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Introduction Community-acquired pneumonia (CAP) is common and remains the leading infectious cause of death worldwide. Antibiotics remain the mainstay of treatment, but organisms are often not identified, necessitating empirical treatment. Current treatment guidelines recommend combination therapy with beta-lactams and macrolides or monotherapy with fluoroquinolones for non-severe CAP. However, rising antibiotic resistance and safety concerns have led to increased doxycycline use, despite limited evidence supporting its efficacy. Our goal is to conduct a pragmatic, open-label, randomised clinical trial comparing the effectiveness of azithromycin with that of doxycycline in combination with beta-lactam therapy in adult patients hospitalised for CAP. Methods and analysis Patients presenting to the emergency department or directly referred to the hospital with a clinical presentation concerning for CAP and need for hospitalisation are eligible. We plan to enrol 1120 adults hospitalised at six hospitals across four states, including rural, suburban and urban settings and academic and community hospitals. Randomisation will be 1:1 using an electronic health record (EHR)-embedded screening and randomisation tool triggered by the treating clinician’s orders for azithromycin or doxycycline. Outcomes will be ascertained pragmatically via EHR-based data retrieval and will not require additional study visits. Our primary outcome is days alive and out of the hospital through day 28. Secondary outcomes include oxygen-free days; a composite of a need for advanced respiratory support or in-hospital mortality with analyses of each component separately; an ordinal measure of clinical deterioration defined by a prespecified severity scale; and 60-day and 180-day mortality. Safety outcomes are the incidence of Clostridioides difficile infection and QT prolongation. Analyses will follow an intention-to-treat framework, with per-protocol analyses for sensitivity. The primary endpoint will be compared between groups using a stratified van Elteren test, with supportive analyses using proportional odds regression and analysis of covariance adjusted for key covariates. Ethics and dissemination The Mayo Clinic Institutional Review Board reviewed and approved this protocol with a waiver of written consent, requiring verbal consent to be obtained by the clinician initiating the antibiotics (IRB# 24–0 06 503). Findings will be disseminated through peer-reviewed publications and international conference presentations. Trial registration number NCT07164131 .

Background/Objective: To externally validate our previously published machine learning model for identifying hospitalized patients with community-acquired pneumonia (CAP) at low risk of respiratory deterioration or death using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Methods: This is a retrospective cohort study of adult patients (≥18 years) who were admitted with CAP and acute hypoxemic respiratory failure using the publicly available MIMIC-IV critical care dataset (Beth Israel Deaconess Medical Center, Boston, MA). We conducted an external validation study of a previously developed gradient boosting machine (GBM) model without recalibration using data available within the first 6 h of hospital admission. Results: For the primary composite outcome (need for advanced respiratory support [high flow nasal cannula (HFNC), non-invasive mechanical ventilation (NIMV), invasive mechanical ventilation (IMV)] or in-hospital death), the gradient boosting model demonstrated comparable performance in the derivation and external validation cohorts. The area under the receiver operating characteristic curve (AUC) was 0.713 in the Mayo cohort (n = 4379) and 0.689 in the MIMIC-IV cohort. Accuracy was 0.612 (95% confidence interval [CI], 0.595–0.628) versus 0.606 (95% CI 0.600–0.611), specificity 0.574 versus 0.523, sensitivity 0.723 versus 0.754, NPV 0.860 versus 0.842, and PPV 0.364 versus 0.401, respectively. For secondary outcomes, model discrimination was comparable between cohorts. The AUC for in-hospital mortality was 0.727 in the Mayo Cohort versus 0.733 in MIMIC-IV; for IMV, 0.736 versus 0.724; and for NIMV, 0.732 versus 0.708. Conclusions: Our machine learning algorithm demonstrated good discrimination and a high negative predictive value for identifying low-risk hospitalized CAP patients for respiratory deterioration or death in the external MIMIC-IV dataset, supporting its potential utility for prognostic enrichment in pneumonia clinical trials.

Abstract Rationale Community-acquired pneumonia (CAP) remains a leading cause of morbidity and mortality worldwide; current guidelines recommend either the use of β-lactam therapy with a macrolide (azithromycin; AZM) or monotherapy with a fluoroquinolone for treatment. Limited evidence exists on their comparative effectiveness. To address this gap, we examined the differences in outcomes among CAP patients treated with β-lactam therapy plus AZM or fluoroquinolone monotherapymethods: We emulated a randomized clinical trial that hypothetically assigned patients to β-lactam therapy plus AZM or fluoroquinolone. Eligible patients were all adults hospitalized for nonsevere community-acquired pneumonia (CAP) based on ATS/IDSA criteria; at Mayo Clinic hospitals (3 academic and 16 community) between May 2018 and September 2022 and received one of the two treatments within 12 hours of admission. Ensemble machine learning with augmented inverse probability weighting (AIPW) was used to evaluate “intention to treat” effects on hospital-free days (HFDs), 180-day mortality, use of advanced respiratory support, in-hospital mortality, and the composite of advanced respiratory support and/or in-hospital mortality. We used the E-value and post-discharge systolic blood pressure (SBP) (negative outcome) to evaluate effects of potential unmeasured confounding and alternative “doubly robust” inverse probably weighting with regression adjustment (IPWRA) to evaluate robustness of the findings. Results 2,451 patients (2,142 β-lactam therapy plus AZM and 309 fluoroquinolone) were eligible and included in the analyses: 53.9% were female, 86.8% were White, and mean age was 58.4 years (SD: 17.02). Compared with β-lactam therapy plus AZM, the fluoroquinolone group experienced significantly higher HFD (1.50 days; 95% CI: 1.08, 1.91), lower use of advanced respiratory support (RR: 0.32; 95% CI: 0.09, 0.54), lower in-hospital mortality (RR: 0.14; 95% CI: 0.00, 0.40), and composite of advanced respiratory support and/or in-hospital mortality (RR: 0.29; 95% CI: 0.08, 0.49). Moderate to large e-values (ranging from 3.50 to 4.74) and use of negative outcomes (post-discharge SBP) suggested that unmeasured confounding is unlikely to change the findings. Sensitivity analysis using IPWRA showed very similar results. Conclusion Among hospitalized patients with non-severe CAP, treatment with fluoroquinolone monotherapy was associated with more hospital-free days, lower in-hospital mortality, and reduced need for advanced respiratory support compared with AZM and β-lactam combination. The findings highlight the role of fluoroquinolone as a beneficial alternative CAP patients. However, further studies are needed to explore the underlying mechanisms driving these differences and assess whether specific patient subgroups may benefit most from quinolone-based therapy. This abstract is funded by: none

Abstract Background Community-acquired pneumonia (CAP) is a significant public health concern associated with increased rates of hospital admissions and mortality. The purpose of the current study was to compare beta-lactam plus azithromycin or doxycycline vs fluoroquinolones in adults hospitalized with CAP. Methods We searched several databases from inception to 10 June 2024. Two reviewers independently screened, selected, and extracted data. Disagreements were resolved by consensus or a third reviewer. Study quality was assessed in duplicate with the Cochrane Risk of Bias 2 for randomized studies and the Newcastle-Ottawa Scale for nonrandomized studies. Meta-analysis was conducted by a random effect model when feasible. Network meta-analysis was performed to compare direct and indirect evidence. The GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation) was followed to rate the certainty of evidence. Results Twenty studies were included (20 beta-lactam + azithromycin, 7 beta-lactam + doxycycline, 12 levofloxacin, and 4 moxifloxacin): 6 were randomized, enrolling 861 participants (mean age, 61.8 years; 43.2% women), and 14 were nonrandomized, enrolling 185 928 participants (mean age, 65.2 years; 42.9% women). Direct comparison and network meta-analysis results showed no statistically significant differences and likely equal effectiveness between beta-lactam + azithromycin and beta-lactam + doxycycline in terms of in-hospital mortality, need for intensive care unit admission or invasive mechanical ventilation, or safety outcomes including Clostridioides difficile infection and QT prolongation. Conclusions The current evidence demonstrated no likely difference in outcomes between azithromycin and doxycycline in adults hospitalized with CAP receiving beta-lactam. Head-to-head randomized clinical trials are needed to validate these results.

Introduction Sepsis is a global health priority with nearly 50 million cases annually. Cardiovascular dysfunction is common, frequently manifesting as hypotension that persists despite fluid resuscitation. Most affected patients require the use of intravenous (IV) vasoactive agents, typically necessitating intensive care unit (ICU)-level monitoring, invasive interventions and contributing substantially to healthcare costs. Midodrine, an oral alpha-1 agonist approved for orthostatic hypotension, has increasingly been used off-label as a vasopressor-sparing (reducing IV vasopressor use) strategy in sepsis, despite limited and inconsistent evidence. This pragmatic, randomised, open-label trial evaluates the efficacy and safety of midodrine in patients with sepsis-associated hypotension. We hypothesise that, compared with standard care, midodrine administration will reduce the duration of IV vasopressor use. Methods and analysis A total of 308 adult patients with sepsis-associated hypotension will be enrolled (154 per arm). The intervention group will, in addition to standard of care, receive enteral midodrine 10 mg three times daily. Outcomes will be ascertained pragmatically via electronic health record-based data retrieval and adjudicated by research coordinators blinded to treatment assignment. The primary outcome is time alive and off IV vasopressors in the first 28 days (in hours) after randomisation. Secondary outcomes include cumulative vasopressor exposure; use and duration of central venous access; cumulative fluid balance over the first 48 hours and up to 7 days of ICU stay; ICU and hospital length of stay; and ICU-, hospital-, and organ support-free days through day 28. Safety outcomes include adverse events potentially attributable to midodrine during hospitalisation including acute kidney injury. Primary analyses will follow an intention-to-treat framework, including all randomised participants according to their assigned treatment groups. Primary and secondary outcomes will be compared using a van Elteren test stratified by randomisation factors. A predefined secondary Bayesian analysis of the primary outcome will provide complementary estimates of treatment effect. Safety outcomes will be summarised descriptively without formal between-arm hypothesis testing. Ethics and dissemination The Mayo Clinic Institutional Review Board approved this protocol and required written informed consent from all participants (IRB# 24–0 00 121). Findings will be disseminated through peer-reviewed publications and international conference presentations. Trial registration number NCT06319248 .

This systematic review examined multicenter randomized controlled trials (RCTs) conducted during the Sepsis-3 era that evaluated pharmaceutical and mechanistic interventions in adult patients with sepsis or septic shock, with a focus on identifying interventions that demonstrated mortality benefit. A comprehensive search was performed across Ovid MEDLINE, Embase, Cochrane Central, ClinicalTrials.gov, WHO ICTRP, and Web of Science for trials published since 2016. Studies were included if they enrolled adult patients with sepsis or septic shock using Sepsis-3 criteria and reported mortality as either a primary or secondary outcome. Data were extracted by two independent reviewers and included trial design characteristics, funding source, randomization methods, and reported outcomes. Among the 31 eligible multicenter RCTs enrolling over 7,000 patients across 550 centers, only four trials showed a mortality benefit. These included three studies from China—two evaluating herbal anti-inflammatory compounds and one evaluating aminophylline—and one European study assessing corticosteroid therapy in vasopressor-dependent septic shock. The remaining 27 trials reported no mortality benefit, and substantial heterogeneity was observed in patient populations, sepsis definitions, and outcome reporting. Median mortality in control arms was 31.6% (IQR 24.1–45.5), and 35.4% (IQR 25.7–49.6) in intervention arms. These findings suggest that despite extensive efforts, most interventions have not reduced mortality in multicenter sepsis trials. Future research should focus on optimizing trial design, refining patient selection, and incorporating patient-centered outcomes beyond mortality.

Abstract Background Doxycycline is a frequently used alternative treatment for community-acquired pneumonia (CAP) in hospitalized patients; however, the evidence base is limited. We aimed to compare outcomes in CAP patients treated with doxycycline or azithromycin in combination with beta-lactams. Methods We evaluated patients with CAP admitted to Mayo Clinic hospitals from May 2018 to September 2022 and treated with either azithromycin or doxycycline in combination with a beta-lactam. Patients who received both antibiotics or were on either antibiotic as chronic therapy prior to admission were excluded. The primary outcome was mortality. Patients were 1-to-1 matched according to the presence of congestive heart failure, coronary artery disease, chronic obstructive pulmonary disease, human immunodeficiency virus infection, recent immunosuppressant use, and pneumonia severity index class. Results Among 8492 patients (5810 for azithromycin, 2682 for doxycycline), 2671 doxycycline-treated patients were matched with azithromycin-treated patients. In-hospital mortality was significantly lower in the azithromycin group than in the doxycycline group (odds ratio, 0.71; 95% confidence interval [CI], .56–.9), as was 90-day mortality (hazard ratio, 0.83; 95% CI, .73–.95). Patients on azithromycin also had significantly more hospital-free days (HFDs) than those on doxycycline (estimate, 1.37; 95% CI, .99–1.74). Conclusions Among hospitalized patients with CAP, azithromycin was associated with lower mortality and more HFDs compared with doxycycline in combination with beta-lactams. Randomized, controlled trials are needed to assess the effectiveness of each regimen and to compare their potential side effects.

Background: Delirium in hospitalized patients has been consistently associated with worse clinical outcomes, including increased mortality and prolonged hospital stays. COPD exacerbation is a common reason for hospitalization, and understanding the impact of delirium on this population is crucial for improving patient care and outcomes. Methods: We conducted a retrospective cohort study using the National In-Patient Sample dataset to assess the impact of delirium on patients hospitalized with COPD exacerbation. Subjects were identified using International Classification of Diseases, 10th Revision, codes for COPD exacerbation and delirium. Baseline characteristics and outcomes, including in-patient mortality and the use of invasive mechanical ventilation, were compared between subjects with and without delirium using chi-square analysis. Multivariate regression analysis was used to adjust for potential confounders. Results: A total of 8,062,333 subjects hospitalized with COPD exacerbation were included, of whom 574,005 (7.2%) had a diagnosis of delirium. Most subjects in both groups were white, covered by Medicare, and treated in large urban teaching hospitals. Subjects with delirium had higher rates of dementia, malnutrition, and chronic kidney disease. The rates of in-patient mortality (13.85% vs 4.29%, P < .01) and use of invasive mechanical ventilation (26.7% vs 7.79%, P < .01) were significantly higher in the delirium group. Delirium was associated with higher odds of mortality (adjusted odds ratio [aOR] 2.48, P < .01) and use of mechanical ventilation (aOR 3.92, P < .01). Subjects with delirium had longer and more costly hospital stays. Conclusions: Delirium was associated with worse outcomes in subjects hospitalized with COPD exacerbation.