date, and rationale mapped to criteria elements. Adjudications were performed blinded to treatment assignment. Discordant results were reviewed by clinical staff for final determination. This approach ensured consistent and reproduceable adherence to established algorithms while minimizing subjective variability. We analyzed adjudicated VAP and HAP as a single nosocomial pneumonia endpoint because the study accrued a limited number of pneumonia events, and separating outcomes would yield imprecise, underpowered estimates with wide confidence intervals. Combining VAP and HAP is clinically defensible because they represent a spectrum of hospital-acquired lower respiratory tract infections with overlapping pathophysiology (e.g., microaspiration, impaired cough/mucociliary clearance, sedation-related hypoventilation), shared prevention targets (e.g., oral hygiene, secretion management, aspiration mitigation, early mobility), and similar downstream consequences (prolonged ICU stay, antibiotic exposure, resource use). Accordingly, we standardized incidence using ICU patient-days as the at-risk denominator, which captures the time-varying risk of pneumonia throughout critical illness, including both mechanically ventilated and non-ventilated periods. VAP prevention bundle adherence was assessed as a composite process measure to identify care differences. Daily adherence to each component was recorded and calculated as the proportion of events documented "Yes" among all evaluable events. Days without mechanical ventilation and "Unknown" responses were excluded. Scores were compared using non-parametric testing. For bundle adherence, we used an opportunity-based approach to avoid denominator dilution: elements were assessed only on days when the element was applicable (e.g., “readiness to wean/SBT” only when mechanically ventilated; aspiration-related elements only when enteral access was present), but all elements contributed to an overall composite adherence summary reflecting delivery of pneumonia-prevention care across the ICU stay. This approach preserves statistical power, aligns exposure measurement with clinical eligibility, and maintains interpretability for a pragmatic quality-improvement intervention. Progression Criteria Feasibility was defined a priori as: (1) enrollment of ≥ 80% of eligible ICU patients, (2) ≥ 90% adherence to scheduled nasal swab collection, (3) ≥ 70% adherence to scheduled aPDT treatments without serious device-related adverse events, (4) ≥ 95% completion of pneumonia adjudication within 30 days of study completion, and (5) ≤ 10% missing primary outcome data. Meeting these thresholds would support progression to a multicenter definitive trial. Statistical Analysis To evaluate longitudinal changes in semi-quantitative pathogenic burden, we fitted generalized linear mixed-effects regression models with semi-quantitative score as the dependent variable and treatment group, ICU day, and their interaction (Group × ICU day) as fixed effects. The interaction term, representing differential change in burden over time between groups, was the primary parameter of interest. Two-sided p < 0.05 was considered statistically significant. Statistical analyses were conducted using R (R Foundation for Statistical Computing, Vienna, Austria). We constructed a hierarchical composite endpoint analyzed by win–loss framework, 25, 26 ranking outcomes by clinical importance: Tier 1: Absence of adjudicated VAP/HAP Tier 2: Microbiologic clearance (positive Day 0 swab → negative last-day swab) Tier 3: Early cumulative pathogen burden (trapezoidal AUC of semi-quantitative cultures, Days 0/4/8; only positive cultures contributed; negatives assigned AUC = 0) Treatment and control participants were compared pairwise hierarchically. The participant with more favorable outcome at the highest differing tier was the "winner"; identical outcomes across tiers were ties. Win ratio (WR) = wins/losses. Calculations were performed in Python using custom scripts with nonparametric, pairwise algorithms ensuring reproducibility and transparency. This approach preserved clinical prioritization of pneumonia prevention while retaining sensitivity to upstream microbiologic effects expected from a decolonization-based intervention. Results During the 4-month study period, a total of 382 patients were admitted to the Royal Columbian Hospital ICU, of whom 299 met eligibility criteria. Fifty-two patients with an ICU length of stay < 48 hours were excluded. See Fig. 1 . The final analytic cohort comprised 126 patients in the control phase and 101 patients in the intervention phase; 20 patients present during both phases were excluded. Baseline demographic and clinical characteristics were similar between groups, including illness severity, ICU and hospital length of stay, and 60-day mortality. See Table 1 . Table 1 Group Baseline Characteristics Baseline Characteristics Control Treatment Number of Patients 126 101 Age (Years) (Median [IQR]) 60.0 [45.0–72.0] 60.5 [51.2–68.2] % Male at Birth 62.3 75.0 ICU LOS (days) 7.5 [4.0–13.0] 9.0 [5.0-14.2] Hospital Length of Stay (days) 15.0 [9.0-26.5] 16.0 [11.0-28.8] % ICU mortality (28d) 15.2% 16.0% % Hospital mortality (60d) 21.7% 22.0% APACHE IV Score (Median [IQR]) 71 [56–94] 71 [58–75] SOFA Score (Median [IQR]) 9.0 [6.0–12.0] 8.0 [4.5–10.0] Days on Mechanical Ventilation (Median [IQR]) 5 [3–8] 6 [3–12] % existing CAP/HAP? 16.2% 20.0% % Positive Peripheral Blood Test on admission? 10.0% 14% Diagnostic Categories: Neurologic 14.6% 11% Cardiac Arrest/Cardiac 14.6% 5.0% Other 36.2% 55.0% Shock 7.7% 4.0% Respiratory Failure 8.5% 9.0% Sepsis/Infection Related 9.2% 5.0% Trauma 4.6% 9.0% Gastrointestinal 4.6% 2.0% Protocol adherence to scheduled nasal swab collection was high (97.7%). Reasons for missed swabs included operational factors (28%), patient refusal (22%), discharge or study exit (17%), end-of-life care or clinical instability (17%), and anatomical or bleeding contraindications (11%). During the intervention phase, 633 aPDT treatment opportunities were identified, of which 57.8% received full treatment, 12.0% partial treatment, and 30.2% no treatment. The most common reasons for missed or partial treatments were patient or family refusal (40%), clinical instability (20%), and operational or system-related factors (20%). No intervention-related adverse events were observed. The two AI-based adjudication systems produced concordant decisions for 48 of 52 suspected pneumonia events. The discrepant cases underwent targeted manual review by a clinically trained study team member, and all four were adjudicated as not meeting criteria for VAP or HAP. The observed incidence of adjudicated VAP/HAP was 13.9% during the intervention phase compared with 19.0% during the control phase, corresponding to an absolute risk difference of 5.1%, a relative risk reduction of 26.8%, and a number needed to treat of 20. When adjusted for time at risk, the incidence was 9.0 per 1,000 ICU patient-days in the intervention phase versus 14.9 per 1,000 ICU patient-days in the control phase, yielding an incidence rate ratio (IRR) of 0.61 (95% CI 0.31–1.17; p = 0.14). This represents a 39.5% relative reduction in infection rate. Together, these complementary analyses suggest a clinically meaningful reduction in VAP/HAP associated with the intervention, although the study was not powered to detect statistically significant differences. Among patients with pathogenic bacteria–positive nasal swabs, baseline semi-quantitative culture scores were modestly higher in the intervention group at Day 0, although this difference was not statistically significant (p = 0.40). In the control group, pathogenic bacterial burden remained stable from Day 0 to Day 8 (mean 1.44 − 1.44), whereas in the intervention group it declined from 1.57 at Day 0 to 0.45 at Day 8. See Fig. 2 . Cumulative pathogen burden, quantified as area under the curve from Days 0–8, was significantly lower in the intervention group compared with controls (p < 0.01). In generalized linear mixed-effects models restricted to all pathogenic bacteria–positive swabs, treatment was associated with both a lower overall bacterial burden with a significantly steeper decline over time (group × day interaction, p < 0.001). When analyses were further restricted to patients who changed their test result over their course of stay (positive to negative or negative to positive), and adjusted for co-variates of age, sex, Charleston comorbidity score, APACHE score and total-ICU days, total-ICU is significant (p = 0.018). When VAP prevention bundle adherence was assessed as a composite measure and restricted to ventilated ICU days, overall adherence did not differ between groups (median [IQR] 0.70 [0.60–0.80]). See Fig. 3 . Although higher documented adherence to selected bundle components of oral care and secretion management practice was observed during the intervention phase, adherence to sedation targets, readiness-to-wean assessments, and spontaneous breathing or awakening trials was similar between groups. Importantly, overall composite bundle adherence was comparable, suggesting that observed differences in microbiologic burden and pneumonia incidence were not attributable to systematic differences in guideline-concordant ventilator care. A total of 227 participants contributed to the hierarchical composite endpoint analysis, yielding 12,726 pairwise comparisons. The intervention group achieved 3,144 wins and 2,439 losses, with 7,143 ties, resulting in a win ratio of 1.29 favoring treatment. Although the point estimate favored the intervention, the 95% confidence interval (0.74–2.31) reflected uncertainty in the magnitude of effect. Outcome differences were most frequently driven by Tier 1 (VAP/HAP), with additional contributions from Tier 2 (microbiologic clearance) and Tier 3 (early cumulative pathogen burden), indicating that each tier contributed meaningfully to outcome discrimination. Discussion This pilot study evaluated the feasibility of implementing nasal antimicrobial photodynamic therapy (aPDT) using the Steriwave device in critically ill adults and explored its association with nasal bacterial burden and ICU-acquired pneumonia. Nasal aPDT was successfully integrated into routine ICU care with acceptable adherence and no observed adverse events, consistent with prior reports of photodynamic disinfection in surgical populations. 27 – 29 The unit-wide implementation strategy supported feasibility while minimizing potential cross-transmission and provides an operational framework to inform a planned multicenter trial. Given longstanding concerns regarding the subjectivity and reproducibility of VAP and HAP diagnosis, we emphasized transparent, rule-based adjudication aligned with established surveillance definitions rather than bedside diagnosis. 30 – 32 Clinical Findings Implementation of nasal aPDT was associated with a lower observed incidence of adjudicated VAP/HAP, decreasing from 19.0% in the control phase to 13.9% during the intervention phase. Although not powered for definitive clinical outcomes, the magnitude and direction of this association are clinically relevant and consistent with prior literature demonstrating that modest reductions in VAP/HAP incidence can yield meaningful patient and system-level benefits. 28 , 29 VAP and HAP remain among the most consequential preventable complications in critically ill patients, having established associations with prolonged mechanical ventilation, excess ICU length of stay, and downstream complications. 32 – 34 Using conservative estimates of 3–7 excess ICU days per episode of VAP/HAP, the observed reduction corresponds to approximately 15–36 ICU days saved per 100 ICU patients. 35 In resource-constrained critical care environments, this degree of ICU capacity preservation has direct implications for patient flow and workforce sustainability. While implications for mortality remain exploratory, published estimates of attributable mortality for VAP/HAP (5–10%) suggest that the observed reduction falls within a range plausibly associated with survival benefit in a definitively powered trial, supporting inclusion of mortality as a future outcome. 34 Treatment fidelity in the intervention arm warrants consideration. Although 57.8% of aPDT opportunities resulted in full delivery, 12.0% were partial and 30.2% were not administered. No intervention-related adverse events were observed, indicating that incomplete delivery reflected tolerability and contextual factors rather than safety concerns. A substantial proportion of missed treatments were due to patient or family refusal. Autonomy is often limited in the ICU and the option to decline may represent an important expression of agency. 36 Additionally, the presence of nasogastric or orogastric tubes, which frequently cause oropharyngeal discomfort, likely reduced tolerance for additional nasal or oral manipulation. Clinical instability and operational constraints further limited delivery, reflecting real-world implementation challenges in a high-acuity setting. Analytically, incomplete exposure would be expected to bias effects toward the null, suggesting that the observed microbiologic differences may underestimate the biological impact achievable with full adherence. Hierarchical Composite Endpoint and Microbiologic Findings The hierarchical composite endpoint provided a more informative assessment of treatment effects than binary pneumonia outcomes alone. 25 , 26 Incorporation of microbiologic clearance and early cumulative pathogen burden captured treatment-associated differences that would not have been detected using pneumonia incidence alone. 37 , 38 The win–loss analysis demonstrated a consistent directional signal favoring treatment, with outcome differences arising from pneumonia prevention (Tier 1), accelerated microbiologic clearance (Tier 2), and reduced cumulative pathogen exposure during the ICU period (Tier 3). This pattern supports a biologically plausible mechanism whereby nasal aPDT modifies airway microbial dynamics upstream of overt clinical infection. 39 The wide confidence intervals around the win ratio reflect the expected imprecision of a feasibility pilot with modest sample size and low event rates. 40 Analyses of cumulative pathogen burden further support the composite endpoint interpretation. Among patients with positive cultures, treated participants demonstrated lower cumulative microbial exposure, consistent with reduced bacterial persistence or more rapid suppression. Comparison With Antibiotic-Based Decolonization Compared with mupirocin-based decolonization strategies, aPDT offers a non-antibiotic mechanism that avoids selective pressure for resistance while maintaining broad-spectrum activity. 27 , 41 , 42 Its localized action and favorable safety profile make it a potentially attractive adjunct for infection prevention and antimicrobial stewardship, particularly given rising mupirocin resistance. 20 , 29 Methodological Considerations A notable feature of this study was the use of AI-assisted, rule-based adjudication of VAP/HAP combined with a biologically informed hierarchical composite endpoint. Application of prespecified criteria aligned with CDC/NHSN definitions and blinded adjudication standardized outcome classification while reducing subjectivity and operational challenges inherent to manual chart review. 43 – 47 Feasibility Metrics Feasibility objectives included recruitment capacity, protocol adherence, data completeness, adjudication feasibility, and safety. Recruitment targets were met, with enrollment approaching expected ICU admission volume and inclusion of most eligible patients. Adherence to scheduled nasal swab collection was high (97.7%), exceeding the ≥ 90% feasibility threshold and supporting reliable longitudinal sampling. During the intervention phase, 57.8% of scheduled aPDT treatments were delivered in full and 12.0% partially delivered. Although full adherence was below the aspirational ≥ 70% target, no intervention-related serious adverse events occurred, confirming procedural safety. Missed treatments were primarily due to refusal, clinical instability, or operational factors. Pneumonia adjudication was completed with high concordance and minimal missing primary outcome data. Overall, recruitment, data capture, adjudication, and safety endpoints were feasible, with treatment delivery optimization identified as the main target for refinement in a future multicenter trial. Limitations This study has limitations. As a feasibility pilot, it was not powered for definitive clinical endpoints, and effect estimates should be interpreted cautiously. The block design introduces the possibility of temporal confounding, although no concurrent changes in ICU infection-prevention practices occurred. Microbiologic sampling was limited to the early ICU course. AI-assisted adjudication remains dependent on the quality of underlying clinical data. The single-center, non-randomized design limits generalizability and introduces potential performance bias. Strengths and Future Directions Strengths include pragmatic integration within standard ICU workflows, high protocol adherence, and blinded outcome adjudication. Feasibility objectives were achieved, supporting progression to a definitive multicenter cluster-randomized crossover trial. Future studies powered for clinical endpoints are needed to determine whether early modulation of airway microbial burden translates into sustained reductions in pneumonia incidence, ICU length of stay, and mortality. Conclusion This pilot study demonstrates that nasal antimicrobial photodynamic therapy using APDT treatment is feasible, safe, and integrates into routine ICU care. The intervention was associated with a lower observed incidence of VAP/HAP and reduced nasal pathogen burden, without adverse events. Convergent signals across clinical and microbiologic endpoints support a biologically plausible mechanism by which nasal decolonization may reduce ICU-acquired infection risk. These findings justify advancement to a multicenter cluster-randomized trial powered for clinical outcomes. Abbreviations aPDT – Antimicrobial photodynamic therapy AI – Artificial intelligence APACHE – Acute Physiology and Chronic Health Evaluation AUC – Area under the curve BSI – Bloodstream infection CAP – Community-acquired pneumonia CDC – Centers for Disease Control and Prevention ESBL – Extended-spectrum beta-lactamase HAI – Healthcare-associated infection HAP – Hospital-acquired pneumonia ICU – Intensive care unit IRR – Incidence rate ratio IQR – Interquartile range LOS – Length of stay MRSA – Methicillin-resistant Staphylococcus aureus MSSA – Methicillin-sensitive Staphylococcus aureus NHSN – National Healthcare Safety Network SOFA – Sequential Organ Failure Assessment VAP – Ventilator-associated pneumonia WR – Win ratio Declarations Ethics approval and consent to participate The Fraser Health Research Ethics Board approved the study under waiver of consent (Tri-Council Policy Statement 2 Article 3.7A), approval number 2024142, given the minimal risk nature of the study and the clinical circumstances at the time of enrollment. A deferred consent process was implemented. Patients with decision-making capacity at the time of enrollment were informed about the study and provided the opportunity to decline participation. For patients who lacked capacity, a temporary substitute decision maker (TSDM), when available at admission, was informed of the study and could decline participation on the patient’s behalf. If a TSDM was not available at the time of enrollment but became available subsequently, they were informed of the study as soon as feasible and were given the opportunity to withdraw the patient from ongoing participation. Patients who regained decision-making capacity during the study were informed of their enrollment at the earliest opportunity and were provided the option to continue or withdraw without consequence. Consent for publication Not applicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare no competing interests. Funding This study was supported by an operating grant from Ondine Biomedical Inc. to the Royal Columbian Hospital Foundation. The funder had no role in study design; data collection, analysis, or interpretation; manuscript preparation; or the decision to submit the manuscript for publication. Authors' contributions Elizabeth Rohrs: Conceptualization; Methodology; Investigation; Project administration; Supervision; Data curation; Formal analysis (oversight); Writing – original draft, review & editing. Marlena Ornowska: Conceptualization; Methodology; Investigation; Data curation; Project administration; Writing – review & editing. Jessica Wittmann: Conceptualization; Project administration; Investigation; Data curation; Writing – review & editing. Sean Hernandez: Investigation; Data curation; Writing – review & editing. Clare Reynolds: Investigation; Data curation; Writing – review & editing. Isabella Dakin: Investigation; Data curation; Writing – review & editing. Lin Zhang: Formal analysis; Methodology; Data curation; Writing – review & editing. Diana Whellams: Methodology (microbiology); Writing – review & editing. Shazia Masud: Investigation (microbiology); Writing – review & editing. Steven Reynolds: Conceptualization; Funding acquisition; Methodology; Supervision; Writing – review & editing. All authors reviewed and approved the final manuscript and agree to be accountable for all aspects of the work. 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In: https://www.cdc.gov/nhsn/pdfs/pscmanual/6pscvapcurrent.pdf. Finkelstein DM, Schoenfeld DA (1999) Combining mortality and longitudinal measures in clinical trials. Stat Med 18:1341–54 Pocock SJ, Ariti CA, Collier TJ, Wang D (2012) The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. Eur Heart J 33:176–82 Biel MA (2010) Photodynamic therapy of bacterial and fungal biofilm infections. Methods Mol Biol 635:175–94 Moskven E, Banaszek D, Sayre EC, et al (2023) Effectiveness of prophylactic intranasal photodynamic disinfection therapy and chlorhexidine gluconate body wipes for surgical site infection prophylaxis in adult spine surgery. Can J Surg 66:E550–E560 Bryce E, Wong T, Forrester L, Masri B, Jeske D, Barr K, Errico S, Roscoe D (2014) Nasal photodisinfection and chlorhexidine wipes decrease surgical site infections: a historical control study and propensity analysis. J Hosp Infect 88:89–95 Stern SE, Christensen MA, Nevers MR, Ying J, McKenna C, Munro S, Rhee C, Samore MH, Klompas M, Jones BE (2023) Electronic surveillance criteria for non–ventilator-associated hospital-acquired pneumonia: Assessment of reliability and validity. Infect Control Hosp Epidemiol 44:1769–1775 Nora D, Póvoa P (2017) Antibiotic consumption and ventilator-associated pneumonia rates, some parallelism but some discrepancies. Ann Transl Med 450–450 Klompas M, Branson R, Cawcutt K, et al (2022) Strategies to prevent ventilator-associated pneumonia, ventilator-associated events, and nonventilator hospital-acquired pneumonia in acute-care hospitals: 2022 Update. Infect Control Hosp Epidemiol 43:687–713 Klompas M, Magill S, Robicsek A, et al (2012) Objective surveillance definitions for ventilator-associated pneumonia. Crit Care Med 40:3154–61 Melsen WG, Rovers MM, Groenwold RHH, et al (2013) Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis 13:665–71 Zimlichman E, Henderson D, Tamir O, Franz C, Song P, Yamin CK, Keohane C, Denham CR, Bates DW Health care-associated infections: a meta-analysis of costs and financial impact on the US health care system. JAMA Intern Med 173:2039–46 Rosa Ramos JG, Vasconcelos C, Dadalto L (2025) Practical approaches to the tasks of preserving autonomy and respecting vulnerability among critically ill adult patients: a narrative review. Critical care science 37:e20250234 Chastre J, Luyt C-E, Combes A, Trouillet J-L (2006) Use of quantitative cultures and reduced duration of antibiotic regimens for patients with ventilator-associated pneumonia to decrease resistance in the intensive care unit. Clin Infect Dis 43 Suppl 2:S75-81 Kalil AC, Metersky ML, Klompas M, et al (2016) Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 63:e61–e111 O’Dwyer DN, Dickson RP, Moore BB (2016) The Lung Microbiome, Immunity, and the Pathogenesis of Chronic Lung Disease. J Immunol 196:4839–47 Thabane L, Ma J, Chu R, Cheng J, Ismaila A, Rios LP, Robson R, Thabane M, Giangregorio L, Goldsmith CH (2010) A tutorial on pilot studies: the what, why and how. BMC Med Res Methodol 10:1 Wainwright M (1998) Photodynamic antimicrobial chemotherapy (PACT). J Antimicrob Chemother 42:13–28 Maisch T (2015) Resistance in antimicrobial photodynamic inactivation of bacteria. Photochem Photobiol Sci 14:1518–26 Xu F, Morales FL, Amaral LAN (2024) Robust extraction of pneumonia-associated clinical states from electronic health records. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2417688121 Magill SS, Klompas M, Balk R, et al (2013) Developing a new, national approach to surveillance for ventilator-associated events: executive summary. Clin Infect Dis 57:1742–6 Camargo LFA, De Marco FV, Barbas CSV, et al (2004) Ventilator associated pneumonia: comparison between quantitative and qualitative cultures of tracheal aspirates. Crit Care 8:R422-30 Klompas M (2010) Interobserver variability in ventilator-associated pneumonia surveillance. Am J Infect Control 38:237–9 Ashrafi N, Abdollahi A, Alaei K, Pishgar M (2025) Enhanced prediction of ventilator-associated pneumonia in patients with traumatic brain injury using advanced machine learning techniques. Sci Rep 15:11363 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8960209","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":601484230,"identity":"f94737b3-baa2-44b7-a72a-98d58fa78e66","order_by":0,"name":"Elizabeth 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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Marlena","middleName":"","lastName":"Ornowska","suffix":""},{"id":601484234,"identity":"eaf6269f-7ae8-43d0-b4a6-121ea0cc874f","order_by":2,"name":"Jessica Wittmann","email":"","orcid":"","institution":"Advancing Innovation in Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jessica","middleName":"","lastName":"Wittmann","suffix":""},{"id":601484235,"identity":"d95d787a-7559-43b7-a743-db210a45bfe1","order_by":3,"name":"Sean Hernandez","email":"","orcid":"","institution":"Advancing Innovation in Medicine","correspondingAuthor":false,"prefix":"","firstName":"Sean","middleName":"","lastName":"Hernandez","suffix":""},{"id":601484236,"identity":"a2c68687-f09f-40e5-8f44-0007cd6aaaec","order_by":4,"name":"Clare Reynolds","email":"","orcid":"","institution":"Advancing Innovation in Medicine","correspondingAuthor":false,"prefix":"","firstName":"Clare","middleName":"","lastName":"Reynolds","suffix":""},{"id":601484237,"identity":"e86d13b5-32ca-4e02-9fb9-806bbb6e736e","order_by":5,"name":"Isabella Dakin","email":"","orcid":"","institution":"Advancing Innovation in Medicine","correspondingAuthor":false,"prefix":"","firstName":"Isabella","middleName":"","lastName":"Dakin","suffix":""},{"id":601484238,"identity":"05886534-b5bc-41d9-a774-ab13537a98b3","order_by":6,"name":"Lin Zhang","email":"","orcid":"","institution":"Simon Fraser University","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Zhang","suffix":""},{"id":601484239,"identity":"eb7f624a-485f-4d3d-a249-b6643cc37f22","order_by":7,"name":"Diana Whellams","email":"","orcid":"","institution":"Fraser Health","correspondingAuthor":false,"prefix":"","firstName":"Diana","middleName":"","lastName":"Whellams","suffix":""},{"id":601484240,"identity":"1929014a-93f4-4f94-bb81-9900bb401f0d","order_by":8,"name":"Shazia Masud","email":"","orcid":"","institution":"Fraser Health","correspondingAuthor":false,"prefix":"","firstName":"Shazia","middleName":"","lastName":"Masud","suffix":""},{"id":601484241,"identity":"d51a30b5-5e58-4e35-9507-3ac2e1de1248","order_by":9,"name":"Steven Reynolds","email":"","orcid":"","institution":"Advancing Innovation in Medicine","correspondingAuthor":false,"prefix":"","firstName":"Steven","middleName":"","lastName":"Reynolds","suffix":""}],"badges":[],"createdAt":"2026-02-24 18:09:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8960209/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8960209/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13054-026-06008-7","type":"published","date":"2026-04-07T15:58:16+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":104404909,"identity":"80b60344-d25b-49f8-b557-6a726c21f441","added_by":"auto","created_at":"2026-03-11 12:21:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":43037,"visible":true,"origin":"","legend":"\u003cp\u003eStudy Consort Diagram\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8960209/v1/eb07ed67a8f85d8bc731a811.png"},{"id":104258438,"identity":"790d8d50-6b17-4ad9-9b20-49e7ecb7b095","added_by":"auto","created_at":"2026-03-09 17:37:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":74083,"visible":true,"origin":"","legend":"\u003cp\u003eNasal Swab Semi-Quantitative Results at Day 0, 4 and 8. Mean semi-quantitative swab result on the left axis and sample size is described on the right axis.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8960209/v1/9bc1d776e59ccf59f5f96002.png"},{"id":104258437,"identity":"632fa433-22f4-44b3-b6f6-a730cac1058c","added_by":"auto","created_at":"2026-03-09 17:37:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":75187,"visible":true,"origin":"","legend":"\u003cp\u003eVAP Prevention Bundle Adherence\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8960209/v1/3248bb36a6991f41c9fa6728.png"},{"id":106808891,"identity":"38306ba0-26fd-4c93-bd1a-ac2b32b5df0d","added_by":"auto","created_at":"2026-04-13 16:04:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":993692,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8960209/v1/a10958dc-cec5-42e7-aa1a-9fcfc6040166.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Suppression of Microbial Burden to Reduce Pneumonia in Critical Illness: the SMURF Feasibility Pilot Study","fulltext":[{"header":"Key messages","content":"\u003cul\u003e\n \u003cli\u003eHealthcare-associated infections remain a major cause of morbidity and mortality in the ICU, and current nasal decolonization strategies are limited by antibiotic resistance.\u003c/li\u003e\n \u003cli\u003eNasal antimicrobial photodynamic therapy (aPDT) offers a non-antibiotic approach to reducing nasal bacterial carriage through light-activated microbial inactivation.\u003c/li\u003e\n \u003cli\u003eIn this pilot study, implementation of nasal aPDT was feasible, safe, and associated with reduced bacterial load and lower observed infection rates.\u003c/li\u003e\n \u003cli\u003eThese findings support a future multicenter randomized controlled trial to evaluate the impact of aPDT on infection prevention and antibiotic stewardship in critical care.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eHealthcare-associated infections (HAIs) remain a major source of morbidity and mortality among hospitalized patients, particularly those in intensive care units (ICUs).\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Approximately 7% of Intensive Care Unit (ICU) patients develop an HAI after the second hospital day, contributing to prolonged length of stay and increased antibiotic exposure.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and bloodstream infections (BSI) are among the most consequential HAIs, collectively accounting for an estimated 10,000 deaths and more than 3.4\u0026nbsp;million excess ICU days annually in the United States alone.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMost ICU-acquired infections are associated with invasive devices such as central venous catheters and endotracheal tubes.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Although indispensable for critical care, these devices carry inherent infection risk that is difficult to eliminate through device modification alone. In addition to device-related transmission, nasal and hand carriage of pathogenic organisms represent key sources of nosocomial spread.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e While hand hygiene is a cornerstone of infection prevention, the nasal cavity remains an underrecognized reservoir for organisms including Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Escherichia coli.\u003csup\u003e\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eNasal decolonization strategies aim to reduce both patient self-infection and cross-transmission by suppressing this reservoir.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Given that approximately 20% of individuals are persistent carriers of S. aureus, universal decolonization protocols have been adopted in high-risk settings such as ICUs.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Topical mupirocin is effective in reducing MRSA carriage and infection rates and is included in several infection-prevention guidelines.\u003csup\u003e\u003cspan additionalcitationids=\"CR16 CR17 CR18\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e However, widespread use has driven the emergence of resistance, with some centers reporting mupirocin resistance in up to 63% of MRSA isolates.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e These trends highlight the need for effective non-antibiotic alternatives.\u003c/p\u003e \u003cp\u003eAntimicrobial photodynamic therapy (aPDT) is a non-antibiotic approach that uses light-activated photosensitizers to generate reactive oxygen species, resulting in rapid microbial killing without selecting for resistance.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e The Steriwave device (Ondine Biomedical, Vancouver, Canada) applies methylene blue to the anterior nares followed by red light illumination (670 nm), producing targeted microbial inactivation. Prior studies have demonstrated reductions in surgical site infections and SARS-CoV-2 viral load with a favorable safety profile.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e However, the feasibility and potential impact of nasal aPDT in the ICU setting have not been established.\u003c/p\u003e \u003cp\u003eThis pilot study evaluated the feasibility and preliminary efficacy of nasal aPDT for reducing nasal bacterial carriage and preventing VAP and HAP in critically ill adults.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Setting\u003c/h2\u003e \u003cp\u003eWe conducted a prospective, single-center, non-randomized, sequential pre-post pilot study in a mixed medical-surgical adult ICU at Royal Columbian Hospital, Fraser Health Authority, British Columbia, Canada, assessing the feasibility and preliminary efficacy of intranasal antimicrobial aPDT using the Steriwave device for preventing ICU-acquired infections. The study was conducted between March and September 2025. The Fraser Health Research Ethics Board approved the study under waiver of consent (Tri-Council Policy Statement 2 Article 3.7A), approval number 2024142. Data were collected prospectively from electronic medical records, laboratory reports, and bedside documentation using Fraser Health's validated data capture system. Participants were followed throughout ICU stay and for four days post-discharge, with in-hospital mortality recorded to 60 days post-admission. As a pilot study, no formal sample size calculation was performed. We anticipated approximately 400 participants based on 100 monthly ICU admissions. As a feasibility pilot, all analyses were prespecified and exploratory, intended to inform endpoint selection and power calculations for a subsequent multicenter cluster-randomized crossover trial rather than to support confirmatory inference.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Phases and Intervention\u003c/h3\u003e\n\u003cp\u003eThe four-month study comprised a two-month control phase followed by a two-month intervention phase. Control patients received standard ICU care, including chlorhexidine bathing but no nasal decolonization. Intervention patients received intranasal aPDT every 48 hours until ICU discharge. The aPDT procedure involved applying a photosensitizer compound (methylene blue dye) to both nares using pre-saturated swabs, followed by illumination with 670 nm red light to each naris for approximately two minutes. This process was repeated once for a complete treatment cycle. Trained ICU nurses performed all treatments under research team supervision.\u003c/p\u003e\n\u003ch3\u003eEligibility Criteria\u003c/h3\u003e\n\u003cp\u003eAdults aged\u0026thinsp;\u0026ge;\u0026thinsp;19 years with expected ICU stay\u0026thinsp;\u0026gt;\u0026thinsp;48 hours were eligible. Exclusions included pregnancy/breastfeeding, known allergy to methylene blue or chlorhexidine, nasal/facial trauma preventing nares access, or physician-determined contraindications. Co-enrollment in other studies was considered case-by-case.\u003c/p\u003e\n\u003ch3\u003eNasal Surveillance and Microbiologic Assessment\u003c/h3\u003e\n\u003cp\u003eNasal swabs were collected at ICU admission and every four days thereafter (immediately pre-treatment during intervention phase). Samples were collected using Copan ESwabs and transported under controlled conditions (\u0026le;\u0026thinsp;2h room temperature or refrigerated 4\u0026ndash;8\u0026deg;C, processed within 48h). Swabs were cultured for Staphylococcus aureus (MRSA/MSSA) and multidrug-resistant gram-negative organisms (collectively termed non-respiratory pathogenic bacteria). Samples were plated on sheep blood agar and ESBL chromogenic media (CHROMagar\u0026trade; ESBL, Chromagar, France) for detection of resistant gram-negative organisms. Laboratory technicians performed assessments blinded to study phase. Semi-quantitative growth was reported on a 0\u0026ndash;4 scale: 0 (no growth), 1 (scant), 2 (light), 3 (moderate), 4 (heavy). Collection days were mapped to the nearest protocol timepoint (Day 0, 4, or 8); samples within \u0026plusmn;\u0026thinsp;2 days were assigned to the timepoint that was missed. Cumulative bacterial exposure (Days 0\u0026ndash;8) was quantified using area under the curve (AUC) of semi-quantitative score versus time, calculated by trapezoidal rule with bucketed timepoints (0, 4, 8). AUCs were compared using Mann\u0026ndash;Whitney U test.\u003c/p\u003e\n\u003ch3\u003ePneumonia Event Adjudication\u003c/h3\u003e\n\u003cp\u003eSuspected VAP/HAP events were adjudicated using a structured framework aligned with CDC/NHSN pneumonia criteria.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e We employed AI-assisted adjudication to standardize criteria application. Clinical, radiographic, microbiologic, and ventilator data were abstracted into a prespecified dataset. Two independent AI-based decision-support systems independently applied decision rules through sequential assessment of imaging, clinical signs, microbiologic evidence, timing, and ventilator exposure to classify events as VAP, HAP, or no pneumonia. Outputs included event presence, type, date, and rationale mapped to criteria elements. Adjudications were performed blinded to treatment assignment. Discordant results were reviewed by clinical staff for final determination. This approach ensured consistent and reproduceable adherence to established algorithms while minimizing subjective variability.\u003c/p\u003e \u003cp\u003eWe analyzed adjudicated VAP and HAP as a single nosocomial pneumonia endpoint because the study accrued a limited number of pneumonia events, and separating outcomes would yield imprecise, underpowered estimates with wide confidence intervals. Combining VAP and HAP is clinically defensible because they represent a spectrum of hospital-acquired lower respiratory tract infections with overlapping pathophysiology (e.g., microaspiration, impaired cough/mucociliary clearance, sedation-related hypoventilation), shared prevention targets (e.g., oral hygiene, secretion management, aspiration mitigation, early mobility), and similar downstream consequences (prolonged ICU stay, antibiotic exposure, resource use). Accordingly, we standardized incidence using ICU patient-days as the at-risk denominator, which captures the time-varying risk of pneumonia throughout critical illness, including both mechanically ventilated and non-ventilated periods.\u003c/p\u003e \u003cp\u003eVAP prevention bundle adherence was assessed as a composite process measure to identify care differences. Daily adherence to each component was recorded and calculated as the proportion of events documented \"Yes\" among all evaluable events. Days without mechanical ventilation and \"Unknown\" responses were excluded. Scores were compared using non-parametric testing. For bundle adherence, we used an opportunity-based approach to avoid denominator dilution: elements were assessed only on days when the element was applicable (e.g., \u0026ldquo;readiness to wean/SBT\u0026rdquo; only when mechanically ventilated; aspiration-related elements only when enteral access was present), but all elements contributed to an overall composite adherence summary reflecting delivery of pneumonia-prevention care across the ICU stay. This approach preserves statistical power, aligns exposure measurement with clinical eligibility, and maintains interpretability for a pragmatic quality-improvement intervention.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eProgression Criteria\u003c/h2\u003e \u003cp\u003eFeasibility was defined a priori as: (1) enrollment of \u0026ge;\u0026thinsp;80% of eligible ICU patients, (2)\u0026thinsp;\u0026ge;\u0026thinsp;90% adherence to scheduled nasal swab collection, (3)\u0026thinsp;\u0026ge;\u0026thinsp;70% adherence to scheduled aPDT treatments without serious device-related adverse events, (4)\u0026thinsp;\u0026ge;\u0026thinsp;95% completion of pneumonia adjudication within 30 days of study completion, and (5)\u0026thinsp;\u0026le;\u0026thinsp;10% missing primary outcome data. Meeting these thresholds would support progression to a multicenter definitive trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eTo evaluate longitudinal changes in semi-quantitative pathogenic burden, we fitted generalized linear mixed-effects regression models with semi-quantitative score as the dependent variable and treatment group, ICU day, and their interaction (Group \u0026times; ICU day) as fixed effects. The interaction term, representing differential change in burden over time between groups, was the primary parameter of interest. Two-sided p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were conducted using R (R Foundation for Statistical Computing, Vienna, Austria).\u003c/p\u003e \u003cp\u003eWe constructed a hierarchical composite endpoint analyzed by win\u0026ndash;loss framework,\u003csup\u003e25, 26\u003c/sup\u003e ranking outcomes by clinical importance:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eTier 1: Absence of adjudicated VAP/HAP\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTier 2: Microbiologic clearance (positive Day 0 swab \u0026rarr; negative last-day swab)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTier 3: Early cumulative pathogen burden (trapezoidal AUC of semi-quantitative cultures, Days 0/4/8; only positive cultures contributed; negatives assigned AUC\u0026thinsp;=\u0026thinsp;0)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eTreatment and control participants were compared pairwise hierarchically. The participant with more favorable outcome at the highest differing tier was the \"winner\"; identical outcomes across tiers were ties. Win ratio (WR) = wins/losses. Calculations were performed in Python using custom scripts with nonparametric, pairwise algorithms ensuring reproducibility and transparency. This approach preserved clinical prioritization of pneumonia prevention while retaining sensitivity to upstream microbiologic effects expected from a decolonization-based intervention.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the 4-month study period, a total of 382 patients were admitted to the Royal Columbian Hospital ICU, of whom 299 met eligibility criteria. Fifty-two patients with an ICU length of stay\u0026thinsp;\u0026lt;\u0026thinsp;48 hours were excluded. See Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The final analytic cohort comprised 126 patients in the control phase and 101 patients in the intervention phase; 20 patients present during both phases were excluded. Baseline demographic and clinical characteristics were similar between groups, including illness severity, ICU and hospital length of stay, and 60-day mortality. See Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGroup Baseline Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline Characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of Patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (Years) (Median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.0 [45.0\u0026ndash;72.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.5 [51.2\u0026ndash;68.2]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e% Male at Birth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU LOS (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.5 [4.0\u0026ndash;13.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.0 [5.0-14.2]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospital Length of Stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.0 [9.0-26.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.0 [11.0-28.8]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e% ICU mortality (28d)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e% Hospital mortality (60d)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPACHE IV Score (Median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71 [56\u0026ndash;94]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 [58\u0026ndash;75]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOFA Score (Median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.0 [6.0\u0026ndash;12.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.0 [4.5\u0026ndash;10.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays on Mechanical Ventilation (Median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 [3\u0026ndash;8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 [3\u0026ndash;12]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e% existing CAP/HAP?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e% Positive Peripheral Blood Test on admission?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiagnostic Categories:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeurologic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac Arrest/Cardiac\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShock\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSepsis/Infection Related\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrauma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eProtocol adherence to scheduled nasal swab collection was high (97.7%). Reasons for missed swabs included operational factors (28%), patient refusal (22%), discharge or study exit (17%), end-of-life care or clinical instability (17%), and anatomical or bleeding contraindications (11%). During the intervention phase, 633 aPDT treatment opportunities were identified, of which 57.8% received full treatment, 12.0% partial treatment, and 30.2% no treatment. The most common reasons for missed or partial treatments were patient or family refusal (40%), clinical instability (20%), and operational or system-related factors (20%). No intervention-related adverse events were observed.\u003c/p\u003e \u003cp\u003eThe two AI-based adjudication systems produced concordant decisions for 48 of 52 suspected pneumonia events. The discrepant cases underwent targeted manual review by a clinically trained study team member, and all four were adjudicated as not meeting criteria for VAP or HAP. The observed incidence of adjudicated VAP/HAP was 13.9% during the intervention phase compared with 19.0% during the control phase, corresponding to an absolute risk difference of 5.1%, a relative risk reduction of 26.8%, and a number needed to treat of 20. When adjusted for time at risk, the incidence was 9.0 per 1,000 ICU patient-days in the intervention phase versus 14.9 per 1,000 ICU patient-days in the control phase, yielding an incidence rate ratio (IRR) of 0.61 (95% CI 0.31\u0026ndash;1.17; p\u0026thinsp;=\u0026thinsp;0.14). This represents a 39.5% relative reduction in infection rate. Together, these complementary analyses suggest a clinically meaningful reduction in VAP/HAP associated with the intervention, although the study was not powered to detect statistically significant differences.\u003c/p\u003e \u003cp\u003eAmong patients with pathogenic bacteria\u0026ndash;positive nasal swabs, baseline semi-quantitative culture scores were modestly higher in the intervention group at Day 0, although this difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.40). In the control group, pathogenic bacterial burden remained stable from Day 0 to Day 8 (mean 1.44 \u0026minus;\u0026thinsp;1.44), whereas in the intervention group it declined from 1.57 at Day 0 to 0.45 at Day 8. See Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Cumulative pathogen burden, quantified as area under the curve from Days 0\u0026ndash;8, was significantly lower in the intervention group compared with controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). In generalized linear mixed-effects models restricted to all pathogenic bacteria\u0026ndash;positive swabs, treatment was associated with both a lower overall bacterial burden with a significantly steeper decline over time (group \u0026times; day interaction, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). When analyses were further restricted to patients who changed their test result over their course of stay (positive to negative or negative to positive), and adjusted for co-variates of age, sex, Charleston comorbidity score, APACHE score and total-ICU days, total-ICU is significant (p\u0026thinsp;=\u0026thinsp;0.018).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWhen VAP prevention bundle adherence was assessed as a composite measure and restricted to ventilated ICU days, overall adherence did not differ between groups (median [IQR] 0.70 [0.60\u0026ndash;0.80]). See Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Although higher documented adherence to selected bundle components of oral care and secretion management practice was observed during the intervention phase, adherence to sedation targets, readiness-to-wean assessments, and spontaneous breathing or awakening trials was similar between groups. Importantly, overall composite bundle adherence was comparable, suggesting that observed differences in microbiologic burden and pneumonia incidence were not attributable to systematic differences in guideline-concordant ventilator care.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA total of 227 participants contributed to the hierarchical composite endpoint analysis, yielding 12,726 pairwise comparisons. The intervention group achieved 3,144 wins and 2,439 losses, with 7,143 ties, resulting in a win ratio of 1.29 favoring treatment. Although the point estimate favored the intervention, the 95% confidence interval (0.74\u0026ndash;2.31) reflected uncertainty in the magnitude of effect. Outcome differences were most frequently driven by Tier 1 (VAP/HAP), with additional contributions from Tier 2 (microbiologic clearance) and Tier 3 (early cumulative pathogen burden), indicating that each tier contributed meaningfully to outcome discrimination.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis pilot study evaluated the feasibility of implementing nasal antimicrobial photodynamic therapy (aPDT) using the Steriwave device in critically ill adults and explored its association with nasal bacterial burden and ICU-acquired pneumonia. Nasal aPDT was successfully integrated into routine ICU care with acceptable adherence and no observed adverse events, consistent with prior reports of photodynamic disinfection in surgical populations.\u003csup\u003e\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e The unit-wide implementation strategy supported feasibility while minimizing potential cross-transmission and provides an operational framework to inform a planned multicenter trial. Given longstanding concerns regarding the subjectivity and reproducibility of VAP and HAP diagnosis, we emphasized transparent, rule-based adjudication aligned with established surveillance definitions rather than bedside diagnosis.\u003csup\u003e\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eClinical Findings\u003c/h2\u003e \u003cp\u003eImplementation of nasal aPDT was associated with a lower observed incidence of adjudicated VAP/HAP, decreasing from 19.0% in the control phase to 13.9% during the intervention phase. Although not powered for definitive clinical outcomes, the magnitude and direction of this association are clinically relevant and consistent with prior literature demonstrating that modest reductions in VAP/HAP incidence can yield meaningful patient and system-level benefits.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e VAP and HAP remain among the most consequential preventable complications in critically ill patients, having established associations with prolonged mechanical ventilation, excess ICU length of stay, and downstream complications.\u003csup\u003e\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e Using conservative estimates of 3\u0026ndash;7 excess ICU days per episode of VAP/HAP, the observed reduction corresponds to approximately 15\u0026ndash;36 ICU days saved per 100 ICU patients.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e In resource-constrained critical care environments, this degree of ICU capacity preservation has direct implications for patient flow and workforce sustainability. While implications for mortality remain exploratory, published estimates of attributable mortality for VAP/HAP (5\u0026ndash;10%) suggest that the observed reduction falls within a range plausibly associated with survival benefit in a definitively powered trial, supporting inclusion of mortality as a future outcome.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTreatment fidelity in the intervention arm warrants consideration. Although 57.8% of aPDT opportunities resulted in full delivery, 12.0% were partial and 30.2% were not administered. No intervention-related adverse events were observed, indicating that incomplete delivery reflected tolerability and contextual factors rather than safety concerns. A substantial proportion of missed treatments were due to patient or family refusal. Autonomy is often limited in the ICU and the option to decline may represent an important expression of agency.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e Additionally, the presence of nasogastric or orogastric tubes, which frequently cause oropharyngeal discomfort, likely reduced tolerance for additional nasal or oral manipulation. Clinical instability and operational constraints further limited delivery, reflecting real-world implementation challenges in a high-acuity setting. Analytically, incomplete exposure would be expected to bias effects toward the null, suggesting that the observed microbiologic differences may underestimate the biological impact achievable with full adherence.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eHierarchical Composite Endpoint and Microbiologic Findings\u003c/h2\u003e \u003cp\u003eThe hierarchical composite endpoint provided a more informative assessment of treatment effects than binary pneumonia outcomes alone.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Incorporation of microbiologic clearance and early cumulative pathogen burden captured treatment-associated differences that would not have been detected using pneumonia incidence alone.\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e The win\u0026ndash;loss analysis demonstrated a consistent directional signal favoring treatment, with outcome differences arising from pneumonia prevention (Tier 1), accelerated microbiologic clearance (Tier 2), and reduced cumulative pathogen exposure during the ICU period (Tier 3). This pattern supports a biologically plausible mechanism whereby nasal aPDT modifies airway microbial dynamics upstream of overt clinical infection.\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e The wide confidence intervals around the win ratio reflect the expected imprecision of a feasibility pilot with modest sample size and low event rates.\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e Analyses of cumulative pathogen burden further support the composite endpoint interpretation. Among patients with positive cultures, treated participants demonstrated lower cumulative microbial exposure, consistent with reduced bacterial persistence or more rapid suppression.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eComparison With Antibiotic-Based Decolonization\u003c/h2\u003e \u003cp\u003eCompared with mupirocin-based decolonization strategies, aPDT offers a non-antibiotic mechanism that avoids selective pressure for resistance while maintaining broad-spectrum activity.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e Its localized action and favorable safety profile make it a potentially attractive adjunct for infection prevention and antimicrobial stewardship, particularly given rising mupirocin resistance.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eMethodological Considerations\u003c/h2\u003e \u003cp\u003eA notable feature of this study was the use of AI-assisted, rule-based adjudication of VAP/HAP combined with a biologically informed hierarchical composite endpoint. Application of prespecified criteria aligned with CDC/NHSN definitions and blinded adjudication standardized outcome classification while reducing subjectivity and operational challenges inherent to manual chart review.\u003csup\u003e\u003cspan additionalcitationids=\"CR44 CR45 CR46\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eFeasibility Metrics\u003c/h2\u003e \u003cp\u003eFeasibility objectives included recruitment capacity, protocol adherence, data completeness, adjudication feasibility, and safety. Recruitment targets were met, with enrollment approaching expected ICU admission volume and inclusion of most eligible patients. Adherence to scheduled nasal swab collection was high (97.7%), exceeding the \u0026ge;\u0026thinsp;90% feasibility threshold and supporting reliable longitudinal sampling. During the intervention phase, 57.8% of scheduled aPDT treatments were delivered in full and 12.0% partially delivered. Although full adherence was below the aspirational\u0026thinsp;\u0026ge;\u0026thinsp;70% target, no intervention-related serious adverse events occurred, confirming procedural safety. Missed treatments were primarily due to refusal, clinical instability, or operational factors. Pneumonia adjudication was completed with high concordance and minimal missing primary outcome data. Overall, recruitment, data capture, adjudication, and safety endpoints were feasible, with treatment delivery optimization identified as the main target for refinement in a future multicenter trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThis study has limitations. As a feasibility pilot, it was not powered for definitive clinical endpoints, and effect estimates should be interpreted cautiously. The block design introduces the possibility of temporal confounding, although no concurrent changes in ICU infection-prevention practices occurred. Microbiologic sampling was limited to the early ICU course. AI-assisted adjudication remains dependent on the quality of underlying clinical data. The single-center, non-randomized design limits generalizability and introduces potential performance bias.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and Future Directions\u003c/h2\u003e \u003cp\u003eStrengths include pragmatic integration within standard ICU workflows, high protocol adherence, and blinded outcome adjudication. Feasibility objectives were achieved, supporting progression to a definitive multicenter cluster-randomized crossover trial. Future studies powered for clinical endpoints are needed to determine whether early modulation of airway microbial burden translates into sustained reductions in pneumonia incidence, ICU length of stay, and mortality.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis pilot study demonstrates that nasal antimicrobial photodynamic therapy using APDT treatment is feasible, safe, and integrates into routine ICU care. The intervention was associated with a lower observed incidence of VAP/HAP and reduced nasal pathogen burden, without adverse events. Convergent signals across clinical and microbiologic endpoints support a biologically plausible mechanism by which nasal decolonization may reduce ICU-acquired infection risk. These findings justify advancement to a multicenter cluster-randomized trial powered for clinical outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eaPDT \u0026ndash; Antimicrobial photodynamic therapy\u003c/p\u003e\n\u003cp\u003eAI \u0026ndash; Artificial intelligence\u003c/p\u003e\n\u003cp\u003eAPACHE \u0026ndash; Acute Physiology and Chronic Health Evaluation\u003c/p\u003e\n\u003cp\u003eAUC \u0026ndash; Area under the curve\u003c/p\u003e\n\u003cp\u003eBSI \u0026ndash; Bloodstream infection\u003c/p\u003e\n\u003cp\u003eCAP \u0026ndash; Community-acquired pneumonia\u003c/p\u003e\n\u003cp\u003eCDC \u0026ndash; Centers for Disease Control and Prevention\u003c/p\u003e\n\u003cp\u003eESBL \u0026ndash; Extended-spectrum beta-lactamase\u003c/p\u003e\n\u003cp\u003eHAI \u0026ndash; Healthcare-associated infection\u003c/p\u003e\n\u003cp\u003eHAP \u0026ndash; Hospital-acquired pneumonia\u003c/p\u003e\n\u003cp\u003eICU \u0026ndash; Intensive care unit\u003c/p\u003e\n\u003cp\u003eIRR \u0026ndash; Incidence rate ratio\u003c/p\u003e\n\u003cp\u003eIQR \u0026ndash; Interquartile range\u003c/p\u003e\n\u003cp\u003eLOS \u0026ndash; Length of stay\u003c/p\u003e\n\u003cp\u003eMRSA \u0026ndash; Methicillin-resistant Staphylococcus aureus\u003c/p\u003e\n\u003cp\u003eMSSA \u0026ndash; Methicillin-sensitive Staphylococcus aureus\u003c/p\u003e\n\u003cp\u003eNHSN \u0026ndash; National Healthcare Safety Network\u003c/p\u003e\n\u003cp\u003eSOFA \u0026ndash; Sequential Organ Failure Assessment\u003c/p\u003e\n\u003cp\u003eVAP \u0026ndash; Ventilator-associated pneumonia\u003c/p\u003e\n\u003cp\u003eWR \u0026ndash; Win ratio\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Fraser Health Research Ethics Board approved the study under waiver of consent (Tri-Council Policy Statement 2 Article 3.7A), approval number 2024142, given the minimal risk nature of the study and the clinical circumstances at the time of enrollment. A deferred consent process was implemented. Patients with decision-making capacity at the time of enrollment were informed about the study and provided the opportunity to decline participation. For patients who lacked capacity, a temporary substitute decision maker (TSDM), when available at admission, was informed of the study and could decline participation on the patient’s behalf. If a TSDM was not available at the time of enrollment but became available subsequently, they were informed of the study as soon as feasible and were given the opportunity to withdraw the patient from ongoing participation. Patients who regained decision-making capacity during the study were informed of their enrollment at the earliest opportunity and were provided the option to continue or withdraw without consequence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by an operating grant from Ondine Biomedical Inc. to the Royal Columbian Hospital Foundation. The funder had no role in study design; data collection, analysis, or interpretation; manuscript preparation; or the decision to submit the manuscript for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eElizabeth Rohrs: Conceptualization; Methodology; Investigation; Project administration; Supervision; Data curation; Formal analysis (oversight); Writing – original draft, review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eMarlena Ornowska: Conceptualization; Methodology; Investigation; Data curation; Project administration; Writing – review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eJessica Wittmann: Conceptualization; Project administration; Investigation; Data curation; Writing – review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eSean Hernandez: Investigation; Data curation; Writing – review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eClare Reynolds: Investigation; Data curation; Writing – review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eIsabella Dakin: Investigation; Data curation; Writing – review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eLin Zhang: Formal analysis; Methodology; Data curation; Writing – review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eDiana Whellams: Methodology (microbiology); Writing – review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eShazia Masud: Investigation (microbiology); Writing – review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eSteven Reynolds: Conceptualization; Funding acquisition; Methodology; Supervision; Writing – review \u0026amp; editing.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eAll authors reviewed and approved the final manuscript and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Derek Bingham, Statistics, Simon Fraser University\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHoran TC, Andrus M, Dudeck MA (2008) CDC/NHSN surveillance definition of health care\u0026ndash;associated infection and criteria for specific types of infections in the acute care setting. 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Di\u0026aacute;lisis y Trasplante 35:143\u0026ndash;147\u003c/li\u003e\n\u003cli\u003eSmith M, Herwaldt L (2023) Nasal decolonization: What antimicrobials and antiseptics are most effective before surgery and in the ICU. Am J Infect Control 51:A64\u0026ndash;A71\u003c/li\u003e\n\u003cli\u003eDiekema DJ, Hsueh P-R, Mendes RE, Pfaller MA, Rolston K V., Sader HS, Jones RN (2019) The Microbiology of Bloodstream Infection: 20-Year Trends from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother. https://doi.org/10.1128/AAC.00355-19\u003c/li\u003e\n\u003cli\u003eLowy FD (1998) \u003cem\u003eStaphylococcus aureus\u003c/em\u003e Infections. New England Journal of Medicine 339:520\u0026ndash;532\u003c/li\u003e\n\u003cli\u003eKluytmans J, van Belkum A, Verbrugh H (1997) Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev 10:505\u0026ndash;520\u003c/li\u003e\n\u003cli\u003eChmielowiec-Korzeniowska A, Tymczyna L, Wlazło Ł, Nowakowicz-Dębek B, Trawińska B (2020) Staphylococcus aureus carriage state in healthy adult population and phenotypic and genotypic properties of isolated strains. Advances in Dermatology and Allergology 37:184\u0026ndash;189\u003c/li\u003e\n\u003cli\u003ePoovelikunnel T, Gethin G, Humphreys H (2015) Mupirocin resistance: clinical implications and potential alternatives for the eradication of MRSA. Journal of Antimicrobial Chemotherapy 70:2681\u0026ndash;2692\u003c/li\u003e\n\u003cli\u003eKaur D, Narayan P (2014) Mupirocin resistance in nasal carriage of \u003cem\u003eStaphylococcus aureus\u003c/em\u003e among healthcare workers of a tertiary care rural hospital. Indian Journal of Critical Care Medicine 18:716\u0026ndash;721\u003c/li\u003e\n\u003cli\u003ePalepou M (1998) Evaluation of disc diffusion and Etest for determining the susceptibility of Staphylococcus aureus to mupirocin. Journal of Antimicrobial Chemotherapy 42:577\u0026ndash;583\u003c/li\u003e\n\u003cli\u003eHuang SS, Septimus E, Kleinman K, et al (2013) Targeted versus Universal Decolonization to Prevent ICU Infection. New England Journal of Medicine 368:2255\u0026ndash;2265\u003c/li\u003e\n\u003cli\u003eUniversal ICU Decolonization Toolkit: An Enhanced Protocol. Agency for Healthcare Research and Quality. In: https://www.ahrq.gov/sites/default/files/publications/files/universalicu.pdf. \u003c/li\u003e\n\u003cli\u003eNetto dos Santos KR, de Souza Fonseca L, Gontijo Filho PP (1996) Emergence of high-level mupirocin resistance in methicillin-resistant Staphylococcus aureus isolated from Brazilian university hospitals. Infect Control Hosp Epidemiol 17:813\u0026ndash;6\u003c/li\u003e\n\u003cli\u003eNicolas Loebel, R Andersen (2020) Antimicrobial Photodisinfection Therapy: Essential Technology for Infection Control. Vancouver\u003c/li\u003e\n\u003cli\u003eMoskven E, Banaszek D, Sayre EC, et al (2023) Effectiveness of prophylactic intranasal photodynamic disinfection therapy and chlorhexidine gluconate body wipes for surgical site infection prophylaxis in adult spine surgery. Canadian Journal of Surgery 66:E550\u0026ndash;E560\u003c/li\u003e\n\u003cli\u003ePires L, Wilson BC, Bremner R, et al (2022) Translational feasibility and efficacy of nasal photodynamic disinfection of SARS-CoV-2. Sci Rep 12:14438\u003c/li\u003e\n\u003cli\u003eCenters for Disease Control and Prevention. Pneumonia (Ventilator-associated [VAP] and non-ventilator-associated Pneumonia [PNEU]) Event. National Healthcare Safety Network (NHSN) Patient Safety Component Manual. In: https://www.cdc.gov/nhsn/pdfs/pscmanual/6pscvapcurrent.pdf. \u003c/li\u003e\n\u003cli\u003eFinkelstein DM, Schoenfeld DA (1999) Combining mortality and longitudinal measures in clinical trials. Stat Med 18:1341\u0026ndash;54\u003c/li\u003e\n\u003cli\u003ePocock SJ, Ariti CA, Collier TJ, Wang D (2012) The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. Eur Heart J 33:176\u0026ndash;82\u003c/li\u003e\n\u003cli\u003eBiel MA (2010) Photodynamic therapy of bacterial and fungal biofilm infections. Methods Mol Biol 635:175\u0026ndash;94\u003c/li\u003e\n\u003cli\u003eMoskven E, Banaszek D, Sayre EC, et al (2023) Effectiveness of prophylactic intranasal photodynamic disinfection therapy and chlorhexidine gluconate body wipes for surgical site infection prophylaxis in adult spine surgery. Can J Surg 66:E550\u0026ndash;E560\u003c/li\u003e\n\u003cli\u003eBryce E, Wong T, Forrester L, Masri B, Jeske D, Barr K, Errico S, Roscoe D (2014) Nasal photodisinfection and chlorhexidine wipes decrease surgical site infections: a historical control study and propensity analysis. J Hosp Infect 88:89\u0026ndash;95\u003c/li\u003e\n\u003cli\u003eStern SE, Christensen MA, Nevers MR, Ying J, McKenna C, Munro S, Rhee C, Samore MH, Klompas M, Jones BE (2023) Electronic surveillance criteria for non\u0026ndash;ventilator-associated hospital-acquired pneumonia: Assessment of reliability and validity. Infect Control Hosp Epidemiol 44:1769\u0026ndash;1775\u003c/li\u003e\n\u003cli\u003eNora D, P\u0026oacute;voa P (2017) Antibiotic consumption and ventilator-associated pneumonia rates, some parallelism but some discrepancies. Ann Transl Med 450\u0026ndash;450\u003c/li\u003e\n\u003cli\u003eKlompas M, Branson R, Cawcutt K, et al (2022) Strategies to prevent ventilator-associated pneumonia, ventilator-associated events, and nonventilator hospital-acquired pneumonia in acute-care hospitals: 2022 Update. Infect Control Hosp Epidemiol 43:687\u0026ndash;713\u003c/li\u003e\n\u003cli\u003eKlompas M, Magill S, Robicsek A, et al (2012) Objective surveillance definitions for ventilator-associated pneumonia. Crit Care Med 40:3154\u0026ndash;61\u003c/li\u003e\n\u003cli\u003eMelsen WG, Rovers MM, Groenwold RHH, et al (2013) Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis 13:665\u0026ndash;71\u003c/li\u003e\n\u003cli\u003eZimlichman E, Henderson D, Tamir O, Franz C, Song P, Yamin CK, Keohane C, Denham CR, Bates DW Health care-associated infections: a meta-analysis of costs and financial impact on the US health care system. JAMA Intern Med 173:2039\u0026ndash;46\u003c/li\u003e\n\u003cli\u003eRosa Ramos JG, Vasconcelos C, Dadalto L (2025) Practical approaches to the tasks of preserving autonomy and respecting vulnerability among critically ill adult patients: a narrative review. Critical care science 37:e20250234\u003c/li\u003e\n\u003cli\u003eChastre J, Luyt C-E, Combes A, Trouillet J-L (2006) Use of quantitative cultures and reduced duration of antibiotic regimens for patients with ventilator-associated pneumonia to decrease resistance in the intensive care unit. Clin Infect Dis 43 Suppl 2:S75-81\u003c/li\u003e\n\u003cli\u003eKalil AC, Metersky ML, Klompas M, et al (2016) Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 63:e61\u0026ndash;e111\u003c/li\u003e\n\u003cli\u003eO\u0026rsquo;Dwyer DN, Dickson RP, Moore BB (2016) The Lung Microbiome, Immunity, and the Pathogenesis of Chronic Lung Disease. J Immunol 196:4839\u0026ndash;47\u003c/li\u003e\n\u003cli\u003eThabane L, Ma J, Chu R, Cheng J, Ismaila A, Rios LP, Robson R, Thabane M, Giangregorio L, Goldsmith CH (2010) A tutorial on pilot studies: the what, why and how. BMC Med Res Methodol 10:1\u003c/li\u003e\n\u003cli\u003eWainwright M (1998) Photodynamic antimicrobial chemotherapy (PACT). J Antimicrob Chemother 42:13\u0026ndash;28\u003c/li\u003e\n\u003cli\u003eMaisch T (2015) Resistance in antimicrobial photodynamic inactivation of bacteria. Photochem Photobiol Sci 14:1518\u0026ndash;26\u003c/li\u003e\n\u003cli\u003eXu F, Morales FL, Amaral LAN (2024) Robust extraction of pneumonia-associated clinical states from electronic health records. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2417688121\u003c/li\u003e\n\u003cli\u003eMagill SS, Klompas M, Balk R, et al (2013) Developing a new, national approach to surveillance for ventilator-associated events: executive summary. Clin Infect Dis 57:1742\u0026ndash;6\u003c/li\u003e\n\u003cli\u003eCamargo LFA, De Marco FV, Barbas CSV, et al (2004) Ventilator associated pneumonia: comparison between quantitative and qualitative cultures of tracheal aspirates. Crit Care 8:R422-30\u003c/li\u003e\n\u003cli\u003eKlompas M (2010) Interobserver variability in ventilator-associated pneumonia surveillance. Am J Infect Control 38:237\u0026ndash;9\u003c/li\u003e\n\u003cli\u003eAshrafi N, Abdollahi A, Alaei K, Pishgar M (2025) Enhanced prediction of ventilator-associated pneumonia in patients with traumatic brain injury using advanced machine learning techniques. Sci Rep 15:11363\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cric","sideBox":"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)","snPcode":"13054","submissionUrl":"https://submission.nature.com/new-submission/13054/3","title":"Critical Care","twitterHandle":"@Crit_Care","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Antimicrobial photodynamic therapy, Nasal decolonization, Ventilator-associated pneumonia, Hospital-acquired pneumonia, Critical Care, Infection prevention.","lastPublishedDoi":"10.21203/rs.3.rs-8960209/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8960209/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Nasal antimicrobial photodynamic therapy (aPDT) is a non-antibiotic decolonization strategy with potential to reduce ICU-acquired infections without contributing to antimicrobial resistance. We conducted a feasibility pilot to evaluate implementation of intranasal aPDT in critically ill adults and to generate preliminary estimates of microbiologic and clinical outcomes to inform a future definitive trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDesign:\u003c/strong\u003e Prospective, single-center, non-randomized feasibility pilot study with sequential control and intervention phases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSetting:\u003c/strong\u003e Adult mixed medical–surgical intensive care units at a tertiary academic hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients:\u003c/strong\u003e Adults ≥19 years with an expected ICU stay \u0026gt;48 hours.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention:\u003c/strong\u003e During the intervention phase, patients received intranasal aPDT every 48 hours until ICU discharge. Control-phase patients received standard ICU care without nasal decolonization. Nasal swabs were obtained at ICU admission and every four days.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMain feasibility outcomes:\u003c/strong\u003e Recruitment rate, protocol adherence, safety, data completeness, and ability to adjudicate pneumonia events using blinded, rule-based criteria aligned with CDC/NHSN definitions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A total of 227 patients were analyzed (126 control, 101 intervention). Recruitment targets were met. Adherence to scheduled nasal swab collection was 97.7%. During the intervention phase, 57.8% of scheduled aPDT treatments were delivered in full and 12.0% partially delivered. No intervention-related serious adverse events were observed. Pneumonia adjudication was completed with high inter-system concordance and minimal missing data, supporting adequacy of data capture tools. Exploratory analyses demonstrated significantly lower early cumulative nasal pathogen burden in the intervention group (p\u0026lt;0.01). The incidence of adjudicated VAP/HAP was 9.0 per 1,000 ICU patient-days during the intervention phase compared with 14.9 per 1,000 ICU patient-days during the control phase (incidence rate ratio 0.61, 95% CI 0.31–1.17). A hierarchical composite endpoint incorporating pneumonia, microbiologic clearance, and cumulative pathogen burden yielded a win ratio of 1.29 (95% CI 0.74–2.31) favoring treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Implementation of nasal aPDT in the ICU was feasible and safe, with high sampling adherence and successful blinded adjudication. Exploratory signals of reduced pathogen burden and lower pneumonia incidence support progression to a multicenter randomized trial powered for clinical endpoints.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration: \u003c/strong\u003eNCT06867458 clinicaltrials.gov, Registration date March 6, 2025\u003c/p\u003e","manuscriptTitle":"Suppression of Microbial Burden to Reduce Pneumonia in Critical Illness: the SMURF Feasibility Pilot Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-09 17:37:16","doi":"10.21203/rs.3.rs-8960209/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-19T15:03:10+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-17T02:55:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-06T08:16:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"51031728355971833678064532976472598933","date":"2026-03-06T07:41:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"173758037804634242112246962429042387627","date":"2026-03-05T16:40:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-03T21:51:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"4443568448184600727653901943890383203","date":"2026-03-03T20:52:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-03T19:29:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-27T05:34:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-27T05:33:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Critical Care","date":"2026-02-24T17:53:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cric","sideBox":"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)","snPcode":"13054","submissionUrl":"https://submission.nature.com/new-submission/13054/3","title":"Critical Care","twitterHandle":"@Crit_Care","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"09dbf5fb-c058-400a-a93f-e16065a0621e","owner":[],"postedDate":"March 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-13T16:01:20+00:00","versionOfRecord":{"articleIdentity":"rs-8960209","link":"https://doi.org/10.1186/s13054-026-06008-7","journal":{"identity":"critical-care","isVorOnly":false,"title":"Critical Care"},"publishedOn":"2026-04-07 15:58:16","publishedOnDateReadable":"April 7th, 2026"},"versionCreatedAt":"2026-03-09 17:37:16","video":"","vorDoi":"10.1186/s13054-026-06008-7","vorDoiUrl":"https://doi.org/10.1186/s13054-026-06008-7","workflowStages":[]},"version":"v1","identity":"rs-8960209","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8960209","identity":"rs-8960209","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}