Enhancing pathogen description and antibiotic regimen selection in community-acquired pneumonia through RT-qPCR assays.

Background: Adults with community-acquired pneumonia (CAP) in China suffer high morbidity. CAP is caused by a multitude of pathogens; however, pathogen-directed clinical symptoms are often lacking. Therefore, patients lacking an accurate microbiological diagnosis are administered with empirical antimicrobials. Methods: We collected bronchoalveolar lavage fluid, as well as clinical and laboratory data from 650 adult patients with CAP admitted to three hospitals in Hubei, Sichuan, and Zhejiang provinces in China. Specimens were cultured and tested using real-time reverse transcription qPCR (RT-qPCR) assays for the presence of 42 respiratory bacteria and viruses. CAP was investigated with respect to regions, genders, and age and patterns of infections or co-infections. Employing clinical guidelines adapted for diagnosis, we assessed retrospectively the appropriate pathogen-directed therapy and compared it with the initial empirical therapies. Results: Our study identified that 21.38% (139/650) of the patients were classified as having Severe CAP (S-CAP), with a higher prevalence among males, older adults, and during the warm season. Bacterial pathogens were detected in 35.53% (231/650) of cases. K. pneumoniae, H. influenzae, and S. aureus were the most prevalent bacteria across different demographics and regions. Viral pathogens were found in 48.76% (317/650) of patients Epstein-Barr, Human rhinovirus, and Cytomegalovirus were the most common viruses. Co-infections were present in 24.31% (158/650) of cases, with viral-bacterial co-infections being the most frequent. The RT-qPCR demonstrated significantly higher detection rates for key pathogens compared to standard culture methods. It showed potential in optimizing antimicrobial prescriptions by allowing for de-escalation in 18.30% (95/518) of patients, among which reducing the number of excessive antibiotics mainly comprised decreasing the use of 2nd or 3rd generation cephalosporins (5.79%, 30/518) and ß-lactamase inhibitor combinations. Conclusion: The study highlights the significant burden of S-CAP, particularly among specific demographics and seasons. The prevalence of bacterial and viral pathogens, along with the high rate of co-infections, emphasizes the need for comprehensive diagnostic approaches. The RT-qPCR assays emerge as a superior diagnostic tool, offering enhanced pathogen detection capabilities and facilitating more precise antimicrobial therapy. This could lead to improved patient outcomes and contribute to the rational use of antimicrobials, addressing the growing concern of antibiotic resistance.

Dynamics of platelet parameters in children with severe community-acquired pneumonia between viral and bacterial infections.

Background: Changes in platelet parameters may vary according to the different pathogens. However, little is known about the differences in platelet parameters in children with severe community-acquired pneumonia (CAP) children of viral and bacterial infections. Methods: This was a single-center retrospective study that included 156 children with severe CAP. Dynamic changes in platelet parameters, including platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW) and plateletcrit (PCT), were recorded at 24 h, 48 h, 72 h, and day 7 of admission, as well as at discharge. Results: At 72 h of admission, PLT in the viral infection group was significantly lower than that in the bacterial infection and bacterial and viral coinfections group. Meanwhile, the curve of changes in PLT (ΔPLT) in the viral infection group was clearly separated from the other two groups at this time point. Receiver operating characteristic (ROC) analysis showed that PLT at 72 h of admission could assist in distinguishing bacterial and viral infections in severe pneumonia children with the area under curve (AUC) value of 0.683 [95% confidence interval (CI): 0.561-0.805, P=0.007]. However, its sensitivity and specificity were not high, at 68% and 65%, respectively. Conclusions: Although the diagnostic value of platelet parameters in bacterial and viral infection in children with severe CAP is limited, they are still expected to be combined with other indicators to provide a reference for timely treatment.

Machine learning-based identification of cuproptosis-related markers and immune infiltration in severe community-acquired pneumonia.

BACKGROUND: Severe community-acquired pneumonia (SCAP) is one of the world's most common diseases and a major etiology of acute respiratory distress syndrome (ARDS). Cuproptosis is a novel form of regulated cell death that can occur in various diseases. METHODS: Our study explored the degree of immune cell infiltration during the onset of severe CAP and identified potential biomarkers related to cuproptosis. Gene expression matrix was obtained from GEO database indexed GSE196399. Three machine learning algorithms were applied: The least absolute shrinkage and selection operator (LASSO), the random forest, and the support vector machine-recursive feature elimination (SVM-RFE). Immune cell infiltration was quantified by single-sample gene set enrichment analysis (ssGSEA) scoring. Nomogram was constructed to verify the applicability of using cuproptosis-related genes to predict the onset of severe CAP and its deterioration toward ARDS. RESULTS: Nine cuproptosis-related genes were differentially expressed between the severe CAP group and the control group: ATP7B, DBT, DLAT, DLD, FDX1, GCSH, LIAS, LIPT1, and SLC31A1. All 13 cuproptosis-related genes were involved in immune cell infiltration. A three-gene diagnostic model was constructed to predict the onset of severe CAP: GCSH, DLD, and LIPT1. CONCLUSION: Our study confirmed the involvement of the newly discovered cuproptosis-related genes in the progression of SCAP.

Impact of Molecular Syndromic Diagnosis of Severe Pneumonia in the Management of Critically Ill Patients.

The impact of syndromic molecular diagnosis in the management of nosocomial infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens has been incompletely characterized. We evaluated the performance of a molecular syndromic platform (BioFire FilmArray-Pneumonia plus Panel) in patients with pneumonia in the intensive care unit (ICU) of a University Hospital in Greece over a 2-year period. We evaluated 79 consecutive patients diagnosed with pneumonia in the ICU (2018-2020), including 55 patients with ventilator associated pneumonia (VAP). We included 40 control patients diagnosed with pneumonia in the ICU the year before the study (2017-2018). We identified 16 cases of VAP due to XDR bacterial pathogens. We found an excellent agreement (89.4% 76/85 reported results) between the results of syndromic platform and conventional cultures of tracheal aspirates. The molecular syndromic test significantly improved time to diagnosis versus conventional culture (3.5 h vs 72 h, P < 0.0001), and identified new pathogens not detected by cultures in 49% of the cases. However, three cases of pneumonia with targets not included in the molecular platform, were not detected. Implementation of the molecular syndromic facilitated treatment modification from broad to narrow spectrum antimicrobial therapy, resulting in significant reductions in antibiotic consumption in the study group compared to the control group, without a negative impact in patient outcome. The implementation of syndromic molecular diagnosis in critically ill patients with pneumonia is associated with timely and improved diagnosis and has significant impact on reduction of antibiotic consumption. IMPORTANCE The impact of syndromic molecular diagnosis in the management of nosocomial infections caused by MDR/XDR pathogens has been incompletely characterized. We evaluated the performance of a molecular syndromic platform (BioFire FilmArray -Pneumonia plus Panel) in 79 patients with pneumonia in the intensive care unit (ICU) of a University Hospital in Greece over a 2-year period (2018-2020) compared to 40 control patients diagnosed with pneumonia in the ICU the year before the study (2017-2018). Importantly, implementation of syndromic pneumonia panel improved time to diagnosis, identified new pathogens not detected by cultures in 49% of the cases and resulted in a significant reduction in antibiotic consumption compared to the year before initiation of the study without a negative impact in mortality of patients. Collectively, our study demonstrates the positive value of PCR syndromic testing in the management of pneumonia in ICUs high rates of MDR/XDR nosocomial pathogens.

Pharmacokinetic/Pharmacodynamic Target Attainment Based on Measured versus Predicted Unbound Ceftriaxone Concentrations in Critically Ill Patients with Pneumonia: An Observational Cohort Study.

The impact of ceftriaxone pharmacokinetic alterations on protein binding and PK/PD target attainment still remains unclear. We evaluated pharmacokinetic/pharmacodynamic (PK/PD) target attainment of unbound ceftriaxone in critically ill patients with severe community-acquired pneumonia (CAP). Besides, we evaluated the accuracy of predicted vs. measured unbound ceftriaxone concentrations, and its impact on PK/PD target attainment. A prospective observational cohort study was carried out in adult patients admitted to the intensive care unit with severe CAP. Ceftriaxone 2 g q24h intermittent infusion was administered to all patients. Successful PK/PD target attainment was defined as unbound trough concentrations above 1 or 4 mg/L throughout the whole dosing interval. Acceptable overall PK/PD target attainment was defined as successful target attainment in ≥90% of all dosing intervals. Measured unbound ceftriaxone concentrations (CEFu) were compared to unbound concentrations predicted from various protein binding models. Thirty-one patients were included. The 1 mg/L and 4 mg/L targets were reached in 26/32 (81%) and 15/32 (47%) trough samples, respectively. Increased renal function was associated with the failure to attain both PK/PD targets. Unbound ceftriaxone concentrations predicted by the protein binding model developed in the present study showed acceptable bias and precision and had no major impact on PK/PD target attainment. We showed suboptimal (i.e., <90%) unbound ceftriaxone PK/PD target attainment when using a standard 2 g q24h dosing regimen in critically ill patients with severe CAP. Renal function was the major driver for the failure to attain the predefined targets, in accordance with results found in general and septic ICU patients. Interestingly, CEFu was reliably predicted from CEFt without major impact on clinical decisions regarding PK/PD target attainment. This suggests that, when carefully selecting a protein binding model, CEFu does not need to be measured. As a result, the turn-around time and cost for ceftriaxone quantification can be substantially reduced.

Management of Pneumonia in the Pediatric Critical Care Unit: An Area for Antimicrobial Stewardship.

BACKGROUND: Pediatric pneumonia is one of the most common causes of childhood infection requiring hospitalization and is a substantial driver of antimicrobial use among hospitalized children. About 12-20% of pediatric patients hospitalized with community-acquired pneumonia (CAP) require critical care. Additionally, nosocomial pneumonias (i.e. hospital-acquired and ventilator- associated pneumonias) are responsible for 15-53% of hospital-associated infections and are the most common indication for empiric antibiotics in the pediatric intensive care unit. OBJECTIVE: Respiratory infections, especially pneumonias, are a strong area for antimicrobial stewardship program (ASP) interventions, as they have been shown to improve patient outcomes while reducing inappropriate antimicrobial use, antimicrobial resistance, and overall costs. METHOD: Optimizing the selection of appropriate antimicrobial therapies is difficult for pediatric pneumonias because of the ill-defined definitive diagnostic criteria and difficulty differentiating between viral and bacterial etiology. RESULT: The aim of this review is to highlight the role of antimicrobial stewardship efforts in the treatment of pneumonias in critically ill children by discussing the emerging role of diagnostic criteria, the etiology of disease, appropriate targeted antimicrobial selection, and the optimization of antibiotic dosing and pharmacodynamic targets.

Corticosteroid therapy for severe community-acquired pneumonia: a meta-analysis.

BACKGROUND: The debate about the efficacy of corticosteroids in the treatment of severe community-acquired pneumonia (CAP) is still a longstanding dilemma. We performed a meta-analysis including 4 randomized controlled trials (RCTs) to evaluate the effect of corticosteroids on the treatment of severe CAP in adults. METHODS: We performed a systematic review of published and unpublished clinical trials. Databases, including PubMed, Embase, CINAHL, and Cochrane (from their establishment to July 2013), were searched for relevant articles. Only RCTs of corticosteroids as adjunctive therapy in adult patients with severe CAP were selected. RESULTS: Four trials enrolling 264 patients with severe CAP were included. Use of corticosteroids significantly reduced hospital mortality compared with conventional therapy and placebo (Peto odds ratio = 0.39, 95% CI 0.17-0.90). The quality of the evidence underlying the pooled estimate of effect on hospital mortality was low, downgraded for inconsistency and imprecision. CONCLUSIONS: On the basis of the current limited evidence, we suggest that, although corticosteroid therapy may reduce mortality and improve the prognosis of adult patients with severe CAP, the results should be interpreted with caution due to the instability of pooled estimates. Reliable treatment recommendations will be raised only when large sufficiently powered multi-center RCTs are conducted.