Comparison of the efficacy of initial empirical antibiotic regimens in severe community-acquired pneumonia: a network meta-analysis

Comparison of the efficacy of initial empirical antibiotic regimens in severe community-acquired pneumonia: a network meta-analysis | 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 Comparison of the efficacy of initial empirical antibiotic regimens in severe community-acquired pneumonia: a network meta-analysis Min Wang, Jing Zhang, Xiaoming Wang, Qian Wang, Lian Wang, Han Zhuang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6121400/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 May, 2025 Read the published version in BMC Pulmonary Medicine → Version 1 posted 8 You are reading this latest preprint version Abstract Background Severe community-acquired pneumonia (SCAP) remains a leading cause of morbidity and mortality worldwide. Identifying the optimal antibiotic regimen for treating SCAP is crucial for improving patient outcomes. Methods We searched the PubMed, Embase, and Cochrane Central Register of Controlled Clinical Trials databases to identify studies reporting initial empirical antibiotic regimens in patients with SCAP. We performed a network meta-analysis to compare the relative efficacy of different antibiotic regimens in treating SCAP. The primary outcome was overall mortality. The second outcomes were 30-day mortality and in-hospital mortality. Results This network meta-analysis included 1 randomized clinical trial and 13 observational studies with 8142 patients, categorized into five treatment groups: β-lactam antibiotics, β-lactam antibiotics plus doxycycline, β-lactam antibiotics plus fluoroquinolones, β-lactam antibiotics plus macrolides, and fluoroquinolones monotherapy. β-lactam antibiotics plus macrolides was ranked as the most effective treatment (surface under the cumulative ranking curve, 92.0%; mean rank, 1.3). The β-lactam antibiotics plus macrolides combination significantly reduced overall mortality compared to β-lactam antibiotics alone (RR, 0.79; 95% CI, 0.64–0.96) and β-lactam antibiotics plus fluoroquinolones (RR, 0.67; 95% CI, 0.64–0.82). Conclusion Our findings suggest that β-lactam antibiotics plus macrolides may be the optimal treatment for SCAP. β-lactam antibiotics monotherapy and β-lactam antibiotics plus fluoroquinolones should not be recommended due to their inferior outcomes. Severe community-acquired pneumonia network meta-analysis β-lactam antibiotics macrolides fluoroquinolones mortality Figures Figure 1 Figure 2 Figure 3 Introduction Severe community-acquired pneumonia (SCAP) is the most life-threatening form of community-acquired pneumonia (CAP) and often necessitates intensive care unit (ICU) admission due to invasive mechanical ventilation or septic shock requiring vasopressors. 1 The overall mortality rate for SCAP exceeds 20%, and it is a leading cause of acute respiratory distress syndrome. 2 Studies indicate that early administration of antibiotics can reduce hospital mortality and ICU admission rates, so an appropriate initial antibiotic regimen is important for patients with SCAP. 3 The most frequently identified pathogens causing SCAP are Streptococcus pneumoniae, Staphylococcus aureus (including MRSA), Pseudomonas aeruginosa, and other gram-negative bacteria, viruses, and atypical pathogens. 4 , 5 Understanding these pathogens is critical, as it informs the selection of appropriate initial empirical antibiotic regimens, which are essential for reducing mortality and ICU admissions in SCAP patients. The Infectious Diseases Society of America and American Thoracic Society (IDSA/ATS) and the latest European community-acquired pneumonia (CAP) guidelines recommend a β-lactam antibiotics plus a macrolides for patients with SCAP. The combination of a β-lactam antibiotics and a respiratory fluoroquinolones, however, remains controversial and lacks definitive evidence to support its superiority. 6 , 7 Moreover, recent retrospective cohort studies have suggested that β-lactam antibiotics plus macrolides, fluoroquinolones monotherapy, and β-lactam antibiotics plus doxycycline may yield similar outcomes in non-severe CAP. 8 However, few studies have directly compared fluoroquinolones monotherapy and β-lactam antibiotics plus tetracycline in SCAP. 9 – 11 Despite the recommendations provided by guidelines, the optimal antibiotic regimen for SCAP remains a subject of ongoing debate. Questions persist regarding whether a β-lactam antibiotics plus macrolides combination is superior to a β-lactam antibiotics plus fluoroquinolones, and the efficacy of fluoroquinolones monotherapy and β-lactam antibiotics plus doxycycline as potentially suboptimal options is still unclear. Conventional pairwise meta-analyses, which rely on direct comparisons, are relatively limited and pose challenges in evaluating these antibiotic regimens. Therefore, we conducted a network meta-analysis (NMA) to gain a more comprehensive understanding of the outcomes associated with different antibiotic treatments. Methods Protocol and Registration This NMA was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analysis (PRISMA-NMA) guidelines ( eTable 1 ) and was prospectively registered on PROSPERO (CRD42024574220). 12 Literature Search We systematically searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials from inception to April 11, 2024, to identify relevant RCTs and observational studies evaluating empirical antibiotic therapy for SCAP. The complete search strategy is provided in eTable 2. Additionally, we conducted backwards citation searches by screening the reference lists of included studies for potentially relevant articles. Study Inclusion and exclusion Criteria Studies were included if they met the following criteria: (1) SCAP defined as meeting IDSA/ATS criteria for SCAP or admitted to the ICU; (2) were RCTs or observational cohort studies comparing β-lactam antibiotics, fluoroquinolones, or β-lactam antibiotics based combination regimens; and (3) reported mortality outcomes for at least two antibiotic regimens. Studies were excluded if they lacked a comparator group, involved hospital-acquired pneumonia (HAP) or ventilator-acquired pneumonia (VAP), or focused on targeted therapy based on known pathogen-specific results. Data Extraction Two independent reviewers (XW and LW) extracted study characteristics, patient demographics, treatment regimens, and mortality outcomes. Discrepancies were resolved by discussion. Quality Assessment Two authors (HZ and QW) independently performed the assessment, with any disagreements resolved through discussion. The quality of the evidence was evaluated using the revised tool for risk of bias (ROB2) for randomized controlled trials (RCTs) and the Newcastle-Ottawa Scale (NOS) for observational studies. 13 , 14 Outcome measure The primary outcome was overall mortality, used to evaluate the effectiveness of different antibiotic regimens in SCAP treatment. When available, 30-day all-cause mortality was prioritized; otherwise, in-hospital all-cause mortality was used. Secondary outcomes included 30-day all-cause mortality and in-hospital all-cause mortality analyzed separately. Statistical Analysis This NMA was performed within a frequentist framework using a random-effects model in Stata (network and mvmeta packages). 15 Mortality risk was estimated as relative risk (RR) with 95% confidence intervals (CIs), and results were visualized using forest plots and league tables. Treatment rankings for each outcome were determined by the surface under the cumulative ranking curve (SUCRA), where higher SUCRA values indicate better rankings. 16 To ensure result robustness, we evaluated inconsistency and heterogeneity. 17 Both overall and loop inconsistencies were assessed, 15 , 18 and heterogeneity was quantified using the restricted maximum likelihood method. A τ² value 0.5 indicated high heterogeneity. 19 Small-study effects were examined via funnel plots, with Egger’s test applied to detect publication bias. Statistical significance was set at P < 0.05. Results Characteristics of the studies The flowchart of study selection for this network meta-analysis is shown in Fig. 1 . In total, 1RCT and 13 observational studies with 8142 patients were included, 9 , 20 – 32 including 5 groups: β-lactam antibiotics, β-lactam antibiotics plus doxycycline, β-lactam antibiotics plus fluoroquinolones, β-lactam antibiotics plus macrolides, and fluoroquinolones alone. The basic characteristics of the included studies are summarized in Table 1 . The quality of studies included is summarized in eTable 3 and eFigure 1 . Table 1 Basic Characteristics of Included Studies Study Country Study design Population Disease severity score (mean) Mechanical ventilation (%) Severe sepsis or septic shock (%) Interventions Patients, No. Mean age, (range), y Reported outcomes Risk of bias* Rello, 2002 20 Spain Retrospective study Patients admitted to ICU APACHE II score 18.5 77.4 Septic shock (32.3%) BL 31 NR In-hospital mortality Low APACHE II score 18.8 92.1 Septic shock (31.5%) F 38 NR APACHE II score 19.1 46.1 Septic shock (0%) BL + M 274 NR Leroy, 2005 54 International Randomized controlled trials Patients admitted to ICU SAPS II score 34.0 51 Septic shock (0%) BL + F 201 60 In-hospital mortality Low SAPS II score 33.0 51.6 Septic shock (0%) F 194 60 Bratzler, 2008 22 United States Retrospective study Patients admitted to ICU NR NR NR BL + F 207 NR 30-day mortality, in-hospital mortality Low BL + M 693 NR BL 509 NR F 418 NR Martin, 2010 23 Spain Prospective study Patients meeting IDSA/ATS SCAP criteria SAPS II score 49.2 100 Severe sepsis and septic shock (96.2%) BL + F 54 57.1 30-day mortality, in-hospital mortality High SAPS II score 44.3 100 Severe sepsis and septic shock (86.9%) BL + M 46 58.2 Wilson, 2012 24 United States Retrospective study Patients admitted to ICU NR 43 Septic shock (27%) BL + F 883 75 30-day mortality Low NR 37 Septic shock (20.7%) BL + M 1106 74 Adrie, 2013 25 France Prospective study Patients admitted to ICU SAPS II score 47 72.2 Septic shock (40.1%) BL 471 60 In-hospital mortality Low SAPS II score 43 58.3 Septic shock (58.3%) BL + F 230 64 SAPS II score 37 44.5 Septic shock (44.5%) BL + M 164 64 Karhu, 2013 26 Finland Retrospective study Patients meeting IDSA/ATS SCAP criteria IDSA/ATS SCAP criteria fulfilled (83.7%) 63.1 Septic shock (48.1%) BL + F 104 54 30-day mortality, in-hospital mortality Low IDSA/ATS SCAP criteria fulfilled (68.9%) 42.5 Septic shock (38.7%) BL + M 106 55 Ceccato, 2017 27 International Retrospective study Patients meeting IDSA/ATS SCAP criteria PSI score 94.2 NR NR BL + F 78 61 In-hospital mortality High PSI score 132.3 NR NR BL + M 28 75 Rahmel, 2017 28 Germany Retrospective study Patients admitted to ICU SAPS II score 40 NR NR BL + F 44 41 30-day mortality Low SAPS II score 47 NR NR F 42 45 Ito, 2019 29 Japan Prospective study Patients meeting IDSA/ATS SCAP criteria NR NR NR BL 236 NR 30-day mortality High BL + M 48 NR Suzuki, 2019 30 Japan Retrospective study Patients meeting IDSA/ATS SCAP criteria IDSA/ATS SCAP criteria fulfilled (100%) 79.1 Septic shock (51.7%) BL + F 560 72 30-day mortality Low IDSA/ATS SCAP criteria fulfilled (100%) 80 Septic shock (53.7%) BL + M 560 73 Kyriazopoulou, 2020 31 Greece Retrospective study Patients meeting IDSA/ATS SCAP criteria APACHE II score 15.3 NR Septic shock (18.5%) BL + M 260 260 30-day mortality Low APACHE II score 16.8 NR Septic shock (23.8%) F 130 130 APACHE II score 16.1 NR Septic shock (18.5%) BL 130 130 Greco, 2023 9 USA Prospective study Patients meeting IDSA/ATS SCAP criteria APACHE IV score 35 53 Septic shock (34%) BL + D 86 64 30-day mortality, in-hospital mortality Low APACHE IV score 35 63 Septic shock (38%) BL + M 63 58 Oh, 2024 32 Korea Retrospective study Patients meeting IDSA/ATS SCAP criteria PSI score 152.3 11.5 NR BL 64 73 30-day mortality, in-hospital mortality Low PSI score 158.2 21.4 NR BL + F 84 75 Legend: BL, β-lactam antibiotics; D, doxycycline; M, macrolides; F, fluoroquinolones; ICU, intensive care unit; NR, not reported; SCAP, severe community-acquired pneumonia; SAPS, simplified acute physiology score; IDSA/ATS, Infectious Diseases Society of America/American Thoracic Society; APACHE, Acute Physiology and Chronic Health Evaluation; PSI, Pneumonia Severity Index. *The risk of bias in observational trials and randomized controlled trials was assessed using the Newcastle-Ottawa quality assessment scale (NOS) and the revised tool for risk of bias (ROB2) for randomized controlled trials, respectively. Table 2 . League Tables of All Outcomes Panel A. Overall mortality LB+M 1.16 (0.88,1.53) 1.26 (0.67,2.34) 1.28 (1.05,1.57) 1.50 (1.22,1.84) 0.86 (0.66,1.14) F 1.09 (0.55,2.14) 1.11 (0.83,1.48) 1.30 (0.99,1.70) 0.80 (0.43,1.48) 0.92 (0.47,1.82) BL+D 1.02 (0.53,1.96) 1.20 (0.62,2.30) 0.78 (0.64,0.96) 0.90 (0.68,1.21) 0.98 (0.51,1.89) BL 1.17 (0.94,1.47) 0.67 (0.54,0.82) 0.77 (0.59,1.01) 0.84 (0.43,1.61) 0.85 (0.68,1.07) BL+F Legend: BL, β-lactam antibiotics; D, doxycycline; M, macrolides; F, fluoroquinolones. Significant results are indicated in bold. Panel B. 30-day mortality BL+M 1.31 (0.99,1.73) 1.26 (0.65,2.43) 1.30 (0.99,1.70) 1.37 (1.10,1.72) 0.76 (0.58,1.01) F 0.96 (0.47,1.97) 0.99 (0.73,1.34) 1.05 (0.79,1.40) 0.80 (0.41,1.54) 1.04 (0.51,2.13) BL+D 1.03 (0.50,2.11) 1.09 (0.54,2.20) 0.77 (0.59,1.01) 1.01 (0.75,1.37) 0.97 (0.47,1.98) BL 1.06 (0.79,1.43) 0.73 (0.58,0.91) 0.95 (0.71,1.27) 0.91 (0.45,1.84) 0.94 (0.70,1.27) BL+F Legend: BL, β-lactam antibiotics; D, doxycycline; M, macrolides; F, fluoroquinolones. Significant results are indicated in bold. Panel C. In-hospital mortality BL+M 1.16 (0.88,1.53) 1.26 (0.67,2.34) 1.28 (1.05,1.57) 1.50 (1.22,1.84) 0.86 (0.66,1.14) F 1.09 (0.55,2.14) 1.11 (0.83,1.48) 1.30 (0.99,1.70) 0.80 (0.43,1.48) 0.92 (0.47,1.82) BL+D 1.02 (0.53,1.96) 1.20 (0.62,2.30) 0.78 (0.64,0.96) 0.90 (0.68,1.21) 0.98 (0.51,1.89) BL 1.17 (0.94,1.47) 0.67 (0.54,0.82) 0.77 (0.59,1.01) 0.84 (0.43,1.61) 0.85 (0.68,1.07) BL+F Legend: BL, β-lactam antibiotics; D, doxycycline; M, macrolides; F, fluoroquinolones. Significant results are indicated in bold. Network geometry and synthesis of results The network geometry for mortality is shown in Fig. 2 . 5 studies reported 30-day mortality, 4 studies reported in-hospital mortality, and 7 studies reported both. The SUCRA values and treatment ranks for overall mortality are presented in Fig. 3 A. β-lactam antibiotics plus macrolides had the highest rank (SUCRA, 91.0%; mean rank, 1.3), followed by fluoroquinolones (SUCRA, 53.7%; mean rank, 2.9), β-lactam antibiotics plus doxycycline (SUCRA, 42.1%; mean rank, 3.3) and β-lactam antibiotics plus doxycycline (SUCRA, 41.6%; mean rank, 3.3). β-lactam antibiotics plus fluoroquinolones had the lowest rank. β-lactam antibiotics plus macrolides didn’t show a significant reducing mortality compared to fluoroquinolones (RR, 0.86; 95% CI, 0.66–1.44) and β-lactam antibiotics plus doxycycline (RR, 0.80; 95% CI, 0.43–1.48). β-lactam antibiotics plus macrolides was associated with a significant reduction in mortality compared to β-lactam antibiotics (RR, 0.79; 95% CI, 0.64–0.96) and β-lactam antibiotics plus fluoroquinolones (RR, 0.67; 95% CI, 0.64–0.82). The difference was not significant among other comparisons (Table 2 A). Secondary outcomes To assess the effect of different antibiotic regimens on mortality over time, we evaluated both 30-day mortality (Table 2 B) and in-hospital mortality (Table 2 C). β-lactam antibiotics plus macrolides and fluoroquinolones ranked first and second for both 30-day mortality and in-hospital mortality (Fig. 3 B- 3 C). β-lactam antibiotics plus fluoroquinolones ranked the lowest. For 30-day mortality, β-lactam antibiotics plus macrolides significantly reduced mortality compared to β-lactam antibiotics plus fluoroquinolones (RR, 0.73; 95% CI, 0.58–0.91) but not compared to β-lactam antibiotics alone (RR, 0.77; 95% CI, 0.59–1.01) (Table 2 B). For in-hospital mortality, β-lactam antibiotics plus macrolides also showed a better mortality compared to β-lactam antibiotics plus fluoroquinolones (RR, 0.67; 95% CI, 0.54–0.82) and β-lactam antibiotics alone (RR, 0.78; 95% CI, 0.64–0.96) (Table 2 C). Heterogeneity, inconsistency, and small-study effects Heterogeneity and inconsistency are shown in Table 3 . Heterogeneity was low for all outcomes. Loop inconsistency for β-lactam antibiotics, β-lactam antibiotics plus fluoroquinolones, and β-lactam antibiotics plus macrolides was found for overall mortality (indirect effect estimate, 0.42; 95% CI, 0.03–0.81; P = 0.011) and 30-day mortality (indirect effect estimate, 0.53; 95% CI, 0.14–0.91; P = 0.000) ( eFigure 2 in the Supplement). A funnel plot was used to demonstrate small-study effects, revealing no publication bias visually ( eFigure 3 in the Supplement). Table 3 Tests for Inconsistency, Heterogeneity, and Small-Study Effects. Outcome Inconsistency at the overall level Heterogeneity Small-Study Effects χ2 P value τ^2 Egger's test P value Overall mortality 14.37 0.072 0.013 0.891 30-day mortality 13.65 0.058 0.028 0.933 In-hospital mortality 0.94 0.998 0.008 0.844 Legend: Inconsistency and heterogeneity across studies was quantified using the restricted maximum likelihood (REML) method. Small-study effects were assessed using Begg's test. Discussion To the best of our knowledge, we are the first to combine both direct and indirect evidence to compare initial antibiotic options for patients with SCAP. Our analysis provides important insights to guide clinical decision-making regarding antibiotic choice for these patients. From our analysis, we derived several key findings: β-lactam plus macrolide emerged as the best choice for patients with SCAP, in alignment with international guidelines 6 , 7 Fluoroquinolone monotherapy can be considered a reasonable alternative when β-lactam plus macrolide is not appropriate. However, β-lactam plus fluoroquinolone should be avoided. Early antibiotic therapy has been shown to reduce mortality in patients with SCAP. 33 Although atypical microorganisms are responsible for 8–20% of SCAP cases, their role in the disease process is significant. 5 , 34 Therefore, empiric antibiotic treatment targeting atypical pathogens is associated with a reduction in clinical failure rates among hospitalized adults with CAP. 35 , 36 In addition to their antibacterial effects, macrolides possess broad anti-inflammatory properties. 37 When combined with β-lactams, macrolides improve early clinical responses, reduce inflammation, enhance gas exchange, alleviate sepsis and organ failure, and lower mortality risk. 38 , 39 Consistent with the result of a previous study, 10 we recommend β-lactam plus macrolide as the preferred empirical antibiotic therapy for hospitalized patients with SCAP. However, due to the increasing development of antibiotic resistance, especially to macrolides in Asia, 40 , 41 the use of macrolides in combination with β-lactams may no longer be a rational choice. While previous studies have suggested that β-lactam plus macrolide is more effective than β-lactam plus fluoroquinolone in reducing mortality and length of hospital stay in SCAP, 10 this does not mean that β-lactam plus fluoroquinolone is an appropriate alternative. No studies have directly compared β-lactam plus fluoroquinolone with fluoroquinolone monotherapy or β-lactam combined with other antibiotics (e.g., doxycycline) targeting atypical microorganisms. Previous studies have reported that β-lactam plus macrolide, compared to fluoroquinolone or β-lactam plus doxycycline, results in similar in-hospital mortality rates for patients with non-severe CAP. 8 , 11 , 42 – 44 One prospective observational cohort study also found no significant differences in in-hospital and 30-day mortality between SCAP patients treated with β-lactam plus doxycycline or β-lactam plus azithromycin. 9 Our NMA results indicate that fluoroquinolone or β-lactam plus doxycycline may reduce mortality compared to β-lactam plus fluoroquinolone, although this difference was not statistically significant. Importantly, the evidence for β-lactam plus doxycycline comes from a single observational study, 9 and further research is needed to confirm this finding. Therefore, if β-lactam plus macrolide is not the first choice due to high resistance, fluoroquinolone monotherapy could be a rational alternative. Our results also showed that β-lactam plus fluoroquinolone did not significantly differ from β-lactam monotherapy in mortality outcomes. Several studies suggest that β-lactam monotherapy is associated with worse outcomes, including higher mortality and longer hospital stays. 45 – 48 However, this may be due to the lack of direct comparisons between β-lactam plus fluoroquinolone and other guideline-concordant treatments. 22 , 25 , 49 Given that β-lactam plus fluoroquinolone provides similar bacterial coverage to β-lactam plus macrolide, no significant question has been raised about the recommendation of using β-lactam plus fluoroquinolone in patients with SCAP. Our NAM results indicate that β-lactam plus fluoroquinolone may be associated with lower efficacy compared to fluoroquinolone monotherapy (RR,1.30; 95% CI, 0.99–1.70). The exact reasons for this reduced efficacy remain unclear. One possibility is that the combination does not provide broader coverage of pathogens compared to fluoroquinolone monotherapy. Additionally, overuse of antibiotics may lead to secondary infections, and disruption of the normal microbiota could exacerbate the inflammatory response, leading to worse outcomes. 50 , 51 Therefore, based on our findings, we recommend against using β-lactam plus fluoroquinolone as the treatment for SCAP. In recent years, novel antibiotics such as delafloxacin and omadacycline have shown promising efficacy in treating CAP. 52 , 53 However, these antibiotics should not be used as empirical treatments for SCAP in the initial stages due to insufficient clinical data supporting their effectiveness in severe cases. They should be reserved for situations with relevant risk factors or well-defined pathogen and resistance patterns. Limitations Our study has several limitations. Firstly, we included patients who were admitted to the ICU. Although the IDSA/ATS guidelines recommend that SCAP patients meet the criteria for severe pneumonia when admitted to the ICU, the studies included in our review did not explicitly state that the patients adhered to this specific recommendation. Instead, most of the ICU-admitted patients in these studies were included based on clinical judgment rather than strictly following the IDSA/ATS guidelines. Furthermore, some studies conducted subgroup analyses, which could introduce inconsistencies in baseline characteristics and potential bias. Secondly, 13 of the 14 studies included were observational, limiting our ability to draw definitive causal conclusions. Given the susceptibility of observational studies to confounding factors, future large-scale RCTs are needed to strengthen the evidence base and reduce bias. Thirdly, although guidelines recommend specific β-lactam antibioticss (e.g., cefotaxime, ceftriaxone) for ICU patients without high-risk drug-resistant pathogens, several studies used β-lactam antibioticss outside these recommended classes or did not specify the β-lactam antibiotics used. This inconsistency may have affected treatment efficacy. Lastly, the rising antimicrobial resistance, particularly to macrolidess, is a concern in treating SCAP. Unfortunately, none of the studies included provided data on macrolides resistance, preventing subgroup analyses based on resistance patterns. This data gap limits our ability to assess the real-world effectiveness of macrolidess in the context of resistance. Given these limitations, caution should be exercised in interpreting our findings, and further research is necessary to address these gaps and refine SCAP treatment strategies. Conclusions Our NMA suggests that β-lactam antibiotics plus macrolides may be the most effective treatment option for SCAP. The use of β-lactam antibiotics monotherapy and β-lactam antibiotics plus fluoroquinolones should be avoided, as these regimens demonstrated inferior efficacy in our analysis. However, the methodological limitations of the included studies and the limited availability of relevant clinical data preclude a definitive conclusion. Therefore, large-scale, well-designed RCTs are necessary to determine the most effective regimen for SCAP. Declarations Authors' contributions: Ao Liu, Min Wang designed the study and supervised the overall project; Xiaoming Wang and Lian Wang participated in collecting data; Han Zhuang, Qian Wang participated in analysis; Ao Liu, Jing Zhang and Min Wang provided the statistical analysis and wrote the manuscript. Conflict of interest This manuscript has no potential conflict of interest to disclose. Ethics approval and consent to participate This is a systematic review and meta-analysis; ethics approval and consent to participate are not applicable. Consent for publication Not applicable. The manuscript does not include the participant's identification image or other personal or clinical details. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Conflict of interest The authors declare that they have no conflict of interest. Funding 1 Henan Provincial Medical Science and Technology Research Project Fund No.: SBGJ202303042 2 Henan Provincial Key Research Projects of Higher Education Institutions Fund No.: 24A320005 Clinical trial number not applicable. References Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 Suppl 2(Suppl 2):S27-72. Cilloniz C, Ferrer M, Liapikou A, et al. Acute respiratory distress syndrome in mechanically ventilated patients with community-acquired pneumonia. Eur Respir J. 2018;51(3). Phua J, Dean NC, Guo Q, et al. Severe community-acquired pneumonia: timely management measures in the first 24 hours. Critical Care. 2016;20(1):237. Tsai D, Chiong F, Secombe P, et al. Epidemiology and microbiology of severe community-acquired pneumonia in Central Australia: a retrospective study. Intern Med J. 2022;52(6):1048-1056. Wang S, Tang J, Tan Y, et al. Prevalence of atypical pathogens in patients with severe pneumonia: A systematic review and meta-analysis. BMJ Open. 2023;13(4). Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67. Martin-Loeches I, Torres A, Nagavci B, et al. ERS/ESICM/ESCMID/ALAT guidelines for the management of severe community-acquired pneumonia. Eur Respir J. 2023;61(4). Bai AD, Srivastava S, Wong BKC, et al. Comparative Effectiveness of First-Line and Alternative Antibiotic Regimens in Hospitalized Patients With Nonsevere Community-Acquired Pneumonia: A Multicenter Retrospective Cohort Study. Chest. 2024;165(1):68-78. Greco Kinney A, Kovacic Scherrer N, Sarkar S, et al. β-Lactams plus doxycycline versus azithromycin for treatment of severe community-acquired pneumonia in critically ill patients. J Antimicrob Chemother. 2023;78(12):2816-2823. Lee JH, Kim HJ, Kim YH. Is β-Lactam Plus Macrolide More Effective than β-Lactam Plus Fluoroquinolone among Patients with Severe Community-Acquired Pneumonia?: a Systemic Review and Meta-Analysis. J Korean Med Sci. 2017;32(1):77-84. Uddin M, Mohammed T, Metersky M, et al. Effectiveness of Beta-Lactam plus Doxycycline for Patients Hospitalized with Community-Acquired Pneumonia. Clin Infect Dis. 2022;75(1):118-124. Hutton B, Salanti G, Caldwell DM, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777-784. Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2000. Sterne JA, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. bmj. 2019;366. White IR. Network meta-analysis. The Stata Journal. 2015;15(4):951-985. Salanti G, Ades A, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. Journal of clinical epidemiology. 2011;64(2):163-171. Higgins JPT, Jackson D, Barrett J, et al. Consistency and inconsistency in network meta‐analysis: concepts and models for multi‐arm studies. Research synthesis methods. 2012;3(2):98-110. Shim S, Yoon B-H, Shin I-S, et al. Network meta-analysis: application and practice using Stata. Epidemiology and health. 2017;39. Turner RM, Davey J, Clarke MJ, et al. Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane Database of Systematic Reviews. International journal of epidemiology. 2012;41(3):818-827. Rello J, Catalán M, Díaz E, et al. Associations between empirical antimicrobial therapy at the hospital and mortality in patients with severe community-acquired pneumonia. Intensive Care Med. 2002;28(8):1030-1035. Leroy O, Saux P, Bédos JP, et al. Comparison of levofloxacin and cefotaxime combined with ofloxacin for ICU patients with community-acquired pneumonia who do not require vasopressors. Chest. 2005;128(1):172-183. Bratzler DW, Ma A, Nsa W. Initial antibiotic selection and patient outcomes: observations from the National Pneumonia Project. Clin Infect Dis. 2008;47 Suppl 3:S193-201. Martin-Loeches I, Lisboa T, Rodriguez A, et al. Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia. Intensive Care Med. 2010;36(4):612-620. Wilson BZ, Anzueto A, Restrepo MI, et al. Comparison of two guideline-concordant antimicrobial combinations in elderly patients hospitalized with severe community-acquired pneumonia. Critical Care Medicine. 2012;40(8):2310-2314. Adrie C, Schwebel C, Garrouste-Orgeas M, et al. Initial use of one or two antibiotics for critically ill patients with community-acquired pneumonia: impact on survival and bacterial resistance. Crit Care. 2013;17(6):R265. Karhu J, Ala-Kokko TI, Ohtonen P, et al. Severe community-acquired pneumonia treated with β-lactam-respiratory quinolone vs. β-lactam-macrolide combination. Acta Anaesthesiol Scand. 2013;57(5):587-593. Ceccato A, Cilloniz C, Ranzani OT, et al. Treatment with macrolides and glucocorticosteroids in severe community-acquired pneumonia: A post-hoc exploratory analysis of a randomized controlled trial. PLoS One. 2017;12(6):e0178022. Rahmel T, Asmussen S, Karlik J, et al. Moxifloxacin monotherapy versus combination therapy in patients with severe community-acquired pneumonia evoked ARDS. BMC Anesthesiol. 2017;17(1):78. Ito A, Ishida T, Tachibana H, et al. Azithromycin combination therapy for community-acquired pneumonia: propensity score analysis. Sci Rep. 2019;9(1):18406. Suzuki J, Sasabuchi Y, Hatakeyama S, et al. Azithromycin plus β-lactam versus levofloxacin plus β-lactam for severe community-acquired pneumonia: A retrospective nationwide database analysis. J Infect Chemother. 2019;25(12):1012-1018. Kyriazopoulou E, Sinapidis D, Halvatzis S, et al. Survival benefit associated with clarithromycin in severe community-acquired pneumonia: A matched comparator study. Int J Antimicrob Agents. 2020;55(1):105836. Oh S, Jang W, Kim B. Is the fluoroquinolone combination necessary for empirical antibiotic regimen in severe community-acquired pneumonia? Postgrad Med. 2024. Gattarello S, Lagunes L, Vidaur L, et al. Improvement of antibiotic therapy and ICU survival in severe non-pneumococcal community-acquired pneumonia: a matched case-control study. Crit Care. 2015;19(1):335. Raeven VM, Spoorenberg SMC, Boersma WG, et al. Atypical aetiology in patients hospitalised with community-acquired pneumonia is associated with age, gender and season; a data-analysis on four Dutch cohorts. BMC Infectious Diseases. 2016;16(1). Eljaaly K, Alshehri S, Aljabri A, et al. Clinical failure with and without empiric atypical bacteria coverage in hospitalized adults with community-acquired pneumonia: A systematic review and meta-analysis. BMC Infectious Diseases. 2017;17(1). Eljaaly K, Aljabri A, Rabaan AA, et al. Efficacy of empiric antibiotic coverage in community-acquired pneumonia associated with each atypical bacteria: A meta-analysis. Journal of Clinical Medicine. 2021;10(19). Kricker JA, Page CP, Gardarsson FR, et al. Nonantimicrobial Actions of Macrolides: Overview and Perspectives for Future Development. Pharmacol Rev. 2021;73(4):233-262. Giamarellos-Bourboulis EJ, Siampanos A, Bolanou A, et al. Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2024;12(4):294-304. Dequin PF, Meziani F, Quenot JP, et al. Hydrocortisone in Severe Community-Acquired Pneumonia. N Engl J Med. 2023;388(21):1931-1941. Li J, Liu L, Zhang H, et al. Severe problem of macrolides resistance to common pathogens in China. Front Cell Infect Microbiol. 2023;13:1181633. Wang G, Wu P, Tang R, et al. Global prevalence of resistance to macrolides in Mycoplasma pneumoniae: a systematic review and meta-analysis. J Antimicrob Chemother. 2022;77(9):2353-2363. Babonji AS, Alshehri SJ, Alturaiki AM. Clinical Effectiveness and Outcomes of Azithromycin versus Doxycycline Containing Regimen in Inpatients with Community Acquired Pneumonia: A Retrospective Cohort Study. Journal of Clinical Pharmacy and Therapeutics. 2023;2023. Aldhahri RK, Gabb SG, Shoaib OA, et al. Doxycycline vs. macrolides in combination with a β-lactam antibiotic for the treatment of community-acquired pneumonia in inpatients. Eur J Med Res. 2022;27(1):279. Izadi M, Dadsetan B, Najafi Z, et al. Levofloxacin Versus Ceftriaxone and Azithromycin Combination in the Treatment of Community Acquired Pneumonia in Hospitalized Patients. Recent Pat Antiinfect Drug Discov. 2018;13(3):228-239. Houck PM, MacLehose RF, Niederman MS, et al. Empiric antibiotic therapy and mortality among medicare pneumonia inpatients in 10 western states : 1993, 1995, and 1997. Chest. 2001;119(5):1420-1426. Battleman DS, Callahan M, Thaler HT. Rapid antibiotic delivery and appropriate antibiotic selection reduce length of hospital stay of patients with community-acquired pneumonia: link between quality of care and resource utilization. Arch Intern Med. 2002;162(6):682-688. Waterer GW, Somes GW, Wunderink RG. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med. 2001;161(15):1837-1842. Aspa J, Rajas O, de Castro FR, et al. Impact of initial antibiotic choice on mortality from pneumococcal pneumonia. European Respiratory Journal. 2006;27(5):1010-1019. Mortensen EM, Restrepo MI, Anzueto A, et al. The impact of empiric antimicrobial therapy with a β-lactam and fluoroquinolone on mortality for patients hospitalized with severe pneumonia. Crit Care. 2005;10(1):R8. Bhalodi AA, van Engelen TSR, Virk HS, et al. Impact of antimicrobial therapy on the gut microbiome. Journal of Antimicrobial Chemotherapy. 2019;74(Supplement_1):i6-i15. Zuttion MSSR, Parimon T, Bora SA, et al. Antibiotic use during influenza infection augments lung eosinophils that impair immunity against secondary bacterial pneumonia. The Journal of Clinical Investigation. 2024;134(21). McCurdy S, Nenninger A, Sheets A, et al. Efficacy of delafloxacin versus moxifloxacin against atypical bacterial respiratory pathogens in adults with community-acquired bacterial pneumonia (CABP): Data from the Delafloxacin Phase 3 CABP Trial. (1878-3511 (Electronic)). Torres A, Garrity-Ryan L, Kirsch C, et al. Omadacycline vs moxifloxacin in adults with community-acquired bacterial pneumonia. Int J Infect Dis. 2021;104:501-509. García Vázquez E, Mensa J, Martínez JA, et al. Lower mortality among patients with community-acquired pneumonia treated with a macrolide plus a beta-lactam agent versus a beta-lactam agent alone. Eur J Clin Microbiol Infect Dis. 2005;24(3):190-195. Additional Declarations No competing interests reported. Supplementary Files supplementfile.docx Cite Share Download PDF Status: Published Journal Publication published 20 May, 2025 Read the published version in BMC Pulmonary Medicine → Version 1 posted Editorial decision: Revision requested 21 Apr, 2025 Reviews received at journal 17 Apr, 2025 Reviews received at journal 11 Apr, 2025 Reviewers agreed at journal 11 Apr, 2025 Reviewers agreed at journal 09 Apr, 2025 Reviewers invited by journal 09 Apr, 2025 Submission checks completed at journal 04 Apr, 2025 First submitted to journal 04 Apr, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6121400","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":440668319,"identity":"1cab0c3f-b533-4b71-8e75-00f1038283a0","order_by":0,"name":"Min Wang","email":"","orcid":"","institution":"The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Wang","suffix":""},{"id":440668320,"identity":"1dcb7698-5094-4f45-80dc-de3f12295b8a","order_by":1,"name":"Jing Zhang","email":"","orcid":"","institution":"The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Zhang","suffix":""},{"id":440668321,"identity":"25def44c-88d5-4d14-b2de-98cede9ca48f","order_by":2,"name":"Xiaoming Wang","email":"","orcid":"","institution":"Chengdu BOE hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaoming","middleName":"","lastName":"Wang","suffix":""},{"id":440668323,"identity":"829ddd0c-279f-416f-b142-9fb1ae254e7d","order_by":3,"name":"Qian Wang","email":"","orcid":"","institution":"Chengdu BOE hospital","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Wang","suffix":""},{"id":440668324,"identity":"9d2776ad-c4f1-4ab6-a0d3-99c6c573877a","order_by":4,"name":"Lian Wang","email":"","orcid":"","institution":"Chengdu BOE hospital","correspondingAuthor":false,"prefix":"","firstName":"Lian","middleName":"","lastName":"Wang","suffix":""},{"id":440668325,"identity":"5bc6b60b-061f-4086-8e99-3df42ab06ced","order_by":5,"name":"Han Zhuang","email":"","orcid":"","institution":"Chengdu BOE hospital","correspondingAuthor":false,"prefix":"","firstName":"Han","middleName":"","lastName":"Zhuang","suffix":""},{"id":440668326,"identity":"8cc0b875-7316-41fa-a7f1-c0fa36108a9d","order_by":6,"name":"Ao Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvklEQVRIiWNgGAWjYBACPmYQycbAwA+iEwqI0MIG0yLZANJiQIwWGGlwAMQgSgs7j+GHD2U28sbnVyd+eGDAIM8vdoCQw3iMJWecSzPcduPtZgmgwwxnzk4gqMVAmrftcILZjbMbQFoSDG4T1mL8G6TFeMbZzT+I1WIGtsWAv3cbsbawlVmC/DLjBu82iwQDCcJ+4ec/vPkGKMT4+89uvvmjAsiQJqAFASTAKiWIVQ627wApqkfBKBgFo2AkAQBORzuIr1B+cgAAAABJRU5ErkJggg==","orcid":"","institution":"Chengdu BOE hospital","correspondingAuthor":true,"prefix":"","firstName":"Ao","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-02-27 13:23:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6121400/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6121400/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12890-025-03695-w","type":"published","date":"2025-05-20T15:57:19+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80581694,"identity":"b84363b8-5cdc-47b1-b630-e7a288287b72","added_by":"auto","created_at":"2025-04-14 23:22:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":275411,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA Flowchart\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6121400/v1/07e82802f7ed54fd092f9c4a.png"},{"id":80582426,"identity":"09e6e0ef-bc23-4b04-a9ad-1e0597940ff3","added_by":"auto","created_at":"2025-04-14 23:30:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":102743,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork diagrams of the network meta-analysis.\u003c/p\u003e\n\u003cp\u003eBL, β-lactam antibiotics; D, doxycycline; M, macrolides; F, fluoroquinolones.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6121400/v1/cedfb6e3ff0933163d59fb42.png"},{"id":80580240,"identity":"9535d50c-eccd-419a-b4ed-47d0f9ae2c10","added_by":"auto","created_at":"2025-04-14 23:14:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":505041,"visible":true,"origin":"","legend":"\u003cp\u003eSUCRA Values and Mean Rank for each agent of each outcome\u003c/p\u003e\n\u003cp\u003eA-C: overall mortality, 30-day mortality, in-hospital mortaliy. BL, β-lactam antibiotics; D, doxycycline; M, macrolides; F, fluoroquinolones.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6121400/v1/88fe3ce22927acf9378cca8c.png"},{"id":83459980,"identity":"8a3ff45f-5d2a-467a-a996-a89ce6f864b9","added_by":"auto","created_at":"2025-05-26 16:07:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1948413,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6121400/v1/eabaa444-c05f-4b5a-87a7-0c0f45bf2b25.pdf"},{"id":80580245,"identity":"13d75560-5e8b-4904-b404-e216948a35f1","added_by":"auto","created_at":"2025-04-14 23:14:19","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":954865,"visible":true,"origin":"","legend":"","description":"","filename":"supplementfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-6121400/v1/d1fc7fa7dd945819f7ca546b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of the efficacy of initial empirical antibiotic regimens in severe community-acquired pneumonia: a network meta-analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSevere community-acquired pneumonia (SCAP) is the most life-threatening form of community-acquired pneumonia (CAP) and often necessitates intensive care unit (ICU) admission due to invasive mechanical ventilation or septic shock requiring vasopressors.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The overall mortality rate for SCAP exceeds 20%, and it is a leading cause of acute respiratory distress syndrome.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Studies indicate that early administration of antibiotics can reduce hospital mortality and ICU admission rates, so an appropriate initial antibiotic regimen is important for patients with SCAP.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe most frequently identified pathogens causing SCAP are Streptococcus pneumoniae, Staphylococcus aureus (including MRSA), Pseudomonas aeruginosa, and other gram-negative bacteria, viruses, and atypical pathogens. \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Understanding these pathogens is critical, as it informs the selection of appropriate initial empirical antibiotic regimens, which are essential for reducing mortality and ICU admissions in SCAP patients. The Infectious Diseases Society of America and American Thoracic Society (IDSA/ATS) and the latest European community-acquired pneumonia (CAP) guidelines recommend a β-lactam antibiotics plus a macrolides for patients with SCAP. The combination of a β-lactam antibiotics and a respiratory fluoroquinolones, however, remains controversial and lacks definitive evidence to support its superiority.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Moreover, recent retrospective cohort studies have suggested that β-lactam antibiotics plus macrolides, fluoroquinolones monotherapy, and β-lactam antibiotics plus doxycycline may yield similar outcomes in non-severe CAP.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e However, few studies have directly compared fluoroquinolones monotherapy and β-lactam antibiotics plus tetracycline in SCAP.\u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Despite the recommendations provided by guidelines, the optimal antibiotic regimen for SCAP remains a subject of ongoing debate. Questions persist regarding whether a β-lactam antibiotics plus macrolides combination is superior to a β-lactam antibiotics plus fluoroquinolones, and the efficacy of fluoroquinolones monotherapy and β-lactam antibiotics plus doxycycline as potentially suboptimal options is still unclear. Conventional pairwise meta-analyses, which rely on direct comparisons, are relatively limited and pose challenges in evaluating these antibiotic regimens. Therefore, we conducted a network meta-analysis (NMA) to gain a more comprehensive understanding of the outcomes associated with different antibiotic treatments.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eProtocol and Registration\u003c/h2\u003e \u003cp\u003eThis NMA was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analysis (PRISMA-NMA) guidelines (\u003cb\u003eeTable 1\u003c/b\u003e) and was prospectively registered on PROSPERO (CRD42024574220).\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLiterature Search\u003c/h3\u003e\n\u003cp\u003eWe systematically searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials from inception to April 11, 2024, to identify relevant RCTs and observational studies evaluating empirical antibiotic therapy for SCAP. The complete search strategy is provided in eTable 2. Additionally, we conducted backwards citation searches by screening the reference lists of included studies for potentially relevant articles.\u003c/p\u003e\n\u003ch3\u003eStudy Inclusion and exclusion Criteria\u003c/h3\u003e\n\u003cp\u003eStudies were included if they met the following criteria: (1) SCAP defined as meeting IDSA/ATS criteria for SCAP or admitted to the ICU; (2) were RCTs or observational cohort studies comparing β-lactam antibiotics, fluoroquinolones, or β-lactam antibiotics based combination regimens; and (3) reported mortality outcomes for at least two antibiotic regimens. Studies were excluded if they lacked a comparator group, involved hospital-acquired pneumonia (HAP) or ventilator-acquired pneumonia (VAP), or focused on targeted therapy based on known pathogen-specific results.\u003c/p\u003e\n\u003ch3\u003eData Extraction\u003c/h3\u003e\n\u003cp\u003eTwo independent reviewers (XW and LW) extracted study characteristics, patient demographics, treatment regimens, and mortality outcomes. Discrepancies were resolved by discussion.\u003c/p\u003e\n\u003ch3\u003eQuality Assessment\u003c/h3\u003e\n\u003cp\u003eTwo authors (HZ and QW) independently performed the assessment, with any disagreements resolved through discussion. The quality of the evidence was evaluated using the revised tool for risk of bias (ROB2) for randomized controlled trials (RCTs) and the Newcastle-Ottawa Scale (NOS) for observational studies.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOutcome measure\u003c/h2\u003e \u003cp\u003eThe primary outcome was overall mortality, used to evaluate the effectiveness of different antibiotic regimens in SCAP treatment. When available, 30-day all-cause mortality was prioritized; otherwise, in-hospital all-cause mortality was used. Secondary outcomes included 30-day all-cause mortality and in-hospital all-cause mortality analyzed separately.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThis NMA was performed within a frequentist framework using a random-effects model in Stata (network and mvmeta packages).\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Mortality risk was estimated as relative risk (RR) with 95% confidence intervals (CIs), and results were visualized using forest plots and league tables. Treatment rankings for each outcome were determined by the surface under the cumulative ranking curve (SUCRA), where higher SUCRA values indicate better rankings.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e To ensure result robustness, we evaluated inconsistency and heterogeneity.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Both overall and loop inconsistencies were assessed,\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e and heterogeneity was quantified using the restricted maximum likelihood method. A τ\u0026sup2; value\u0026thinsp;\u0026lt;\u0026thinsp;0.1 indicated low heterogeneity, 0.1\u0026ndash;0.5 indicated moderate heterogeneity, and \u0026gt;\u0026thinsp;0.5 indicated high heterogeneity.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Small-study effects were examined via funnel plots, with Egger\u0026rsquo;s test applied to detect publication bias. Statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of the studies\u003c/h2\u003e \u003cp\u003eThe flowchart of study selection for this network meta-analysis is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In total, 1RCT and 13 observational studies with 8142 patients were included,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e including 5 groups: β-lactam antibiotics, β-lactam antibiotics plus doxycycline, β-lactam antibiotics plus fluoroquinolones, β-lactam antibiotics plus macrolides, and fluoroquinolones alone. The basic characteristics of the included studies are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The quality of studies included is summarized in \u003cb\u003eeTable 3\u003c/b\u003e and \u003cb\u003eeFigure 1\u003c/b\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\u003eBasic Characteristics of Included Studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDisease severity score (mean)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMechanical ventilation (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSevere sepsis or septic shock (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eInterventions\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePatients, No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMean age,\u003c/p\u003e \u003cp\u003e(range), y\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eReported outcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eRisk of bias*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eRello, \u003c/p\u003e \u003cp\u003e2002\u003csup\u003e20\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eSpain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ePatients admitted to ICU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPACHE II score 18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e77.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (32.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eIn-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPACHE II score 18.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e92.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (31.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPACHE II score 19.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e46.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e274\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLeroy, \u003c/p\u003e \u003cp\u003e2005\u003csup\u003e54\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eInternational\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRandomized controlled trials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePatients admitted to ICU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSAPS II score 34.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIn-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSAPS II score 33.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e51.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e194\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eBratzler,\u003c/p\u003e \u003cp\u003e2008\u003csup\u003e22\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eUnited States\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003ePatients admitted to ICU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e207\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e30-day mortality, \u003c/p\u003e \u003cp\u003ein-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e693\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e509\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e418\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMartin, \u003c/p\u003e \u003cp\u003e2010\u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSpain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eProspective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePatients meeting IDSA/ATS SCAP criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSAPS II score 49.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSevere sepsis and septic shock (96.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e57.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e30-day mortality, \u003c/p\u003e \u003cp\u003ein-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSAPS II score 44.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSevere sepsis and septic shock (86.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e58.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eWilson, \u003c/p\u003e \u003cp\u003e2012\u003csup\u003e24\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eUnited States\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePatients admitted to ICU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e883\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e30-day mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (20.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e1106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eAdrie, \u003c/p\u003e \u003cp\u003e2013\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eProspective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ePatients admitted to ICU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSAPS II score 47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e72.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (40.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e471\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eIn-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSAPS II score 43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e58.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (58.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e230\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSAPS II score 37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e44.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (44.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e164\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eKarhu, \u003c/p\u003e \u003cp\u003e2013\u003csup\u003e26\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFinland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePatients meeting IDSA/ATS SCAP criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIDSA/ATS SCAP criteria fulfilled (83.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e63.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (48.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e30-day mortality,\u003c/p\u003e \u003cp\u003ein-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIDSA/ATS SCAP criteria fulfilled (68.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e42.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (38.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCeccato, \u003c/p\u003e \u003cp\u003e2017\u003csup\u003e27\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eInternational\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePatients meeting IDSA/ATS SCAP criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePSI score 94.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIn-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePSI score 132.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRahmel, \u003c/p\u003e \u003cp\u003e2017\u003csup\u003e28\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePatients admitted to ICU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSAPS II score 40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e30-day mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSAPS II score 47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIto, \u003c/p\u003e \u003cp\u003e2019\u003csup\u003e29\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eProspective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePatients meeting IDSA/ATS SCAP criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e30-day mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSuzuki, \u003c/p\u003e \u003cp\u003e2019\u003csup\u003e30\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePatients meeting IDSA/ATS SCAP criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIDSA/ATS SCAP criteria fulfilled (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e79.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (51.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e560\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e30-day mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIDSA/ATS SCAP criteria fulfilled (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (53.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e560\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eKyriazopoulou, \u003c/p\u003e \u003cp\u003e2020\u003csup\u003e31\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eGreece\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ePatients meeting IDSA/ATS SCAP criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPACHE II score 15.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (18.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e30-day mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPACHE II score 16.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPACHE II score 16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (18.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGreco, \u003c/p\u003e \u003cp\u003e2023\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eProspective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePatients meeting IDSA/ATS SCAP criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPACHE IV score 35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (34%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e30-day mortality, \u003c/p\u003e \u003cp\u003ein-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPACHE IV score 35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeptic shock (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOh, \u003c/p\u003e \u003cp\u003e2024\u003csup\u003e32\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eKorea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePatients meeting IDSA/ATS SCAP criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePSI score 152.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e30-day mortality,\u003c/p\u003e \u003cp\u003ein-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePSI score 158.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBL\u0026thinsp;+\u0026thinsp;F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eLegend: BL, β-lactam antibiotics; D, doxycycline; M, macrolides; F, fluoroquinolones; ICU, intensive care unit; NR, not reported; SCAP, severe community-acquired pneumonia; SAPS, simplified acute physiology score; IDSA/ATS, Infectious Diseases Society of America/American Thoracic Society; APACHE, Acute Physiology and Chronic Health Evaluation; PSI, Pneumonia Severity Index. *The risk of bias in observational trials and randomized controlled trials was assessed using the Newcastle-Ottawa quality assessment scale (NOS) and the revised tool for risk of bias (ROB2) for randomized controlled trials, respectively.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. League Tables of All Outcomes\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePanel A.\u0026nbsp;\u003c/strong\u003eOverall mortality\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"661\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLB+M\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.16 (0.88,1.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.26 (0.67,2.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.28 (1.05,1.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.50 (1.22,1.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.86 (0.66,1.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.09 (0.55,2.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.11 (0.83,1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.30 (0.99,1.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.80 (0.43,1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.92 (0.47,1.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBL+D\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.02 (0.53,1.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.20 (0.62,2.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.78 (0.64,0.96)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.90 (0.68,1.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.98 (0.51,1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.17 (0.94,1.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.67 (0.54,0.82)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.77 (0.59,1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.84 (0.43,1.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.85 (0.68,1.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBL+F\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eLegend: BL, \u0026beta;-lactam antibiotics; D, doxycycline; M, macrolides; F, fluoroquinolones. Significant results are indicated in bold.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePanel B.\u0026nbsp;\u003c/strong\u003e30-day mortality\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBL+M\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.31 (0.99,1.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.26 (0.65,2.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.30 (0.99,1.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.37 (1.10,1.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.76 (0.58,1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.96 (0.47,1.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.99 (0.73,1.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.05 (0.79,1.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.80 (0.41,1.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.04 (0.51,2.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBL+D\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.03 (0.50,2.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.09 (0.54,2.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.77 (0.59,1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.01 (0.75,1.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.97 (0.47,1.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.06 (0.79,1.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.73 (0.58,0.91)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.95 (0.71,1.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.91 (0.45,1.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.94 (0.70,1.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBL+F\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eLegend: BL, \u0026beta;-lactam antibiotics; D, doxycycline; M, macrolides; F, fluoroquinolones. Significant results are indicated in bold.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePanel C.\u0026nbsp;\u003c/strong\u003eIn-hospital mortality\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBL+M\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.16 (0.88,1.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.26 (0.67,2.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.28 (1.05,1.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.50 (1.22,1.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.86 (0.66,1.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.09 (0.55,2.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.11 (0.83,1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.30 (0.99,1.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.80 (0.43,1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.92 (0.47,1.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBL+D\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.02 (0.53,1.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.20 (0.62,2.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.78 (0.64,0.96)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.90 (0.68,1.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.98 (0.51,1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.17 (0.94,1.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.67 (0.54,0.82)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.77 (0.59,1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.84 (0.43,1.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.85 (0.68,1.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBL+F\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eLegend: BL, \u0026beta;-lactam antibiotics; D, doxycycline; M, macrolides; F, fluoroquinolones. Significant results are indicated in bold.\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eNetwork geometry and synthesis of results\u003c/h2\u003e \u003cp\u003eThe network geometry for mortality is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. 5 studies reported 30-day mortality, 4 studies reported in-hospital mortality, and 7 studies reported both.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe SUCRA values and treatment ranks for overall mortality are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA. β-lactam antibiotics plus macrolides had the highest rank (SUCRA, 91.0%; mean rank, 1.3), followed by fluoroquinolones (SUCRA, 53.7%; mean rank, 2.9), β-lactam antibiotics plus doxycycline (SUCRA, 42.1%; mean rank, 3.3) and β-lactam antibiotics plus doxycycline (SUCRA, 41.6%; mean rank, 3.3). β-lactam antibiotics plus fluoroquinolones had the lowest rank.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eβ-lactam antibiotics plus macrolides didn\u0026rsquo;t show a significant reducing mortality compared to fluoroquinolones (RR, 0.86; 95% CI, 0.66\u0026ndash;1.44) and β-lactam antibiotics plus doxycycline (RR, 0.80; 95% CI, 0.43\u0026ndash;1.48). β-lactam antibiotics plus macrolides was associated with a significant reduction in mortality compared to β-lactam antibiotics (RR, 0.79; 95% CI, 0.64\u0026ndash;0.96) and β-lactam antibiotics plus fluoroquinolones (RR, 0.67; 95% CI, 0.64\u0026ndash;0.82). The difference was not significant among other comparisons (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes\u003c/h2\u003e \u003cp\u003eTo assess the effect of different antibiotic regimens on mortality over time, we evaluated both 30-day mortality (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB) and in-hospital mortality (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). β-lactam antibiotics plus macrolides and fluoroquinolones ranked first and second for both 30-day mortality and in-hospital mortality (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB-\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). β-lactam antibiotics plus fluoroquinolones ranked the lowest.\u003c/p\u003e \u003cp\u003eFor 30-day mortality, β-lactam antibiotics plus macrolides significantly reduced mortality compared to β-lactam antibiotics plus fluoroquinolones (RR, 0.73; 95% CI, 0.58\u0026ndash;0.91) but not compared to β-lactam antibiotics alone (RR, 0.77; 95% CI, 0.59\u0026ndash;1.01) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eFor in-hospital mortality, β-lactam antibiotics plus macrolides also showed a better mortality compared to β-lactam antibiotics plus fluoroquinolones (RR, 0.67; 95% CI, 0.54\u0026ndash;0.82) and β-lactam antibiotics alone (RR, 0.78; 95% CI, 0.64\u0026ndash;0.96) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eHeterogeneity, inconsistency, and small-study effects\u003c/h2\u003e \u003cp\u003eHeterogeneity and inconsistency are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Heterogeneity was low for all outcomes. Loop inconsistency for β-lactam antibiotics, β-lactam antibiotics plus fluoroquinolones, and β-lactam antibiotics plus macrolides was found for overall mortality (indirect effect estimate, 0.42; 95% CI, 0.03\u0026ndash;0.81; P\u0026thinsp;=\u0026thinsp;0.011) and 30-day mortality (indirect effect estimate, 0.53; 95% CI, 0.14\u0026ndash;0.91; P\u0026thinsp;=\u0026thinsp;0.000) (\u003cb\u003eeFigure 2\u003c/b\u003e in the Supplement). A funnel plot was used to demonstrate small-study effects, revealing no publication bias visually (\u003cb\u003eeFigure 3\u003c/b\u003e in the Supplement).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTests for Inconsistency, Heterogeneity, and Small-Study Effects.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eInconsistency at the overall level\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHeterogeneity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSmall-Study Effects\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eχ2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eτ^2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eEgger's test P value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOverall mortality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.891\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e30-day mortality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.933\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIn-hospital mortality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.998\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.844\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eLegend: Inconsistency and heterogeneity across studies was quantified using the restricted maximum likelihood (REML) method. Small-study effects were assessed using Begg's test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, we are the first to combine both direct and indirect evidence to compare initial antibiotic options for patients with SCAP. Our analysis provides important insights to guide clinical decision-making regarding antibiotic choice for these patients. From our analysis, we derived several key findings: β-lactam plus macrolide emerged as the best choice for patients with SCAP, in alignment with international guidelines \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Fluoroquinolone monotherapy can be considered a reasonable alternative when β-lactam plus macrolide is not appropriate. However, β-lactam plus fluoroquinolone should be avoided.\u003c/p\u003e \u003cp\u003eEarly antibiotic therapy has been shown to reduce mortality in patients with SCAP.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Although atypical microorganisms are responsible for 8\u0026ndash;20% of SCAP cases, their role in the disease process is significant.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e Therefore, empiric antibiotic treatment targeting atypical pathogens is associated with a reduction in clinical failure rates among hospitalized adults with CAP.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e In addition to their antibacterial effects, macrolides possess broad anti-inflammatory properties.\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e When combined with β-lactams, macrolides improve early clinical responses, reduce inflammation, enhance gas exchange, alleviate sepsis and organ failure, and lower mortality risk.\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e Consistent with the result of a previous study,\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e we recommend β-lactam plus macrolide as the preferred empirical antibiotic therapy for hospitalized patients with SCAP.\u003c/p\u003e \u003cp\u003eHowever, due to the increasing development of antibiotic resistance, especially to macrolides in Asia,\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e the use of macrolides in combination with β-lactams may no longer be a rational choice. While previous studies have suggested that β-lactam plus macrolide is more effective than β-lactam plus fluoroquinolone in reducing mortality and length of hospital stay in SCAP,\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e this does not mean that β-lactam plus fluoroquinolone is an appropriate alternative. No studies have directly compared β-lactam plus fluoroquinolone with fluoroquinolone monotherapy or β-lactam combined with other antibiotics (e.g., doxycycline) targeting atypical microorganisms. Previous studies have reported that β-lactam plus macrolide, compared to fluoroquinolone or β-lactam plus doxycycline, results in similar in-hospital mortality rates for patients with non-severe CAP.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR43\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e One prospective observational cohort study also found no significant differences in in-hospital and 30-day mortality between SCAP patients treated with β-lactam plus doxycycline or β-lactam plus azithromycin.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Our NMA results indicate that fluoroquinolone or β-lactam plus doxycycline may reduce mortality compared to β-lactam plus fluoroquinolone, although this difference was not statistically significant. Importantly, the evidence for β-lactam plus doxycycline comes from a single observational study,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e and further research is needed to confirm this finding. Therefore, if β-lactam plus macrolide is not the first choice due to high resistance, fluoroquinolone monotherapy could be a rational alternative.\u003c/p\u003e \u003cp\u003eOur results also showed that β-lactam plus fluoroquinolone did not significantly differ from β-lactam monotherapy in mortality outcomes. Several studies suggest that β-lactam monotherapy is associated with worse outcomes, including higher mortality and longer hospital stays.\u003csup\u003e\u003cspan additionalcitationids=\"CR46 CR47\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e However, this may be due to the lack of direct comparisons between β-lactam plus fluoroquinolone and other guideline-concordant treatments.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e Given that β-lactam plus fluoroquinolone provides similar bacterial coverage to β-lactam plus macrolide, no significant question has been raised about the recommendation of using β-lactam plus fluoroquinolone in patients with SCAP. Our NAM results indicate that β-lactam plus fluoroquinolone may be associated with lower efficacy compared to fluoroquinolone monotherapy (RR,1.30; 95% CI, 0.99\u0026ndash;1.70). The exact reasons for this reduced efficacy remain unclear. One possibility is that the combination does not provide broader coverage of pathogens compared to fluoroquinolone monotherapy. Additionally, overuse of antibiotics may lead to secondary infections, and disruption of the normal microbiota could exacerbate the inflammatory response, leading to worse outcomes. \u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e Therefore, based on our findings, we recommend against using β-lactam plus fluoroquinolone as the treatment for SCAP.\u003c/p\u003e \u003cp\u003eIn recent years, novel antibiotics such as delafloxacin and omadacycline have shown promising efficacy in treating CAP.\u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e However, these antibiotics should not be used as empirical treatments for SCAP in the initial stages due to insufficient clinical data supporting their effectiveness in severe cases. They should be reserved for situations with relevant risk factors or well-defined pathogen and resistance patterns.\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eOur study has several limitations. Firstly, we included patients who were admitted to the ICU. Although the IDSA/ATS guidelines recommend that SCAP patients meet the criteria for severe pneumonia when admitted to the ICU, the studies included in our review did not explicitly state that the patients adhered to this specific recommendation. Instead, most of the ICU-admitted patients in these studies were included based on clinical judgment rather than strictly following the IDSA/ATS guidelines. Furthermore, some studies conducted subgroup analyses, which could introduce inconsistencies in baseline characteristics and potential bias. Secondly, 13 of the 14 studies included were observational, limiting our ability to draw definitive causal conclusions. Given the susceptibility of observational studies to confounding factors, future large-scale RCTs are needed to strengthen the evidence base and reduce bias. Thirdly, although guidelines recommend specific β-lactam antibioticss (e.g., cefotaxime, ceftriaxone) for ICU patients without high-risk drug-resistant pathogens, several studies used β-lactam antibioticss outside these recommended classes or did not specify the β-lactam antibiotics used. This inconsistency may have affected treatment efficacy. Lastly, the rising antimicrobial resistance, particularly to macrolidess, is a concern in treating SCAP. Unfortunately, none of the studies included provided data on macrolides resistance, preventing subgroup analyses based on resistance patterns. This data gap limits our ability to assess the real-world effectiveness of macrolidess in the context of resistance. Given these limitations, caution should be exercised in interpreting our findings, and further research is necessary to address these gaps and refine SCAP treatment strategies.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur NMA suggests that β-lactam antibiotics plus macrolides may be the most effective treatment option for SCAP. The use of β-lactam antibiotics monotherapy and β-lactam antibiotics plus fluoroquinolones should be avoided, as these regimens demonstrated inferior efficacy in our analysis. However, the methodological limitations of the included studies and the limited availability of relevant clinical data preclude a definitive conclusion. Therefore, large-scale, well-designed RCTs are necessary to determine the most effective regimen for SCAP.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthors\u0026apos; contributions:\u003c/p\u003e\n\u003cp\u003eAo Liu, Min Wang designed the study and supervised the overall project; Xiaoming Wang and Lian Wang participated in collecting data; Han Zhuang, Qian Wang participated in analysis; Ao Liu, Jing Zhang and Min Wang provided the statistical analysis and wrote the manuscript.\u003c/p\u003e\n\n\u003cp\u003eConflict of interest \u003c/p\u003e\n\u003cp\u003eThis manuscript has no potential conflict of interest to disclose.\u003c/p\u003e\n\n\u003cp\u003eEthics approval and consent to participate \u003c/p\u003e\n\u003cp\u003eThis is a systematic review and meta-analysis; ethics approval and consent to participate are not applicable.\u003c/p\u003e\n\n\u003cp\u003eConsent for publication \u003c/p\u003e\n\u003cp\u003eNot applicable. The manuscript does not include the participant\u0026apos;s identification image or other personal or clinical details.\u003c/p\u003e\n\n\u003cp\u003eAvailability of data and materials \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\n\u003cp\u003eConflict of interest \u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\n\u003cp\u003eFunding \u003c/p\u003e\n\u003cp\u003e1 Henan Provincial Medical Science and Technology Research Project\u003c/p\u003e\n\u003cp\u003eFund No.: SBGJ202303042\u003c/p\u003e\n\u003cp\u003e2 Henan Provincial Key Research Projects of Higher Education Institutions\u003c/p\u003e\n\u003cp\u003eFund No.: 24A320005\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003enot applicable.\u003cbr\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 Suppl 2(Suppl 2):S27-72.\u003c/li\u003e\n\u003cli\u003eCilloniz C, Ferrer M, Liapikou A, et al. Acute respiratory distress syndrome in mechanically ventilated patients with community-acquired pneumonia. Eur Respir J. 2018;51(3).\u003c/li\u003e\n\u003cli\u003ePhua J, Dean NC, Guo Q, et al. Severe community-acquired pneumonia: timely management measures in the first 24 hours. Critical Care. 2016;20(1):237.\u003c/li\u003e\n\u003cli\u003eTsai D, Chiong F, Secombe P, et al. Epidemiology and microbiology of severe community-acquired pneumonia in Central Australia: a retrospective study. Intern Med J. 2022;52(6):1048-1056.\u003c/li\u003e\n\u003cli\u003eWang S, Tang J, Tan Y, et al. Prevalence of atypical pathogens in patients with severe pneumonia: A systematic review and meta-analysis. BMJ Open. 2023;13(4).\u003c/li\u003e\n\u003cli\u003eMetlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67.\u003c/li\u003e\n\u003cli\u003eMartin-Loeches I, Torres A, Nagavci B, et al. ERS/ESICM/ESCMID/ALAT guidelines for the management of severe community-acquired pneumonia. Eur Respir J. 2023;61(4).\u003c/li\u003e\n\u003cli\u003eBai AD, Srivastava S, Wong BKC, et al. Comparative Effectiveness of First-Line and Alternative Antibiotic Regimens in Hospitalized Patients With Nonsevere Community-Acquired Pneumonia: A Multicenter Retrospective Cohort Study. Chest. 2024;165(1):68-78.\u003c/li\u003e\n\u003cli\u003eGreco Kinney A, Kovacic Scherrer N, Sarkar S, et al. \u0026beta;-Lactams plus doxycycline versus azithromycin for treatment of severe community-acquired pneumonia in critically ill patients. J Antimicrob Chemother. 2023;78(12):2816-2823.\u003c/li\u003e\n\u003cli\u003eLee JH, Kim HJ, Kim YH. Is \u0026beta;-Lactam Plus Macrolide More Effective than \u0026beta;-Lactam Plus Fluoroquinolone among Patients with Severe Community-Acquired Pneumonia?: a Systemic Review and Meta-Analysis. J Korean Med Sci. 2017;32(1):77-84.\u003c/li\u003e\n\u003cli\u003eUddin M, Mohammed T, Metersky M, et al. Effectiveness of Beta-Lactam plus Doxycycline for Patients Hospitalized with Community-Acquired Pneumonia. Clin Infect Dis. 2022;75(1):118-124.\u003c/li\u003e\n\u003cli\u003eHutton B, Salanti G, Caldwell DM, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777-784.\u003c/li\u003e\n\u003cli\u003eWells GA, Shea B, O\u0026rsquo;Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2000.\u003c/li\u003e\n\u003cli\u003eSterne JA, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. bmj. 2019;366.\u003c/li\u003e\n\u003cli\u003eWhite IR. Network meta-analysis. The Stata Journal. 2015;15(4):951-985.\u003c/li\u003e\n\u003cli\u003eSalanti G, Ades A, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. Journal of clinical epidemiology. 2011;64(2):163-171.\u003c/li\u003e\n\u003cli\u003eHiggins JPT, Jackson D, Barrett J, et al. Consistency and inconsistency in network meta‐analysis: concepts and models for multi‐arm studies. Research synthesis methods. 2012;3(2):98-110.\u003c/li\u003e\n\u003cli\u003eShim S, Yoon B-H, Shin I-S, et al. Network meta-analysis: application and practice using Stata. Epidemiology and health. 2017;39.\u003c/li\u003e\n\u003cli\u003eTurner RM, Davey J, Clarke MJ, et al. Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane Database of Systematic Reviews. International journal of epidemiology. 2012;41(3):818-827.\u003c/li\u003e\n\u003cli\u003eRello J, Catal\u0026aacute;n M, D\u0026iacute;az E, et al. Associations between empirical antimicrobial therapy at the hospital and mortality in patients with severe community-acquired pneumonia. Intensive Care Med. 2002;28(8):1030-1035.\u003c/li\u003e\n\u003cli\u003eLeroy O, Saux P, B\u0026eacute;dos JP, et al. Comparison of levofloxacin and cefotaxime combined with ofloxacin for ICU patients with community-acquired pneumonia who do not require vasopressors. Chest. 2005;128(1):172-183.\u003c/li\u003e\n\u003cli\u003eBratzler DW, Ma A, Nsa W. Initial antibiotic selection and patient outcomes: observations from the National Pneumonia Project. Clin Infect Dis. 2008;47 Suppl 3:S193-201.\u003c/li\u003e\n\u003cli\u003eMartin-Loeches I, Lisboa T, Rodriguez A, et al. Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia. Intensive Care Med. 2010;36(4):612-620.\u003c/li\u003e\n\u003cli\u003eWilson BZ, Anzueto A, Restrepo MI, et al. Comparison of two guideline-concordant antimicrobial combinations in elderly patients hospitalized with severe community-acquired pneumonia. Critical Care Medicine. 2012;40(8):2310-2314.\u003c/li\u003e\n\u003cli\u003eAdrie C, Schwebel C, Garrouste-Orgeas M, et al. Initial use of one or two antibiotics for critically ill patients with community-acquired pneumonia: impact on survival and bacterial resistance. Crit Care. 2013;17(6):R265.\u003c/li\u003e\n\u003cli\u003eKarhu J, Ala-Kokko TI, Ohtonen P, et al. Severe community-acquired pneumonia treated with \u0026beta;-lactam-respiratory quinolone vs. \u0026beta;-lactam-macrolide combination. Acta Anaesthesiol Scand. 2013;57(5):587-593.\u003c/li\u003e\n\u003cli\u003eCeccato A, Cilloniz C, Ranzani OT, et al. Treatment with macrolides and glucocorticosteroids in severe community-acquired pneumonia: A post-hoc exploratory analysis of a randomized controlled trial. PLoS One. 2017;12(6):e0178022.\u003c/li\u003e\n\u003cli\u003eRahmel T, Asmussen S, Karlik J, et al. Moxifloxacin monotherapy versus combination therapy in patients with severe community-acquired pneumonia evoked ARDS. BMC Anesthesiol. 2017;17(1):78.\u003c/li\u003e\n\u003cli\u003eIto A, Ishida T, Tachibana H, et al. Azithromycin combination therapy for community-acquired pneumonia: propensity score analysis. Sci Rep. 2019;9(1):18406.\u003c/li\u003e\n\u003cli\u003eSuzuki J, Sasabuchi Y, Hatakeyama S, et al. Azithromycin plus \u0026beta;-lactam versus levofloxacin plus \u0026beta;-lactam for severe community-acquired pneumonia: A retrospective nationwide database analysis. J Infect Chemother. 2019;25(12):1012-1018.\u003c/li\u003e\n\u003cli\u003eKyriazopoulou E, Sinapidis D, Halvatzis S, et al. Survival benefit associated with clarithromycin in severe community-acquired pneumonia: A matched comparator study. Int J Antimicrob Agents. 2020;55(1):105836.\u003c/li\u003e\n\u003cli\u003eOh S, Jang W, Kim B. Is the fluoroquinolone combination necessary for empirical antibiotic regimen in severe community-acquired pneumonia? Postgrad Med. 2024.\u003c/li\u003e\n\u003cli\u003eGattarello S, Lagunes L, Vidaur L, et al. Improvement of antibiotic therapy and ICU survival in severe non-pneumococcal community-acquired pneumonia: a matched case-control study. Crit Care. 2015;19(1):335.\u003c/li\u003e\n\u003cli\u003eRaeven VM, Spoorenberg SMC, Boersma WG, et al. Atypical aetiology in patients hospitalised with community-acquired pneumonia is associated with age, gender and season; a data-analysis on four Dutch cohorts. BMC Infectious Diseases. 2016;16(1).\u003c/li\u003e\n\u003cli\u003eEljaaly K, Alshehri S, Aljabri A, et al. Clinical failure with and without empiric atypical bacteria coverage in hospitalized adults with community-acquired pneumonia: A systematic review and meta-analysis. BMC Infectious Diseases. 2017;17(1).\u003c/li\u003e\n\u003cli\u003eEljaaly K, Aljabri A, Rabaan AA, et al. Efficacy of empiric antibiotic coverage in community-acquired pneumonia associated with each atypical bacteria: A meta-analysis. Journal of Clinical Medicine. 2021;10(19).\u003c/li\u003e\n\u003cli\u003eKricker JA, Page CP, Gardarsson FR, et al. Nonantimicrobial Actions of Macrolides: Overview and Perspectives for Future Development. Pharmacol Rev. 2021;73(4):233-262.\u003c/li\u003e\n\u003cli\u003eGiamarellos-Bourboulis EJ, Siampanos A, Bolanou A, et al. Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2024;12(4):294-304.\u003c/li\u003e\n\u003cli\u003eDequin PF, Meziani F, Quenot JP, et al. Hydrocortisone in Severe Community-Acquired Pneumonia. N Engl J Med. 2023;388(21):1931-1941.\u003c/li\u003e\n\u003cli\u003eLi J, Liu L, Zhang H, et al. Severe problem of macrolides resistance to common pathogens in China. Front Cell Infect Microbiol. 2023;13:1181633.\u003c/li\u003e\n\u003cli\u003eWang G, Wu P, Tang R, et al. Global prevalence of resistance to macrolides in Mycoplasma pneumoniae: a systematic review and meta-analysis. J Antimicrob Chemother. 2022;77(9):2353-2363.\u003c/li\u003e\n\u003cli\u003eBabonji AS, Alshehri SJ, Alturaiki AM. Clinical Effectiveness and Outcomes of Azithromycin versus Doxycycline Containing Regimen in Inpatients with Community Acquired Pneumonia: A Retrospective Cohort Study. Journal of Clinical Pharmacy and Therapeutics. 2023;2023.\u003c/li\u003e\n\u003cli\u003eAldhahri RK, Gabb SG, Shoaib OA, et al. Doxycycline vs. macrolides in combination with a \u0026beta;-lactam antibiotic for the treatment of community-acquired pneumonia in inpatients. Eur J Med Res. 2022;27(1):279.\u003c/li\u003e\n\u003cli\u003eIzadi M, Dadsetan B, Najafi Z, et al. Levofloxacin Versus Ceftriaxone and Azithromycin Combination in the Treatment of Community Acquired Pneumonia in Hospitalized Patients. Recent Pat Antiinfect Drug Discov. 2018;13(3):228-239.\u003c/li\u003e\n\u003cli\u003eHouck PM, MacLehose RF, Niederman MS, et al. Empiric antibiotic therapy and mortality among medicare pneumonia inpatients in 10 western states : 1993, 1995, and 1997. Chest. 2001;119(5):1420-1426.\u003c/li\u003e\n\u003cli\u003eBattleman DS, Callahan M, Thaler HT. Rapid antibiotic delivery and appropriate antibiotic selection reduce length of hospital stay of patients with community-acquired pneumonia: link between quality of care and resource utilization. Arch Intern Med. 2002;162(6):682-688.\u003c/li\u003e\n\u003cli\u003eWaterer GW, Somes GW, Wunderink RG. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med. 2001;161(15):1837-1842.\u003c/li\u003e\n\u003cli\u003eAspa J, Rajas O, de Castro FR, et al. Impact of initial antibiotic choice on mortality from pneumococcal pneumonia. European Respiratory Journal. 2006;27(5):1010-1019.\u003c/li\u003e\n\u003cli\u003eMortensen EM, Restrepo MI, Anzueto A, et al. The impact of empiric antimicrobial therapy with a \u0026beta;-lactam and fluoroquinolone on mortality for patients hospitalized with severe pneumonia. Crit Care. 2005;10(1):R8.\u003c/li\u003e\n\u003cli\u003eBhalodi AA, van Engelen TSR, Virk HS, et al. Impact of antimicrobial therapy on the gut microbiome. Journal of Antimicrobial Chemotherapy. 2019;74(Supplement_1):i6-i15.\u003c/li\u003e\n\u003cli\u003eZuttion MSSR, Parimon T, Bora SA, et al. Antibiotic use during influenza infection augments lung eosinophils that impair immunity against secondary bacterial pneumonia. The Journal of Clinical Investigation. 2024;134(21).\u003c/li\u003e\n\u003cli\u003eMcCurdy S, Nenninger A, Sheets A, et al. Efficacy of delafloxacin versus moxifloxacin against atypical bacterial respiratory pathogens in adults with community-acquired bacterial pneumonia (CABP): Data from the Delafloxacin Phase 3 CABP Trial. (1878-3511 (Electronic)).\u003c/li\u003e\n\u003cli\u003eTorres A, Garrity-Ryan L, Kirsch C, et al. Omadacycline vs moxifloxacin in adults with community-acquired bacterial pneumonia. Int J Infect Dis. 2021;104:501-509.\u003c/li\u003e\n\u003cli\u003eGarc\u0026iacute;a V\u0026aacute;zquez E, Mensa J, Mart\u0026iacute;nez JA, et al. Lower mortality among patients with community-acquired pneumonia treated with a macrolide plus a beta-lactam agent versus a beta-lactam agent alone. Eur J Clin Microbiol Infect Dis. 2005;24(3):190-195.\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":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Severe community-acquired pneumonia, network meta-analysis, β-lactam antibiotics, macrolides, fluoroquinolones, mortality","lastPublishedDoi":"10.21203/rs.3.rs-6121400/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6121400/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSevere community-acquired pneumonia (SCAP) remains a leading cause of morbidity and mortality worldwide. Identifying the optimal antibiotic regimen for treating SCAP is crucial for improving patient outcomes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe searched the PubMed, Embase, and Cochrane Central Register of Controlled Clinical Trials databases to identify studies reporting initial empirical antibiotic regimens in patients with SCAP. We performed a network meta-analysis to compare the relative efficacy of different antibiotic regimens in treating SCAP. The primary outcome was overall mortality. The second outcomes were 30-day mortality and in-hospital mortality.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThis network meta-analysis included 1 randomized clinical trial and 13 observational studies with 8142 patients, categorized into five treatment groups: β-lactam antibiotics, β-lactam antibiotics plus doxycycline, β-lactam antibiotics plus fluoroquinolones, β-lactam antibiotics plus macrolides, and fluoroquinolones monotherapy. β-lactam antibiotics plus macrolides was ranked as the most effective treatment (surface under the cumulative ranking curve, 92.0%; mean rank, 1.3). The β-lactam antibiotics plus macrolides combination significantly reduced overall mortality compared to β-lactam antibiotics alone (RR, 0.79; 95% CI, 0.64\u0026ndash;0.96) and β-lactam antibiotics plus fluoroquinolones (RR, 0.67; 95% CI, 0.64\u0026ndash;0.82).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur findings suggest that β-lactam antibiotics plus macrolides may be the optimal treatment for SCAP. β-lactam antibiotics monotherapy and β-lactam antibiotics plus fluoroquinolones should not be recommended due to their inferior outcomes.\u003c/p\u003e","manuscriptTitle":"Comparison of the efficacy of initial empirical antibiotic regimens in severe community-acquired pneumonia: a network meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-14 23:14:14","doi":"10.21203/rs.3.rs-6121400/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-22T03:41:08+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-17T13:33:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-11T08:04:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"41503818584583544931001828070153488682","date":"2025-04-11T07:39:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"247688868470423898915513475703715461039","date":"2025-04-09T13:33:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-09T07:29:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-05T03:04:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2025-04-04T12:14:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"27d8be49-cbf5-4b90-8958-9cd7537bd983","owner":[],"postedDate":"April 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-26T16:00:17+00:00","versionOfRecord":{"articleIdentity":"rs-6121400","link":"https://doi.org/10.1186/s12890-025-03695-w","journal":{"identity":"bmc-pulmonary-medicine","isVorOnly":false,"title":"BMC Pulmonary Medicine"},"publishedOn":"2025-05-20 15:57:19","publishedOnDateReadable":"May 20th, 2025"},"versionCreatedAt":"2025-04-14 23:14:14","video":"","vorDoi":"10.1186/s12890-025-03695-w","vorDoiUrl":"https://doi.org/10.1186/s12890-025-03695-w","workflowStages":[]},"version":"v1","identity":"rs-6121400","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6121400","identity":"rs-6121400","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}