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Background: In the ACCESS trial, the addition of clarithromycin to standard-of-care antibiotics (SoC) enhanced early clinical response and attenuated the inflammatory burden in adults with community-acquired pneumonia (CAP) requiring hospitalisation. A post-hoc analysis was performed to investigate the benefit in specific subgroups., Methods: The primary endpoint comprised two conditions to be met during the first 72 h: ≥50% decrease in respiratory symptom severity score; and any of ≥30% decrease in sequential organ failure assessment score and favourable change in the kinetics of procalcitonin (PCT, defined as ≥80% PCT decrease or PCT <0.25 ng/mL). In this exploratory post-hoc analysis, achievement of the study composite primary endpoint was compared between the two treatment groups within subsets differentiated by demographic characteristics, comorbidities, CAP severity, baseline laboratory findings and corticosteroid co-administration. The impact of clarithromycin treatment on the need for mechanical ventilation (MV) in all subgroups was also analysed., Results: The addition of clarithromycin significantly increased the proportion of patients achieving the primary endpoint across all subgroups and decreased the need for MV in 19 out of the 37 subgroups studied. For instance, the primary endpoint was attained in 32.7% of placebo-treated patients and in 67% of clarithromycin-treated patients with CURB-65 score ≥2 (P<0.0001), whereas MV was required in 18.8% and 7.4% of patients, respectively (P=0.022). The addition of corticosteroids alone was not as clinically advantageous as the use of clarithromycin alone, when added to SoC., Conclusion: Adding clarithromycin to SoC in the ACCESS trial achieved early clinical anti-inflammatory responses and decreased the need for MV in subgroups of hospitalised patients with CAP., Competing Interests: Declarations Funding: The ACCESS trial was sponsored by the Hellenic Institute for the Study of Sepsis (HISS) and financially supported by Abbot Products Operations (Abbott). HISS oversaw the study design, implementation, data analysis, interpretation, and determination regarding publication. The funding source, Abbott, did not take part in the design, execution, analysis, or interpretation of the study, nor did it influence the decision to publish. Publication administration was facilitated by Hughes associates, Oxford, UK. Competing Interests: K. Akinosoglou reports receiving honoraria and consulting fees from healthcare companies, including MSD, Pfizer, 3M Hellas, GSK/ViiV and Gilead. I. Papanikolaou has received honoraria or served as PI for studies from Boehringer-ingelheim, GlaxoSmithKline and AstraZeneca. H. Milionis reports receiving honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer and Servier. E. J. Giamarellos-Bourboulis has received honoraria from Abbott Products Operations, bioMérieux, GSK, UCB, Sobi AB and ThermoFisher Brahms GmbH; independent educational grants from Abbott Products Operations, AbbVie, bioMérieux Inc, Johnson & Johnson, InCyte, MSD, Novartis, UCB, Sanofi and Sobi; and the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grants EPIC-CROWN-2, POINT and Homi-Lung (granted to the Hellenic Institute for the Study of Sepsis). The other authors do not declare any conflict of interest. Ethical Approval: The study was approved by the National Ethics Committee of Greece. Approvals are provided in the Methods section. Sequence Information: Not applicable Randomised Controlled Trial: ClinicalTrials.gov NCT04724044, (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Addition of macrolide antibiotics to β-lactam antibiotics for the treatment of patients in hospital with community-acquired pneumonia is based on results from observational studies and meta-analyses rather than randomised clinical trials. We investigated if addition of the macrolide clarithromycin to treatment with a β-lactam antibiotic in this population could improve early clinical response-the new regulatory endpoint for community-acquired pneumonia-and explored the possible contribution of modulation of the inflammatory host response to that outcome., Methods: The ACCESS trial was a phase 3 prospective, double-blind, randomised controlled trial, in which adults in hospital with community-acquired pneumonia who had systemic inflammatory response syndrome, Sequential Organ Failure Assessment (SOFA) score of 2 or more, and procalcitonin 0·25 ng/mL or more were enrolled in 18 internal medicine departments of public Greek hospitals. Patients were randomly assigned (1:1) by computer-generated block randomisation to standard of care medication (including intravenous administration of a third-generation cephalosporin or intravenous administration of β-lactam plus β-lactamase inhibitor combination) plus either oral placebo or oral clarithromycin 500 mg twice daily for 7 days. Investigators, staff, and patients were masked to group allocation. The primary composite endpoint required that patients fulfilled both of the following conditions after 72 hours (ie, day 4 of treatment): (1) decrease in respiratory symptom severity score of 50% or more as an indicator of early clinical response and (2) decrease in SOFA score of at least 30% or favourable procalcitonin kinetics (defined as ≥80% decrease from baseline or procalcitonin <0·25 ng/mL), or both, as an indicator of early inflammatory response. Participants who were randomly assigned and received allocated treatment were included in the primary analysis population. This trial is complete and is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044)., Findings: Patients were enrolled between Jan 25, 2021, and April 11, 2023, and 278 individuals were randomly allocated to receive standard of care in combination with either clarithromycin (n=139) or placebo (n=139). 134 patients in the clarithromycin group (five withdrew consent) and 133 patients in the placebo group (six withdrew consent) were included in the analysis of the primary endpoint. The primary endpoint was met in 91 (68%) patients in the clarithromycin group and 51 (38%) patients in the placebo group (difference 29·6% [95% CI 17·7-40·3]; odds ratio [OR] 3·40 [95% CI 2·06-5·63]; p<0·0001). Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group (difference 9·4% [95% CI -2·6 to 20·9]; OR 0·67 [95% CI 0·42 to 1·11]; p=0·14). None of the serious TEAEs was judged to be related to treatment assignment., Interpretation: Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to β-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden., Funding: Hellenic Institute for the Study of Sepsis and Abbott Products Operations., Competing Interests: Declaration of interests EJG-B has received honoraria from Abbott Products Operations, bioMérieux, Brahms, GSK, InflaRx, Swedish Orphan Biovitrum, and Xbiotech; independent educational grants from Abbott Products Operations, bioMérieux, InflaRx, Johnson & Johnson, MSD, UCB, and Swedish Orphan Biovitrum; and funding from the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grant EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis). GP has received honoraria or consulting fees from AstraZeneca, Gilead, GSK, Menarini, MSD, Norma, Pfizer, and Sobi, and research grants from the University of Minnesota/University College London, the Hellenic Institute for the Study of Sepsis, Bausch, Roche, Xenothera, FabNTech, and Pfizer. ICP has received honoraria or served as principal investigator for studies from Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca. HM reports receiving honoraria, consulting fees, and non-financial support from health-care companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. GND is an advisor or lecturer for Pfizer, Roche, Sanofi, and Sobi; has received research grants from Gilead; and has served as principal investigator in studies for Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics, Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics, Sobi, and Intercept Pharmaceuticals. KAk reports receiving honoraria and consulting fees from health-care companies, including Angelini, MSD, Pfizer, Swedish Orphan Biovitrum, 3M hellas, GSK/ViiV, and Gilead. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: The aim was to assess the performance of a blood assay combining measurements of MxA (myxovirus resistance protein A) and CRP (C-reactive protein) to differentiate viral from bacterial respiratory infections., Methods: In a prospective study, MxA and CRP were measured in the blood by the AFIAS panel in adults admitted with respiratory infection. Patients were split into discovery and validation cohorts. Final diagnosis was adjudicated by a panel of experts. Microbiology-confirmed cases comprised the discovery cohort, and infections adjudicated as highly probable viral or bacterial comprised the validation cohort., Results: A total of 537 patients were analyzed: 136 patients were adjudicated with definitive viral infections and 131 patients with definitive bacterial infections. Using logistic regression analysis, an equation was developed to calculate the probability for bacterial infection using the absolute value of MxA and CRP. Calculated probability ≥ 0.5 and/or MxA to CRP ratio less than 2 applied as the diagnostic rule for bacterial infections. This rule provided 91.6% sensitivity and 90.4% negative predictive value for the diagnosis of bacterial infections. This diagnostic sensitivity was confirmed in the validation cohort. A MxA/CRP ratio less than 0.15 was associated with unfavorable outcome., Conclusion: The calculation of the probability for bacterial infection using MxA and CRP may efficiently discriminate between viral and bacterial respiratory infections., (© 2023. The Author(s).)

Background: Omicron-1 COVID-19 is less invasive in the general population than previous viral variants. However, clinical course and outcome of hospitalised patients with SARS-CoV-2 pneumonia during the shift of the predominance from Delta to Omicron variants are not fully explored., Methods: During January 2022 consecutively hospitalised patients with SARS-CoV-2 pneumonia were analysed. SARS-CoV-2 variants were identified by a 2-step pre-screening protocol and randomly confirmed by whole genome sequencing analysis. Clinical, laboratory and treatment data split by type of variant were analysed along with logistic regression of factors associated to mortality., Results: 150 patients [mean age (SD) 67.2(15.8) years, male 54%] were analysed. Compared to Delta ( n  = 46), Omicron-1 patients ( n  = 104) were older [mean age (SD): 69.5(15.4) vs 61.9(15.8) years, p  = 0.007], with more comorbidities (89.4% vs 65.2%, p  = 0.001), less obesity (BMI >30Kg/m 2 in 24% vs 43.5%, p  = 0.034) but higher vaccination rates for COVID-19 (52.9% vs 8.7%, p  < 0.001). Severe pneumonia (48.7%), pulmonary embolism (4.7%), need for invasive mechanical ventilation (8%), administration of dexamethasone (76%) and 60-day mortality (22.6%) did not significantly differ. Severe SARS-CoV-2 pneumonia independently predicted mortality [OR 8.297 (CI95% 2.080-33.095), p  = 0.003]. Remdesivir administration ( n  = 135) was protective from death both in unadjusted and adjusted models [OR 0.157 (CI95% 0.026-0.945), p  = 0.043., Conclusions: In a COVID-19 department the severity of pneumonia that did not differ between Omicron-1 and Delta variants predicted mortality whilst remdesivir remained protective in all analyses. Death rates did not differ between SARS-CoV-2 variants. Vigilance and consistency with prevention and treatment guidelines for COVID-19 is mandatory regardless of the predominant SARS-CoV-2 variant.

Intraparenchymal lung abscess development associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a rare complication, with only half a dozen primary cases having been reported in the literature. We present the case of a patient with Waldenström's macroglobulinemia who developed a lung abscess subsequent to a primary SARS-CoV-2 infection. We present a 63-year-old male patient with SARS-CoV-2 infection and a history of Waldenström's macroglobulinemia who developed a cavitating intraparenchymal lung abscess with an air-fluid level in his right lower lobe two weeks following admission to hospital. The patient became septic and developed acute respiratory failure requiring mechanical ventilation and intensive care. He was managed with broad-spectrum antibiotic therapy and aspiration drainage, but unfortunately due to his severe clinical condition died 20 days after his initial admission. The development of a lung abscess in patients with COVID-19, although rare, can be quite compromising and even prove fatal, especially in immunocompromised patients. Clinicians should be aware of this potential complication.

Background: Bloodstream infections (BSI) caused by highly resistant pathogens in non-ICU COVID-19 departments pose important challenges. Methods: We performed a comparative analysis of incidence and microbial epidemiology of BSI in COVID-19 vs. non-COVID-19, non-ICU departments between 1 September 2020-31 October 2021. Risk factors for BSI and its impact on outcome were evaluated by a case-control study which included COVID-19 patients with/without BSI. Results: Forty out of 1985 COVID-19 patients developed BSI. The mean monthly incidence/100 admissions was 2.015 in COVID-19 and 1.742 in non-COVID-19 departments. Enterococcus and Candida isolates predominated in the COVID-19 group (p < 0.001 and p = 0.018, respectively). All Acinetobacter baumannii isolates were carbapenem-resistant (CR). In the COVID-19 group, 33.3% of Klebsiella pneumoniae was CR, 50% of Escherichia coli produced ESBL and 19% of Enterococcus spp. were VRE vs. 74.5%, 26.1% and 8.8% in the non-COVID-19 group, respectively. BSI was associated with prior hospitalization (p = 0.003), >2 comorbidities (p < 0.001), central venous catheter (p = 0.015), severe SARS-CoV-2 pneumonia and lack of COVID-19 vaccination (p < 0.001). In the multivariate regression model also including age and multiple comorbidities, only BSI was significantly associated with adverse in-hospital outcome [OR (CI95%): 21.47 (3.86−119.21), p < 0.001]. Conclusions: BSI complicates unvaccinated patients with severe SARS-CoV-2 pneumonia and increases mortality. BSI pathogens and resistance profiles differ among COVID-19/non-COVID-19 departments, suggesting various routes of pathogen acquisition.

Importance: Severe acute respiratory syndrome coronavirus 2 infection has evolved into a global pandemic. Low-dose colchicine combines anti-inflammatory action with a favorable safety profile., Objective: To evaluate the effect of treatment with colchicine on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19)., Design, Setting, and Participants: In this prospective, open-label, randomized clinical trial (the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention), 105 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from April 3 to April 27, 2020, to either standard medical treatment or colchicine with standard medical treatment. The study took place in 16 tertiary hospitals in Greece., Intervention: Colchicine administration (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg twice daily) with standard medical treatment for as long as 3 weeks., Main Outcomes and Measures: Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death. Secondary end points were (1) the percentage of participants requiring mechanical ventilation, (2) all-cause mortality, and (3) number, type, severity, and seriousness of adverse events. The primary efficacy analysis was performed on an intention-to-treat basis., Results: A total of 105 patients were evaluated (61 [58.1%] men; median [interquartile range] age, 64 [54-76] years) with 50 (47.6%) randomized to the control group and 55 (52.4%) to the colchicine group. Median (interquartile range) peak high-sensitivity cardiac troponin values were 0.0112 (0.0043-0.0093) ng/mL in the control group and 0.008 (0.004-0.0135) ng/mL in the colchicine group (P = .34). Median (interquartile range) maximum C-reactive protein levels were 4.5 (1.4-8.9) mg/dL vs 3.1 (0.8-9.8) mg/dL (P = .73), respectively. The clinical primary end point rate was 14.0% in the control group (7 of 50 patients) and 1.8% in the colchicine group (1 of 55 patients) (odds ratio, 0.11; 95% CI, 0.01-0.96; P = .02). Mean (SD) event-free survival time was 18.6 (0.83) days the in the control group vs 20.7 (0.31) in the colchicine group (log rank P = .03). Adverse events were similar in the 2 groups, except for diarrhea, which was more frequent with colchicine group than the control group (25 patients [45.5%] vs 9 patients [18.0%]; P = .003)., Conclusions and Relevance: In this randomized clinical trial, participants who received colchicine had statistically significantly improved time to clinical deterioration. There were no significant differences in high-sensitivity cardiac troponin or C-reactive protein levels. These findings should be interpreted with caution., Trial Registration: ClinicalTrials.gov Identifier: NCT04326790.

Authors sought to compare the efficacy of monotherapy versus combination antihypertensive therapy in elderly patients. Patients in this study, aged 65 to 85 years, were divided into 4 groups and entered an 8-week treatment period. First group: 22 patients, amlodipine 5 mg/d increasing to 10 mg; second: 20 patients, eprosartan 600 mg/d increasing to 600 mg twice a day; third: 21 patients, amlodipine 5 mg/d and indapamide 2.5 mg/d, increasing amlodipine to 10 mg/d; fourth: 23 patients, imidapril 10 mg/d and indapamide 2.5 mg/d, imidapril doubled to 20 mg/d. A greater drop in systolic and in diastolic blood pressure was obtained by combination of amlodipine and indapamide compared with amlodipine or eprosartan monotherapy. Imidapril and indapamide showed similar efficacy compared with eprosartan monotherapy but not with amlodipine monotherapy. Amlodipine and indapamide appeared more effective than imidapril and indapamide in diastolic blood pressure. Combination treatment with amlodipine and indapamide or imidapril and indapamide effectively reduces blood pressure in elderly patients with essential hypertension.