Impact of Syndromic Molecular Diagnostics on Antimicrobial Adequacy and Time to Therapy in Critically Ill Patients with Pneumonia: A Systematic Review and Meta-Analysis of Randomized Trials

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Conventional cultures are slow and often insensitive, delaying targeted treatment. Syndromic PCR panels offer rapid identification of pathogens and resistance genes directly from respiratory samples, potentially improving early antibiotic optimization. However, the true clinical benefit of these diagnostics in critically ill patients remains uncertain Methods We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing PCR-based molecular diagnostics with standard culture techniques in adult ICU patients with severe community-acquired, hospital-acquired, or ventilator-associated pneumonia. Literature searches were performed in PubMed, Embase, and Cochrane CENTRAL from inception to April 1, 2025. The primary outcomes were adequacy of initial antimicrobial therapy, time to effective antibiotic therapy, and in-hospital mortality. Data were synthesized using random-effects models. Results We included four RCTs comprising 2,031 patients. Syndromic PCR testing significantly increased the likelihood of receiving adequate initial antimicrobial therapy (OR 5.23; 95% CI: 2.27–12.05; p = 0.0001; I² = 83%) and reduced time to directed antibiotic therapy (mean difference − 41.07 hours; 95% CI: − 72.78 to − 9.35; p = 0.01; I² = 100%). No significant difference in in-hospital mortality was observed (RR 1.09; 95% CI: 0.92–1.28; p = 0.32; I² = 0%). Conclusions Syndromic PCR diagnostics improve antibiotic adequacy and accelerate the initiation of targeted therapy in critically ill pneumonia patients, supporting their integration into ICU-based antimicrobial stewardship strategies. Trial registration: PROSPERO CRD420251006301. Pneumonia Molecular Panel Molecular diagnostics Syndromic PCR Rapid PCR Point-of-care Antibiotic stewardship Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Pneumonia remains a major cause of morbidity and mortality among critically ill patients and is a common reason for ICU admission and antimicrobial initiation worldwide(1, 2). Accurate and timely identification of the etiologic pathogen is essential to guide early and appropriate antimicrobial therapy, minimize unnecessary broad-spectrum antibiotic exposure, and improve clinical outcomes (3). However, conventional microbiological cultures often have low sensitivity, are affected by prior antibiotic administration, and can require 48–72 hours to yield actionable results(4, 5). In recent years, molecular diagnostic techniques, particularly multiplex polymerase chain reaction (PCR) assays, have been introduced into clinical practice to address these limitations. These platforms allow for the rapid and simultaneous detection of a wide range of bacterial and viral pathogens directly from respiratory specimens, with results typically available within hours(6, 7). Several syndromic panels also incorporate resistance gene detection, potentially enabling earlier antimicrobial tailoring and stewardship interventions(5, 8). Although the theoretical advantages of syndromic PCR are considerable, the clinical impact of these diagnostic tests in ICU patients with pneumonia remains uncertain. While some studies report improved pathogen detection, more frequent and earlier antibiotic de-escalation, and reduced antibiotic duration (9–11), others fail to show consistent benefits in terms of mortality or stewardship endpoints(12, 13). Notably, the time to effective antibiotic administration is an actionable metric in critical care, as delays in initiating appropriate therapy are strongly associated with worse outcomes, including prolonged organ dysfunction and increased mortality. Syndromic PCR may help shorten this interval by providing rapid, targeted results, but the extent to which this translates into clinical benefit remains nuclear. Moreover, concerns persist regarding the potential for overdiagnosis, misinterpretation of colonization, and cost-effectiveness (4, 14). Given the ongoing uncertainties surrounding the clinical utility of syndromic molecular diagnostics in critically ill patients with pneumonia, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing these platforms with standard microbiological culture. We selected three coprimary outcomes: adequacy of initial antimicrobial therapy, time to effective antibiotic administration, and in-hospital mortality. These outcomes were chosen based on their complementary and clinically relevant roles in guiding early infection management. Adequacy and timeliness of empirical therapy are key actionable metrics associated with improved prognosis in severe infections, while mortality represents the ultimate patient-centered endpoint. Together, these outcomes provide a comprehensive assessment of the diagnostic and therapeutic impact of syndromic PCR in the intensive care setting. Methods This systematic review and meta-analysis was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD420251006301) and conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (15) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines(16). Eligibility Criteria We included studies that met the following criteria: (1) peer-reviewed randomized controlled trials (RCTs); (2) enrolling critically ill adult patients (≥ 18 years) with severe community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or other nosocomial pneumonia, as defined by the original studies; (3) comparing molecular diagnostic methods using polymerase chain reaction (PCR) to conventional microbiological cultures for etiological identification; and (4) reporting at least one of the following outcomes: adequacy of initial antibiotic therapy, time to effective antibiotic administration, or in-hospital mortality. We excluded trials focusing exclusively on single-pathogen pneumonia (e.g., Pneumocystis jirovecii , Staphylococcus aureus ). Search Strategy A comprehensive literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 1, 2025. The search strategy combined controlled vocabulary (e.g., MeSH, Emtree) and free-text terms related to pneumonia, intensive care, and PCR-based diagnostics. The full strategy is available in Supplementary Table S1 . Only English-language articles were included. We conducted manual searches of reference lists of included studies and other relevant reviews. Study Selection Two investigators independently extracted data from each included trial using a standardized data collection form. We extracted all available data on study design, year, setting, sample size, patient characteristics (age, sex, pneumonia type, immunosuppression), diagnostic platform used and timing of use, in-hospital mortality, adequacy of antibiotic therapy, and time to effective treatment. Disagreements were resolved by consensus. The study selection process is illustrated in the PRISMA 2020 flow diagram (Fig. 1 ). Data Extraction Data were extracted independently by two reviewers using a standardized form and included: Study design, year, setting, sample size, patient characteristics (age, sex, pneumonia type, immunosuppression). Diagnostic platform used and timing . Reported outcomes: adequacy of antibiotic therapy, time to effective treatment and mortality. Any disagreements were resolved by consensus. Risk of Bias Assessment The risk of bias for each included study was assessed using the Cochrane Risk of Bias 2.0 (RoB 2) tool (17), evaluating five domains: randomization, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results. Two authors performed the assessments independently, with consensus resolution of disagreements. Studies were classified as having low risk, some concerns, or high risk of bias. Certainty of Evidence To evaluate the overall certainty of the evidence for each outcome, we applied the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. Factors considered included study limitations (risk of bias), inconsistency, indirectness, imprecision, and publication bias. Each outcome was rated as having high, moderate, low, or very low certainty. GRADE assessments were based on the consensus of two authors and summarized in Supplementary Table S4. Outcomes and Sensitivity Analyses The three coprimary outcomes were: Adequacy of initial antimicrobial therapy, Time to effective antibiotic administration, and In-hospital mortality. Adequacy of initial antimicrobial therapy was defined as the concordance between the empirically prescribed antibiotics and the susceptibility profile of the identified pathogen(s), as determined by either culture or molecular testing. Therapy was considered inadequate if it lacked coverage for the identified pathogen, was unnecessarily broad, or exceeded standard treatment duration without justification. Time to effective antibiotic administration was defined as the interval from diagnostic sampling (typically bronchoalveolar lavage or tracheal aspirate collection) to administration of an antibiotic regimen with in vitro activity against the identified pathogen(s) and in-hospital mortality was defined as death occurring during the index hospitalization, irrespective of the length of hospital stay. For each trial, the longest available follow-up during hospitalization (ranging from 28 to 60 days) was considered for outcome assessment. Sensitivity analyses were conducted by excluding studies at high or unclear risk of bias. Data Synthesis and Statistical Analysis Meta-analyses were conducted using Review Manager (RevMan) version 5.4. Risk ratios (RR) and odds ratios (OR) with 95% confidence intervals (CIs) were calculated for dichotomous outcomes, and mean differences (MD) for continuous outcomes. A random-effects model (DerSimonian and Laird) was applied to account for anticipated clinical and methodological heterogeneity. Statistical heterogeneity was assessed via the I² statistic and Cochran’s Q test. I² >50% or p < 0.10 indicated substantial heterogeneity. Sensitivity analyses excluded studies with high or unclear risk of bias. Funnel plots were used to assess publication bias for the coprimary outcomes. A two-sided p-value < 0.05 was considered statistically significant. Results Study Selection and Characteristics As illustrated in Fig. 1 , the initial database search yielded 1,027 records. Following the removal of duplicates and assessment of eligibility criteria, eight studies remained for full-text review. After excluding four publications that did not meet the inclusion criteria, four randomized controlled trials (RCTs) were included, comprising a total of 2,031 patients (18–21). Detailed characteristics of the included studies are presented in Table 1 . Table 1 Baseline characteristics of included studies. Study Design Country Patients MP/SC Male, % MP/SC Age † , y MP/SC CAP , % MP/SC Immunosuppression, % MP/SC PCR test Follow-up † , MP/SC days INHALE WP3 2025 18 RCT England 223/219 66/70 58/59 70/68 5/5 FilmArray 28 FLAGSHIP II 2022 19 RCT Switzerland 71/59 59/63 60/60 74/77 57/56 MAGPIX, RespiFinder-22, Seegene 30 Virk 2024 20 RCT USA 563/589 62/65 62/62 19/22 40/43 FilmArray 30 Poole 2022 21 RCT United Kingdom 100/100 68/88 58/56 42/43 7/8 FilmArray 60 † mean or median; CAP: Community-acquired pneumonia; MP: Molecular Panel; NA: not available; PCR: Polymerase Chain Reaction; RCT: randomized controlled trial; SC: Standard Culture; USA: United States of American. Pooled Analysis of All Studies In the pooled analysis, adequate initial antimicrobial therapy was significantly more frequent in the syndromic PCR group compared to conventional microbiology (odds ratio 5.23; 95% confidence interval [CI] 2.27–12.05; p = 0.0001; I² = 83%) (Fig. 2 ). Time to initiation of targeted antimicrobial therapy was significantly shorter in patients evaluated with syndromic PCR, with a mean difference of − 41.07 hours (95% CI: − 72.78 to − 9.35; p = 0.01; I² = 100%) (Fig. 3 ). In-hospital mortality did not differ significantly between groups (risk ratio 1.07; 95% CI: 0.92–1.26; p = 0.38; I² = 0%) (Fig. 4 ), indicating no evidence of heterogeneity and a neutral effect across trials. Sensitivity Analysis Given the high degree of heterogeneity observed in the outcome of time to targeted therapy (I² = 100%), sensitivity analyses were conducted to assess the robustness of the primary outcomes. For the outcome of adequacy of initial antimicrobial therapy, we performed leave-one-out analyses excluding INHALE WP3, FLAGSHIP II, and Poole trials. The effect estimates remained consistent with the main analysis (Supplementary Figures S3, S4, and S5). For the time to targeted therapy, a leave-one-out sensitivity analysis confirmed that no individual study disproportionately influenced the pooled estimate (Supplementary Figures S6 and S7). Quality Assessment Three trials were judged to have an overall low risk of bias across all domains, while one study (FLAGSHIP II)(19) was rated as having “some concerns” due to deviations from intended interventions and selective reporting (Supplementary Table S2). No study was classified as having a high overall risk of bias. Publication bias was explored through funnel plots for the two primary outcomes: adequacy of initial antimicrobial therapy and time to targeted therapy. For adequacy of therapy, visual inspection of the funnel plot suggested potential asymmetry, with a paucity of small studies showing negative effects. No relevant asymmetry was observed for time to therapy. However, the interpretation of funnel plots is limited by the small number of included studies (n = 4). Egger’s test was not performed due to insufficient statistical power. Funnel plots are presented in Supplementary Figures S1 and S2 . Discussion In this systematic review and meta-analysis of randomized controlled trials, we found that the use of syndromic PCR-based molecular diagnostics in critically ill patients with pneumonia significantly improved the adequacy of initial antimicrobial therapy and reduced the time to effective, targeted treatment. These findings underscore the potential of rapid molecular diagnosis to enhance early therapeutic decision-making, a cornerstone of effective infection management in the intensive care unit (ICU). However, the impact on clinical outcomes, like mortality, was not consistently demonstrated. The improved adequacy of empirical therapy likely reflects the ability of syndromic PCR platforms to rapidly identify bacterial and viral pathogens as well as resistance determinants, directly from respiratory samples. This is particularly relevant in ICU populations, where delayed or inappropriate therapy is associated with worse outcomes, including septic shock and increased mortality (1–3). Our results are in line with prior observational studies and recent meta-analyses suggesting that molecular diagnosis support antimicrobial stewardship efforts by facilitating earlier optimization of antibiotic selection(22–25). Importantly, this is the first meta-analysis to systematically evaluate clinical outcomes, including in-hospital mortality, associated with syndromic molecular diagnosis in critically ill patients with pneumonia. By synthesizing randomized data, our study provides novel insight into the clinical utility of these platforms in real-world ICU practice. The lack of mortality benefit observed across the included studies should be interpreted with caution. Virk et al. observed that there was no effect on most clinical outcomes, including mortality. However, fewer admissions to the ICU were observed among participants with pneumonia in the intervention group than in the control (20)]. Recently, Enne et al. found a worse clinical cure rate in the intervention group, although without reaching full statistical significance(18). Several possible explanations may account for these findings. First, many patients in both study arms received early broad-spectrum empirical therapy, which may have attenuated the potential benefit of earlier pathogen identification. Second, differences in diagnostic implementation strategies and local stewardship practices likely influenced clinical decision-making following test results. Third, interpreting the results (distinguishing colonization from infection) may be challenging and, finally, a misdiagnoses can happen if the causative agent or resistance determinants are not included in the panel. This aligns with recent expert recommendations emphasizing the need for structured diagnostic stewardship programs to guide PCR result interpretation and integration into clinical care [8]. Furthermore, some randomized trials have demonstrated that multiplex PCR testing can lead to significant changes in antibiotic prescribing patterns and earlier de-escalation, supporting its role as a stewardship tool [21]. Indeed, the substantial heterogeneity observed in time to effective therapy (I² = 100%) may reflect variability not only in trial design and patient populations but also in how institutions operationalize diagnostic stewardship protocols following PCR testing. Another important consideration is the generalizability of our findings. All included trials were conducted in high-resource settings with access to advanced diagnostic platforms and integrated infectious disease support. Whether similar benefits would be observed in low-resource ICUs or in centers without structured antimicrobial stewardship programs remains uncertain. This review has limitations. The number of included studies was small, and despite the large pooled sample size, the meta-analysis may be underpowered to detect differences in mortality. The small number of trials included also limits the reliability of formal funnel plot interpretation, and thus, these findings should be interpreted with caution. Definitions of antimicrobial adequacy varied across trials, and other clinically relevant outcomes, such as duration of therapy, resistance development, or cost-effectiveness, were inconsistently reported. Finally, although we performed sensitivity analyses and assessed study quality rigorously, unmeasured confounding and clinical heterogeneity remain possible. Conclusions In conclusion, our findings suggest that syndromic PCR diagnosis represent a promising technological advancement for the rapid detection of pathogens in pneumonia among critically ill patients, with clear benefits in pathogens detection and antibiotic stewardship, although without an impact on in-hospital mortality. The integration of molecular diagnosis into ICU practice may contribute to more rational antimicrobial use and enhance clinical decision-making. Future large-scale, multicenter trials are warranted to determine whether these diagnostic advantages can translate into long-term clinical benefits, including improved survival, reduced antimicrobial exposure, and mitigation of antibiotic resistance. Abbreviations ICU Intensive Care Unit PCR Polymerase Chain Reaction RCT Randomized Controlled Trial CAP Community-Acquired Pneumonia HAP Hospital-Acquired Pneumonia VAP Ventilator-Associated Pneumonia PROSPERO International Prospective Register of Systematic Reviews OR Odds Ratio RR Risk Ratio CI Confidence Interval MD Mean Difference RoB 2 Risk of Bias 2.0 Tool GRADE Grading of Recommendations, Assessment, Development and Evaluation CENTRAL Cochrane Central Register of Controlled Trials SC Standard Culture MP Molecular Panel Declarations Ethics approval and consent to participate Not applicable. This study is a systematic review and meta-analysis of previously published randomized controlled trials and did not involve access to individual patient data. Consent for publication Not applicable. This manuscript does not contain any individual person’s data in any form. Availability of data and materials All data generated or analyzed during this study are included in this published article and its supplementary information files. The review protocol was prospectively registered in PROSPERO (CRD420251006301). Competing interests FJSR reports speaker fees from bioMérieux. The other authors declare that they have no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. No institutional or departmental funds were used. Authors’ contributions YAPS and FJSR conceived the study idea and defined the review objectives and methodology. YAPS, FJSR, BMT, and MHCS conducted the systematic literature search and independently extracted data from eligible studies. YAPS and ELQC performed the statistical analysis and meta-analytical synthesis. ELVC, LPJ, MHCS, and FJSR contributed to the interpretation of the results and the assessment of study quality. YAPS drafted the initial manuscript. All authors critically revised the manuscript for important intellectual content, contributed to the final text, and approved the submitted version. Acknowledgements We would like to thank all study staff, research librarians, and clinicians who contributed indirectly to the completion of this Project. References Torres A, Chalmers JD, Dela Cruz CS, Dominedò C, Kollef M, Martin-Loeches I, et al. Challenges in severe community-acquired pneumonia: a point-of-view review. Intensive Care Med. 2019;45(2):159-71. Torres A, Niederman MS, Chastre J, Ewig S, Fernandez-Vandellos P, Hanberger H, et al. 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Evaluation of the BioFire FilmArray Pneumonia Panel for rapid detection of respiratory bacterial pathogens and antibiotic resistance genes in sputum and endotracheal aspirate specimens. Int J Infect Dis. 2020;95:326-31. Banerjee R, Teng CB, Cunningham SA, Ihde SM, Steckelberg JM, Moriarty JP, et al. Randomized Trial of Rapid Multiplex Polymerase Chain Reaction-Based Blood Culture Identification and Susceptibility Testing. Clin Infect Dis. 2015;61(7):1071-80. MacGowan A, Grier S, Stoddart M, Reynolds R, Rogers C, Pike K, et al. Impact of rapid microbial identification on clinical outcomes in bloodstream infection: the RAPIDO randomized trial. Clin Microbiol Infect. 2020;26(10):1347-54 Additional Declarations Competing interest reported. FJSR reports speaker fees from bioMérieux. The other authors declare that they have no competing interests. Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Published Journal Publication published 22 Aug, 2025 Read the published version in Critical Care → Version 1 posted Editorial decision: Revision requested 16 Jul, 2025 Reviews received at journal 14 Jul, 2025 Reviews received at journal 09 Jul, 2025 Reviews received at journal 08 Jul, 2025 Reviews received at journal 07 Jul, 2025 Reviews received at journal 02 Jul, 2025 Reviewers agreed at journal 01 Jul, 2025 Reviewers agreed at journal 01 Jul, 2025 Reviewers agreed at journal 01 Jul, 2025 Reviewers agreed at journal 30 Jun, 2025 Reviewers agreed at journal 30 Jun, 2025 Reviewers agreed at journal 30 Jun, 2025 Reviewers agreed at journal 26 Jun, 2025 Reviewers invited by journal 26 Jun, 2025 Editor assigned by journal 26 Jun, 2025 Submission checks completed at journal 26 Jun, 2025 First submitted to journal 22 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-6951342","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":478630312,"identity":"019e8807-85c5-4a00-b794-cb60e9cc805e","order_by":0,"name":"Yuri Albuquerque Pessoa dos Santos","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYJCCA3DWxwYGGTCDsYEYLWxAhTMbGHiI0sIA08LMS4wWgxu5Dw8w1NTJm8s3H/5su6OOh4G99/ELxh338GhJNzjAcOyw4c42tjTp3DOHeRh4jptZMJ4pxqMlDegXtgOMG47xmDHnth3gYZBIYzNgbEsgoOVfnT1Qi/Fny7Y6IrUwtjEnArUYSAMZIC3MD/BpkTzzjOFAYt/h5A3H0tIke9sO87DxHGNjSDyDWwvf8TTmDx++1dluOHz48IefbXVy/OxtzB8+7sCtReEAkECRBsYPmwRuDQwM8g1YBJk/4NExCkbBKBgFIw8AAPn8U0ZRsJy8AAAAAElFTkSuQmCC","orcid":"","institution":"Hospital Sírio-Libanês","correspondingAuthor":true,"prefix":"","firstName":"Yuri","middleName":"Albuquerque Pessoa dos","lastName":"Santos","suffix":""},{"id":478630313,"identity":"0fd33899-3918-468e-9583-bfcbac9eec24","order_by":1,"name":"Bruno Martins Tomazini","email":"","orcid":"","institution":"Hospital Sírio-Libanês","correspondingAuthor":false,"prefix":"","firstName":"Bruno","middleName":"Martins","lastName":"Tomazini","suffix":""},{"id":478630315,"identity":"1ac049fc-f5fb-4702-86e3-0b64e2b42c38","order_by":2,"name":"Maurício Henrique Claro Santos","email":"","orcid":"","institution":"Hospital Sírio-Libanês","correspondingAuthor":false,"prefix":"","firstName":"Maurício","middleName":"Henrique Claro","lastName":"Santos","suffix":""},{"id":478630318,"identity":"857e82b6-689f-4551-9d8a-10b307e38d62","order_by":3,"name":"Eduardo Lyra Queiroz","email":"","orcid":"","institution":"Hospital Sírio-Libanês","correspondingAuthor":false,"prefix":"","firstName":"Eduardo","middleName":"Lyra","lastName":"Queiroz","suffix":""},{"id":478630319,"identity":"e21fc58b-ea0c-4f9c-a791-653c73205941","order_by":4,"name":"Laerte Pastore Júnior","email":"","orcid":"","institution":"Hospital Sírio-Libanês","correspondingAuthor":false,"prefix":"","firstName":"Laerte","middleName":"Pastore","lastName":"Júnior","suffix":""},{"id":478630321,"identity":"c38588a3-d426-4783-844d-8a011ca0cf3d","order_by":5,"name":"Eduardo Leite Vieira Costa","email":"","orcid":"","institution":"Hospital Sírio-Libanês","correspondingAuthor":false,"prefix":"","firstName":"Eduardo","middleName":"Leite Vieira","lastName":"Costa","suffix":""},{"id":478630322,"identity":"73bacfa6-5cb9-426c-aee3-f79fd8d8ba72","order_by":6,"name":"Fernando José da Silva Ramos","email":"","orcid":"","institution":"Hospital Sírio-Libanês","correspondingAuthor":false,"prefix":"","firstName":"Fernando","middleName":"José da Silva","lastName":"Ramos","suffix":""}],"badges":[],"createdAt":"2025-06-22 20:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6951342/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6951342/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13054-025-05623-0","type":"published","date":"2025-08-22T16:29:23+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85835928,"identity":"721767bd-2de0-48c6-be54-dde70c77c820","added_by":"auto","created_at":"2025-07-02 08:20:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":213676,"visible":true,"origin":"","legend":"\u003cp\u003ePrisma flow diagram of study screening and selection.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-6951342/v1/7c91bc041e4940c837e2e2c4.png"},{"id":85837627,"identity":"55046b6b-785b-4be6-a59d-32073f5fcce1","added_by":"auto","created_at":"2025-07-02 08:28:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":507224,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest Plot of\u003c/strong\u003e \u003cstrong\u003eAdequacy of Initial Antimicrobial Therapy. \u0026nbsp;\u003c/strong\u003eUse of syndromic molecular panels (PCR panel) was associated with significantly higher rates of adequate initial antimicrobial therapy compared to conventional microbiology (OR 5.23; 95% CI: 2.27–12.05; p = 0.0001).\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-6951342/v1/ae699f94c3de665431c535ee.png"},{"id":85835933,"identity":"74b385ca-c659-4061-87e5-dcebe3ebdc99","added_by":"auto","created_at":"2025-07-02 08:20:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":457470,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest Plot of\u003c/strong\u003e \u003cstrong\u003eTime to Directed Therapy.\u003c/strong\u003e Syndromic PCR testing significantly reduced the time to appropriate directed antibiotic therapy (mean difference: –41.07 hours; 95% CI: –72.78 to –9.35; p = 0.01), although with marked heterogeneity (I² = 100%).\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-6951342/v1/bf408fcca3e961e935e990e6.png"},{"id":85835935,"identity":"d2dd1dc3-4a8d-42fa-a27e-26718d1e9bde","added_by":"auto","created_at":"2025-07-02 08:20:37","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":504178,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest Plot of\u003c/strong\u003e \u003cstrong\u003eIn-Hospital Mortality.\u003c/strong\u003e There was no statistically significant difference in in-hospital mortality between patients evaluated with syndromic PCR panels and those assessed by conventional microbiology (risk ratio 1.07; 95% confidence interval 0.92–1.26; p = 0.38; I² = 0%)\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-6951342/v1/b6d65df8cbebbf7444f14227.png"},{"id":89847288,"identity":"fa80d849-03fb-4b8a-bb8d-a941fccae82d","added_by":"auto","created_at":"2025-08-25 16:42:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2967966,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6951342/v1/9efde3a1-6c5f-4ddd-a584-20c030790b85.pdf"},{"id":85835934,"identity":"6d03143f-5de1-4e6b-8f7c-f817e51cdaab","added_by":"auto","created_at":"2025-07-02 08:20:37","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":1632860,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-6951342/v1/bb7bda24ac5c9ca906555735.docx"}],"financialInterests":"Competing interest reported. FJSR reports speaker fees from bioMérieux. The other authors declare that they have no competing interests.","formattedTitle":"Impact of Syndromic Molecular Diagnostics on Antimicrobial Adequacy and Time to Therapy in Critically Ill Patients with Pneumonia: A Systematic Review and Meta-Analysis of Randomized Trials","fulltext":[{"header":"Background","content":"\u003cp\u003ePneumonia remains a major cause of morbidity and mortality among critically ill patients and is a common reason for ICU admission and antimicrobial initiation worldwide(1, 2). Accurate and timely identification of the etiologic pathogen is essential to guide early and appropriate antimicrobial therapy, minimize unnecessary broad-spectrum antibiotic exposure, and improve clinical outcomes (3). However, conventional microbiological cultures often have low sensitivity, are affected by prior antibiotic administration, and can require 48\u0026ndash;72 hours to yield actionable results(4, 5).\u003c/p\u003e \u003cp\u003eIn recent years, molecular diagnostic techniques, particularly multiplex polymerase chain reaction (PCR) assays, have been introduced into clinical practice to address these limitations. These platforms allow for the rapid and simultaneous detection of a wide range of bacterial and viral pathogens directly from respiratory specimens, with results typically available within hours(6, 7). Several syndromic panels also incorporate resistance gene detection, potentially enabling earlier antimicrobial tailoring and stewardship interventions(5, 8).\u003c/p\u003e \u003cp\u003eAlthough the theoretical advantages of syndromic PCR are considerable, the clinical impact of these diagnostic tests in ICU patients with pneumonia remains uncertain. While some studies report improved pathogen detection, more frequent and earlier antibiotic de-escalation, and reduced antibiotic duration (9\u0026ndash;11), others fail to show consistent benefits in terms of mortality or stewardship endpoints(12, 13). Notably, the time to effective antibiotic administration is an actionable metric in critical care, as delays in initiating appropriate therapy are strongly associated with worse outcomes, including prolonged organ dysfunction and increased mortality. Syndromic PCR may help shorten this interval by providing rapid, targeted results, but the extent to which this translates into clinical benefit remains nuclear. Moreover, concerns persist regarding the potential for overdiagnosis, misinterpretation of colonization, and cost-effectiveness (4, 14).\u003c/p\u003e \u003cp\u003e Given the ongoing uncertainties surrounding the clinical utility of syndromic molecular diagnostics in critically ill patients with pneumonia, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing these platforms with standard microbiological culture. We selected three coprimary outcomes: adequacy of initial antimicrobial therapy, time to effective antibiotic administration, and in-hospital mortality. These outcomes were chosen based on their complementary and clinically relevant roles in guiding early infection management. Adequacy and timeliness of empirical therapy are key actionable metrics associated with improved prognosis in severe infections, while mortality represents the ultimate patient-centered endpoint. Together, these outcomes provide a comprehensive assessment of the diagnostic and therapeutic impact of syndromic PCR in the intensive care setting.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis systematic review and meta-analysis was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD420251006301) and conducted in accordance with the \u003cem\u003eCochrane Handbook for Systematic Reviews of Interventions\u003c/em\u003e (15) and the \u003cem\u003ePreferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020\u003c/em\u003e guidelines(16).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEligibility Criteria\u003c/h2\u003e \u003cp\u003eWe included studies that met the following criteria: (1) peer-reviewed randomized controlled trials (RCTs); (2) enrolling critically ill adult patients (\u0026ge;\u0026thinsp;18 years) with severe community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or other nosocomial pneumonia, as defined by the original studies; (3) comparing molecular diagnostic methods using polymerase chain reaction (PCR) to conventional microbiological cultures for etiological identification; and (4) reporting at least one of the following outcomes: adequacy of initial antibiotic therapy, time to effective antibiotic administration, or in-hospital mortality. We excluded trials focusing exclusively on single-pathogen pneumonia (e.g., \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e, \u003cem\u003eStaphylococcus aureus\u003c/em\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSearch Strategy\u003c/h3\u003e\n\u003cp\u003eA comprehensive literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 1, 2025. The search strategy combined controlled vocabulary (e.g., MeSH, Emtree) and free-text terms related to pneumonia, intensive care, and PCR-based diagnostics. The full strategy is available in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. Only English-language articles were included. We conducted manual searches of reference lists of included studies and other relevant reviews.\u003c/p\u003e\n\u003ch3\u003eStudy Selection\u003c/h3\u003e\n\u003cp\u003eTwo investigators independently extracted data from each included trial using a standardized data collection form. We extracted all available data on study design, year, setting, sample size, patient characteristics (age, sex, pneumonia type, immunosuppression), diagnostic platform used and timing of use, in-hospital mortality, adequacy of antibiotic therapy, and time to effective treatment. Disagreements were resolved by consensus. The study selection process is illustrated in the PRISMA 2020 flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eData Extraction\u003c/h3\u003e\n\u003cp\u003eData were extracted independently by two reviewers using a standardized form and included:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eStudy design, year, setting, sample size, patient characteristics (age, sex, pneumonia type, immunosuppression).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eDiagnostic platform used and timing .\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eReported outcomes: adequacy of antibiotic therapy, time to effective treatment and mortality.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAny disagreements were resolved by consensus.\u003c/p\u003e\n\u003ch3\u003eRisk of Bias Assessment\u003c/h3\u003e\n\u003cp\u003eThe risk of bias for each included study was assessed using the Cochrane Risk of Bias 2.0 (RoB 2) tool (17), evaluating five domains: randomization, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results. Two authors performed the assessments independently, with consensus resolution of disagreements. Studies were classified as having low risk, some concerns, or high risk of bias.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCertainty of Evidence\u003c/h2\u003e \u003cp\u003eTo evaluate the overall certainty of the evidence for each outcome, we applied the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. Factors considered included study limitations (risk of bias), inconsistency, indirectness, imprecision, and publication bias. Each outcome was rated as having high, moderate, low, or very low certainty. GRADE assessments were based on the consensus of two authors and summarized in Supplementary Table S4.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcomes and Sensitivity Analyses\u003c/h3\u003e\n\u003cp\u003eThe three coprimary outcomes were:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAdequacy of initial antimicrobial therapy,\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTime to effective antibiotic administration, and\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIn-hospital mortality.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eAdequacy of initial antimicrobial therapy was defined as the concordance between the empirically prescribed antibiotics and the susceptibility profile of the identified pathogen(s), as determined by either culture or molecular testing. Therapy was considered inadequate if it lacked coverage for the identified pathogen, was unnecessarily broad, or exceeded standard treatment duration without justification.\u003c/p\u003e \u003cp\u003eTime to effective antibiotic administration was defined as the interval from diagnostic sampling (typically bronchoalveolar lavage or tracheal aspirate collection) to administration of an antibiotic regimen with in vitro activity against the identified pathogen(s) and in-hospital mortality was defined as death occurring during the index hospitalization, irrespective of the length of hospital stay. For each trial, the longest available follow-up during hospitalization (ranging from 28 to 60 days) was considered for outcome assessment.\u003c/p\u003e \u003cp\u003eSensitivity analyses were conducted by excluding studies at high or unclear risk of bias.\u003c/p\u003e\n\u003ch3\u003eData Synthesis and Statistical Analysis\u003c/h3\u003e\n\u003cp\u003e Meta-analyses were conducted using Review Manager (RevMan) version 5.4. Risk ratios (RR) and odds ratios (OR) with 95% confidence intervals (CIs) were calculated for dichotomous outcomes, and mean differences (MD) for continuous outcomes. A random-effects model (DerSimonian and Laird) was applied to account for anticipated clinical and methodological heterogeneity.\u003c/p\u003e \u003cp\u003eStatistical heterogeneity was assessed via the I\u0026sup2; statistic and Cochran\u0026rsquo;s Q test. I\u0026sup2; \u0026gt;50% or p\u0026thinsp;\u0026lt;\u0026thinsp;0.10 indicated substantial heterogeneity. Sensitivity analyses excluded studies with high or unclear risk of bias. Funnel plots were used to assess publication bias for the coprimary outcomes. A two-sided p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Selection and Characteristics\u003c/h2\u003e\n \u003cp\u003eAs illustrated in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, the initial database search yielded 1,027 records. Following the removal of duplicates and assessment of eligibility criteria, eight studies remained for full-text review. After excluding four publications that did not meet the inclusion criteria, four randomized controlled trials (RCTs) were included, comprising a total of 2,031 patients (18\u0026ndash;21). Detailed characteristics of the included studies are presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline characteristics of included studies.\u0026nbsp;\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDesign\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCountry\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePatients\u003c/p\u003e\n \u003cp\u003eMP/SC\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMale, %\u003c/p\u003e\n \u003cp\u003eMP/SC\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge\u003csup\u003e\u0026dagger;\u003c/sup\u003e, y\u003c/p\u003e\n \u003cp\u003eMP/SC\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCAP ,\u003c/p\u003e\n \u003cp\u003e% MP/SC\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eImmunosuppression, % MP/SC\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePCR\u003c/p\u003e\n \u003cp\u003etest\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFollow-up\u003csup\u003e\u0026dagger;\u003c/sup\u003e,\u003c/p\u003e\n \u003cp\u003eMP/SC days\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eINHALE WP3 2025\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEngland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e223/219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66/70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58/59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e70/68\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e5/5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFilmArray\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFLAGSHIP II 2022\u003c/strong\u003e\u003csup\u003e19\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSwitzerland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71/59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59/63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60/60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e74/77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57/56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMAGPIX, RespiFinder-22, Seegene\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eVirk 2024\u003c/strong\u003e\u003csup\u003e20\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e563/589\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62/65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62/62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19/22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40/43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFilmArray\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePoole 2022\u003c/strong\u003e\u003csup\u003e21\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnited Kingdom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100/100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68/88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58/56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42/43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFilmArray\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003emean or median; CAP: Community-acquired pneumonia; MP: Molecular Panel; NA: not available; PCR: Polymerase Chain Reaction; RCT: randomized controlled trial; SC: Standard Culture; USA: United States of American.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003ePooled Analysis of All Studies\u003c/h2\u003e\n \u003cp\u003eIn the pooled analysis, adequate initial antimicrobial therapy was significantly more frequent in the syndromic PCR group compared to conventional microbiology (odds ratio 5.23; 95% confidence interval [CI] 2.27\u0026ndash;12.05; p\u0026thinsp;=\u0026thinsp;0.0001; I\u0026sup2; = 83%) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Time to initiation of targeted antimicrobial therapy was significantly shorter in patients evaluated with syndromic PCR, with a mean difference of \u0026minus;\u0026thinsp;41.07 hours (95% CI: \u0026minus;\u0026thinsp;72.78 to \u0026minus;\u0026thinsp;9.35; p\u0026thinsp;=\u0026thinsp;0.01; I\u0026sup2; = 100%) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). In-hospital mortality did not differ significantly between groups (risk ratio 1.07; 95% CI: 0.92\u0026ndash;1.26; p\u0026thinsp;=\u0026thinsp;0.38; I\u0026sup2; = 0%) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e), indicating no evidence of heterogeneity and a neutral effect across trials.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eSensitivity Analysis\u003c/h2\u003e\n \u003cp\u003eGiven the high degree of heterogeneity observed in the outcome of time to targeted therapy (I\u0026sup2; = 100%), sensitivity analyses were conducted to assess the robustness of the primary outcomes.\u003c/p\u003e\n \u003cp\u003eFor the outcome of adequacy of initial antimicrobial therapy, we performed leave-one-out analyses excluding INHALE WP3, FLAGSHIP II, and Poole trials. The effect estimates remained consistent with the main analysis (Supplementary Figures S3, S4, and S5).\u003c/p\u003e\n \u003cp\u003eFor the time to targeted therapy, a leave-one-out sensitivity analysis confirmed that no individual study disproportionately influenced the pooled estimate (Supplementary Figures S6 and S7).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eQuality Assessment\u003c/h2\u003e\n \u003cp\u003eThree trials were judged to have an overall low risk of bias across all domains, while one study (FLAGSHIP II)(19) was rated as having \u0026ldquo;some concerns\u0026rdquo; due to deviations from intended interventions and selective reporting (Supplementary Table S2). No study was classified as having a high overall risk of bias. Publication bias was explored through funnel plots for the two primary outcomes: adequacy of initial antimicrobial therapy and time to targeted therapy. For adequacy of therapy, visual inspection of the funnel plot suggested potential asymmetry, with a paucity of small studies showing negative effects. No relevant asymmetry was observed for time to therapy. However, the interpretation of funnel plots is limited by the small number of included studies (n\u0026thinsp;=\u0026thinsp;4). Egger\u0026rsquo;s test was not performed due to insufficient statistical power. Funnel plots are presented in \u003cem\u003eSupplementary Figures \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e and S2\u003c/em\u003e.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this systematic review and meta-analysis of randomized controlled trials, we found that the use of syndromic PCR-based molecular diagnostics in critically ill patients with pneumonia significantly improved the adequacy of initial antimicrobial therapy and reduced the time to effective, targeted treatment. These findings underscore the potential of rapid molecular diagnosis to enhance early therapeutic decision-making, a cornerstone of effective infection management in the intensive care unit (ICU). However, the impact on clinical outcomes, like mortality, was not consistently demonstrated.\u003c/p\u003e \u003cp\u003eThe improved adequacy of empirical therapy likely reflects the ability of syndromic PCR platforms to rapidly identify bacterial and viral pathogens as well as resistance determinants, directly from respiratory samples. This is particularly relevant in ICU populations, where delayed or inappropriate therapy is associated with worse outcomes, including septic shock and increased mortality (1\u0026ndash;3). Our results are in line with prior observational studies and recent meta-analyses suggesting that molecular diagnosis support antimicrobial stewardship efforts by facilitating earlier optimization of antibiotic selection(22\u0026ndash;25).\u003c/p\u003e \u003cp\u003eImportantly, this is the first meta-analysis to systematically evaluate clinical outcomes, including in-hospital mortality, associated with syndromic molecular diagnosis in critically ill patients with pneumonia. By synthesizing randomized data, our study provides novel insight into the clinical utility of these platforms in real-world ICU practice.\u003c/p\u003e \u003cp\u003eThe lack of mortality benefit observed across the included studies should be interpreted with caution. Virk et al. observed that there was no effect on most clinical outcomes, including mortality. However, fewer admissions to the ICU were observed among participants with pneumonia in the intervention group than in the control (20)]. Recently, Enne et al. found a worse clinical cure rate in the intervention group, although without reaching full statistical significance(18). Several possible explanations may account for these findings. First, many patients in both study arms received early broad-spectrum empirical therapy, which may have attenuated the potential benefit of earlier pathogen identification. Second, differences in diagnostic implementation strategies and local stewardship practices likely influenced clinical decision-making following test results. Third, interpreting the results (distinguishing colonization from infection) may be challenging and, finally, a misdiagnoses can happen if the causative agent or resistance determinants are not included in the panel.\u003c/p\u003e \u003cp\u003eThis aligns with recent expert recommendations emphasizing the need for structured diagnostic stewardship programs to guide PCR result interpretation and integration into clinical care [8]. Furthermore, some randomized trials have demonstrated that multiplex PCR testing can lead to significant changes in antibiotic prescribing patterns and earlier de-escalation, supporting its role as a stewardship tool [21]. Indeed, the substantial heterogeneity observed in time to effective therapy (I\u0026sup2; = 100%) may reflect variability not only in trial design and patient populations but also in how institutions operationalize diagnostic stewardship protocols following PCR testing.\u003c/p\u003e \u003cp\u003eAnother important consideration is the generalizability of our findings. All included trials were conducted in high-resource settings with access to advanced diagnostic platforms and integrated infectious disease support. Whether similar benefits would be observed in low-resource ICUs or in centers without structured antimicrobial stewardship programs remains uncertain.\u003c/p\u003e \u003cp\u003eThis review has limitations. The number of included studies was small, and despite the large pooled sample size, the meta-analysis may be underpowered to detect differences in mortality. The small number of trials included also limits the reliability of formal funnel plot interpretation, and thus, these findings should be interpreted with caution. Definitions of antimicrobial adequacy varied across trials, and other clinically relevant outcomes, such as duration of therapy, resistance development, or cost-effectiveness, were inconsistently reported. Finally, although we performed sensitivity analyses and assessed study quality rigorously, unmeasured confounding and clinical heterogeneity remain possible.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, our findings suggest that syndromic PCR diagnosis represent a promising technological advancement for the rapid detection of pathogens in pneumonia among critically ill patients, with clear benefits in pathogens detection and antibiotic stewardship, although without an impact on in-hospital mortality. The integration of molecular diagnosis into ICU practice may contribute to more rational antimicrobial use and enhance clinical decision-making. Future large-scale, multicenter trials are warranted to determine whether these diagnostic advantages can translate into long-term clinical benefits, including improved survival, reduced antimicrobial exposure, and mitigation of antibiotic resistance.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntensive Care Unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePolymerase Chain Reaction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRandomized Controlled Trial\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCAP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCommunity-Acquired Pneumonia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHAP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHospital-Acquired Pneumonia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVAP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVentilator-Associated Pneumonia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePROSPERO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Prospective Register of Systematic Reviews\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOdds Ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRisk Ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence Interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMean Difference\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRoB 2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRisk of Bias 2.0 Tool\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGRADE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGrading of Recommendations, Assessment, Development and Evaluation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCENTRAL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCochrane Central Register of Controlled Trials\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStandard Culture\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMolecular Panel\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This study is a systematic review and meta-analysis of previously published randomized controlled trials and did not involve access to individual patient data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This manuscript does not contain any individual person\u0026rsquo;s data in any form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article and its supplementary information files. The review protocol was prospectively registered in PROSPERO (CRD420251006301).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFJSR reports speaker fees from bioM\u0026eacute;rieux. The other authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. No institutional or departmental funds were used.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYAPS and FJSR conceived the study idea and defined the review objectives and methodology. YAPS, FJSR, BMT, and MHCS conducted the systematic literature search and independently extracted data from eligible studies. YAPS and ELQC performed the statistical analysis and meta-analytical synthesis. ELVC, LPJ, MHCS, and FJSR contributed to the interpretation of the results and the assessment of study quality. YAPS drafted the initial manuscript. All authors critically revised the manuscript for important intellectual content, contributed to the final text, and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank all study staff, research librarians, and clinicians who contributed indirectly to the completion of this Project.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eTorres A, Chalmers JD, Dela Cruz CS, Domined\u0026ograve; C, Kollef M, Martin-Loeches I, et al. Challenges in severe community-acquired pneumonia: a point-of-view review. Intensive Care Med. 2019;45(2):159-71.\u003c/li\u003e\n \u003cli\u003eTorres A, Niederman MS, Chastre J, Ewig S, Fernandez-Vandellos P, Hanberger H, et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociaci\u0026oacute;n Latinoamericana del T\u0026oacute;rax (ALAT). Eur Respir J. 2017;50(3).\u003c/li\u003e\n \u003cli\u003eKalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. 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. 2016;63(5):e61-e111.\u003c/li\u003e\n \u003cli\u003ePeiffer-Smadja N, Bouadma L, Mathy V, Allouche K, Patrier J, Reboul M, et al. Performance and impact of a multiplex PCR in ICU patients with ventilator-associated pneumonia or ventilated hospital-acquired pneumonia. Crit Care. 2020;24(1):366.\u003c/li\u003e\n \u003cli\u003eCandel FJ, Salavert M, Cant\u0026oacute;n R, Del Pozo JL, Gal\u0026aacute;n-S\u0026aacute;nchez F, Navarro D, et al. The role of rapid multiplex molecular syndromic panels in the clinical management of infections in critically ill patients: an experts-opinion document. Crit Care. 2024;28(1):440.\u003c/li\u003e\n \u003cli\u003eBuchan BW, Windham S, Balada-Llasat JM, Leber A, Harrington A, Relich R, et al. Practical Comparison of the BioFire FilmArray Pneumonia Panel to Routine Diagnostic Methods and Potential Impact on Antimicrobial Stewardship in Adult Hospitalized Patients with Lower Respiratory Tract Infections. J Clin Microbiol. 2020;58(7).\u003c/li\u003e\n \u003cli\u003eTorres A, Lee N, Cilloniz C, Vila J, Van der Eerden M. Laboratory diagnosis of pneumonia in the molecular age. Eur Respir J. 2016;48(6):1764-78.\u003c/li\u003e\n \u003cli\u003eCouturier MR, Bard JD. Direct-from-Specimen Pathogen Identification: Evolution of Syndromic Panels. Clin Lab Med. 2019;39(3):433-51.\u003c/li\u003e\n \u003cli\u003eEchavarr\u0026iacute;a M, Marcone DN, Querci M, Seoane A, Ypas M, Videla C, et al. Clinical impact of rapid molecular detection of respiratory pathogens in patients with acute respiratory infection. J Clin Virol. 2018;108:90-5.\u003c/li\u003e\n \u003cli\u003eGentilotti E, De Nardo P, Cremonini E, G\u0026oacute;rska A, Mazzaferri F, Canziani LM, et al. Diagnostic accuracy of point-of-care tests in acute community-acquired lower respiratory tract infections. A systematic review and meta-analysis. Clin Microbiol Infect. 2022;28(1):13-22.\u003c/li\u003e\n \u003cli\u003eKarolyi M, Pawelka E, Hind J, Baumgartner S, Friese E, Hoepler W, et al. Detection of bacteria via multiplex PCR in respiratory samples of critically ill COVID-19 patients with suspected HAP/VAP in the ICU. Wien Klin Wochenschr. 2022;134(9-10):385-90.\u003c/li\u003e\n \u003cli\u003eAndrews D, Chetty Y, Cooper BS, Virk M, Glass SK, Letters A, et al. Multiplex PCR point of care testing versus routine, laboratory-based testing in the treatment of adults with respiratory tract infections: a quasi-randomised study assessing impact on length of stay and antimicrobial use. BMC Infect Dis. 2017;17(1):671.\u003c/li\u003e\n \u003cli\u003eMattila S, Paalanne N, Honkila M, Pokka T, Tapiainen T. Effect of Point-of-Care Testing for Respiratory Pathogens on Antibiotic Use in Children: A Randomized Clinical Trial. JAMA Netw Open. 2022;5(6):e2216162.\u003c/li\u003e\n \u003cli\u003eDessajan J, Timsit JF. Impact of Multiplex PCR in the Therapeutic Management of Severe Bacterial Pneumonia. Antibiotics (Basel). 2024;13(1).\u003c/li\u003e\n \u003cli\u003eHiggins JPT TJ, Chandler J, Cumpston M, Li T, Page MJ, Welch VA. \u003cem\u003eCochrane Handbook for Systematic Reviews of Interventions\u003c/em\u003e version 6.5 (updated August 2024). Cochrane; 2024.\u003c/li\u003e\n \u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Rev Esp Cardiol (Engl Ed). 2021;74(9):790-9.\u003c/li\u003e\n \u003cli\u003eSterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.\u003c/li\u003e\n \u003cli\u003eEnne VI, Stirling S, Barber JA, High J, Russell C, Brealey D, et al. INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia. Intensive Care Med. 2025;51(2):272-86.\u003c/li\u003e\n \u003cli\u003eDarie AM, Khanna N, Jahn K, Osthoff M, Bassetti S, Schumann DM, et al. Fast multiplex bacterial PCR of bronchoalveolar lavage for antibiotic stewardship in hospitalised patients with pneumonia at risk of Gram-negative bacterial infection (Flagship II): a multicentre, randomised controlled trial. Lancet Respir Med. 2022;10(9):877-87.\u003c/li\u003e\n \u003cli\u003eVirk A, Strasburg AP, Kies KD, Donadio AD, Mandrekar J, Harmsen WS, et al. Rapid multiplex PCR panel for pneumonia in hospitalised patients with suspected pneumonia in the USA: a single-centre, open-label, pragmatic, randomised controlled trial. Lancet Microbe. 2024;5(12):100928.\u003c/li\u003e\n \u003cli\u003ePoole S, Tanner AR, Naidu VV, Borca F, Phan H, Saeed K, et al. Molecular point-of-care testing for lower respiratory tract pathogens improves safe antibiotic de-escalation in patients with pneumonia in the ICU: Results of a randomised controlled trial. J Infect. 2022;85(6):625-33.\u003c/li\u003e\n \u003cli\u003eMoy AC, Kimmoun A, Merkling T, Ber\u0026ccedil;ot B, Cam\u0026eacute;l\u0026eacute;na F, Poncin T, et al. Performance evaluation of a PCR panel (FilmArray\u0026reg; Pneumonia Plus) for detection of respiratory bacterial pathogens in respiratory specimens: A systematic review and meta-analysis. Anaesth Crit Care Pain Med. 2023;42(6):101300.\u003c/li\u003e\n \u003cli\u003eYoo IY, Huh K, Shim HJ, Yun SA, Chung YN, Kang OK, et al. Evaluation of the BioFire FilmArray Pneumonia Panel for rapid detection of respiratory bacterial pathogens and antibiotic resistance genes in sputum and endotracheal aspirate specimens. Int J Infect Dis. 2020;95:326-31.\u003c/li\u003e\n \u003cli\u003eBanerjee R, Teng CB, Cunningham SA, Ihde SM, Steckelberg JM, Moriarty JP, et al. Randomized Trial of Rapid Multiplex Polymerase Chain Reaction-Based Blood Culture Identification and Susceptibility Testing. Clin Infect Dis. 2015;61(7):1071-80.\u003c/li\u003e\n \u003cli\u003eMacGowan A, Grier S, Stoddart M, Reynolds R, Rogers C, Pike K, et al. Impact of rapid microbial identification on clinical outcomes in bloodstream infection: the RAPIDO randomized trial. Clin Microbiol Infect. 2020;26(10):1347-54\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":"Pneumonia, Molecular Panel, Molecular diagnostics, Syndromic PCR, Rapid PCR, Point-of-care, Antibiotic stewardship","lastPublishedDoi":"10.21203/rs.3.rs-6951342/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6951342/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePneumonia is a leading cause of ICU admission and mortality, requiring prompt and adequate antimicrobial therapy to improve outcomes. Conventional cultures are slow and often insensitive, delaying targeted treatment. Syndromic PCR panels offer rapid identification of pathogens and resistance genes directly from respiratory samples, potentially improving early antibiotic optimization. However, the true clinical benefit of these diagnostics in critically ill patients remains uncertain\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing PCR-based molecular diagnostics with standard culture techniques in adult ICU patients with severe community-acquired, hospital-acquired, or ventilator-associated pneumonia. Literature searches were performed in PubMed, Embase, and Cochrane CENTRAL from inception to April 1, 2025. The primary outcomes were adequacy of initial antimicrobial therapy, time to effective antibiotic therapy, and in-hospital mortality. Data were synthesized using random-effects models.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe included four RCTs comprising 2,031 patients. Syndromic PCR testing significantly increased the likelihood of receiving adequate initial antimicrobial therapy (OR 5.23; 95% CI: 2.27\u0026ndash;12.05; p\u0026thinsp;=\u0026thinsp;0.0001; I\u0026sup2; = 83%) and reduced time to directed antibiotic therapy (mean difference \u0026minus;\u0026thinsp;41.07 hours; 95% CI: \u0026minus;\u0026thinsp;72.78 to \u0026minus;\u0026thinsp;9.35; p\u0026thinsp;=\u0026thinsp;0.01; I\u0026sup2; = 100%). No significant difference in in-hospital mortality was observed (RR 1.09; 95% CI: 0.92\u0026ndash;1.28; p\u0026thinsp;=\u0026thinsp;0.32; I\u0026sup2; = 0%).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSyndromic PCR diagnostics improve antibiotic adequacy and accelerate the initiation of targeted therapy in critically ill pneumonia patients, supporting their integration into ICU-based antimicrobial stewardship strategies.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTrial registration:\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePROSPERO CRD420251006301.\u003c/p\u003e","manuscriptTitle":"Impact of Syndromic Molecular Diagnostics on Antimicrobial Adequacy and Time to Therapy in Critically Ill Patients with Pneumonia: A Systematic Review and Meta-Analysis of Randomized Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-02 08:20:32","doi":"10.21203/rs.3.rs-6951342/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-16T23:26:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-14T16:52:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-09T17:51:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-08T15:29:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-07T09:18:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-02T15:44:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"246497391316631901232168640093817638382","date":"2025-07-01T21:22:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"51031728355971833678064532976472598933","date":"2025-07-01T17:01:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"315320694406015086873795196641519213796","date":"2025-07-01T06:17:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"279820135031382334049615748984525041915","date":"2025-06-30T18:29:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"169501426770955316436816664828019332116","date":"2025-06-30T17:35:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"138964395560600762696776772582640807313","date":"2025-06-30T17:28:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"180241734900145025840166653777976983047","date":"2025-06-26T17:18:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-26T16:57:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-26T13:02:54+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-26T13:01:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Critical Care","date":"2025-06-22T20:46:38+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":"15f8df92-9769-4c92-9663-f68741f2332b","owner":[],"postedDate":"July 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-25T16:34:50+00:00","versionOfRecord":{"articleIdentity":"rs-6951342","link":"https://doi.org/10.1186/s13054-025-05623-0","journal":{"identity":"critical-care","isVorOnly":false,"title":"Critical Care"},"publishedOn":"2025-08-22 16:29:23","publishedOnDateReadable":"August 22nd, 2025"},"versionCreatedAt":"2025-07-02 08:20:32","video":"","vorDoi":"10.1186/s13054-025-05623-0","vorDoiUrl":"https://doi.org/10.1186/s13054-025-05623-0","workflowStages":[]},"version":"v1","identity":"rs-6951342","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6951342","identity":"rs-6951342","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}