Moving Beyond Mortality: Development and Application of a Desirability of Outcome Ranking (DOOR) Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.

BACKGROUND: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are frequently caused by multidrug-resistant organisms. Patient-centered endpoints in clinical trials are needed to develop new antibiotics for HABP/VABP. Desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, and interpretation of clinical trials based on a patient-centered, benefit-risk evaluation. METHODS: A multidisciplinary committee created an infectious diseases DOOR endpoint customized for HABP/VABP, incorporating infectious complications, serious adverse events, and mortality. We applied this to 2 previously completed, large randomized controlled trials for HABP/VABP. ZEPHyR compared vancomycin to linezolid and VITAL compared linezolid to tedizolid. For each trial, we evaluated the DOOR distribution and probability, including DOOR component and partial credit analyses. We also applied DOOR in subgroup analyses. RESULTS: In both trials, the HABP/VABP DOOR demonstrated similar overall clinical outcomes between treatment groups. In ZEPHyR, the probability that a participant treated with linezolid would have a more desirable outcome than a participant treated with vancomycin was 50.2% (95% confidence interval [CI], 45.1%--55.3%). In VITAL, the probability that a participant treated with tedizolid would have a more desirable outcome than a participant treated with linezolid was 48.7% (95% CI, 44.8%-52.6%). The DOOR component analysis revealed that participants treated with tedizolid had a less desirable outcome than those treated with linezolid when considering clinical response alone. However, participants with decreased renal function had improved overall outcomes with tedizolid. CONCLUSIONS: The HABP/VABP DOOR provided more granular information about clinical outcomes than is typically presented in clinical trials. HABP/VABP trials would benefit from prospectively using DOOR.

Severe Human Parainfluenza Virus Community- and Healthcare-Acquired Pneumonia in Adults at Tertiary Hospital, Seoul, South Korea, 2010-2019.

The characteristics of severe human parainfluenza virus (HPIV)-associated pneumonia in adults have not been well evaluated. We investigated epidemiologic and clinical characteristics of 143 patients with severe HPIV-associated pneumonia during 2010-2019. HPIV was the most common cause (25.2%) of severe virus-associated hospital-acquired pneumonia and the third most common cause (15.7%) of severe virus-associated community-acquired pneumonia. Hematologic malignancy (35.0%), diabetes mellitus (23.8%), and structural lung disease (21.0%) were common underlying conditions. Co-infections occurred in 54.5% of patients admitted to an intensive care unit. The 90-day mortality rate for HPIV-associated pneumonia was comparable to that for severe influenza virus-associated pneumonia (55.2% vs. 48.4%; p = 0.22). Ribavirin treatment was not associated with lower mortality rates. Fungal co-infections were associated with 82.4% of deaths. Clinicians should consider the possibility of pathogenic co-infections in patients with HPIV-associated pneumonia. Contact precautions and environmental cleaning are crucial to prevent HPIV transmission in hospital settings.

Single-drug versus combination antimicrobial therapy in critically ill patients with hospital-acquired pneumonia and ventilator-associated pneumonia due to Gram-negative pathogens: a multicenter retrospective cohort study.

KEY MESSAGES: In this study including 391 critically ill patients with nosocomial pneumonia due to Gram-negative pathogens, combination therapy was not associated with a reduced hazard of death at Day 28 or a greater likelihood of clinical cure at Day 14. No over-risk of AKI was observed in patients receiving combination therapy. BACKGROUND: The benefits and harms of combination antimicrobial therapy remain controversial in critically ill patients with hospital-acquired pneumonia (HAP), ventilated HAP (vHAP) or ventilator-associated pneumonia (VAP) involving Gram-negative bacteria. METHODS: We included all patients in the prospective multicenter OutcomeRea database with a first HAP, vHAP or VAP due to a single Gram-negative bacterium and treated with initial adequate single-drug or combination therapy. The primary endpoint was Day-28 all-cause mortality. Secondary endpoints were clinical cure rate at Day 14 and a composite outcome of death or treatment-emergent acute kidney injury (AKI) at Day 7. The average effects of combination therapy on the study endpoints were investigated through inverse probability of treatment-weighted regression and multivariable regression models. Subgroups analyses were performed according to the resistance phenotype of the causative pathogens (multidrug-resistant or not), the pivotal (carbapenems or others) and companion (aminoglycosides/polymyxins or others) drug classes, the duration of combination therapy (< 3 or ≥ 3 days), the SOFA score value at pneumonia onset (< 7 or ≥ 7 points), and in patients with pneumonia due to non-fermenting Gram-negative bacteria, pneumonia-related bloodstream infection, or septic shock. RESULTS: Among the 391 included patients, 151 (38.6%) received single-drug therapy and 240 (61.4%) received combination therapy. VAP (overall, 67.3%), vHAP (16.4%) and HAP (16.4%) were equally distributed in the two groups. All-cause mortality rates at Day 28 (overall, 31.2%), clinical cure rate at Day 14 (43.7%) and the rate of death or AKI at Day 7 (41.2%) did not significantly differ between the groups. In inverse probability of treatment-weighted analyses, combination therapy was not independently associated with the likelihood of all-cause death at Day 28 (adjusted odd ratio [aOR], 1.14; 95% confidence interval [CI] 0.73-1.77; P = 0.56), clinical cure at Day 14 (aOR, 0.79; 95% CI 0.53-1.20; P = 0.27) or death or AKI at Day 7 (aOR, 1.07; 95% CI 0.71-1.63; P = 0.73). Multivariable regression models and subgroup analyses provided similar results. CONCLUSIONS: Initial combination therapy exerts no independent impact on Day-28 mortality, clinical cure rate at Day 14, and the hazard of death or AKI at Day 7 in critically ill patients with mono-bacterial HAP, vHAP or VAP due to Gram-negative bacteria.

Efficacy and safety of lascufloxacin for nursing- and healthcare-associated pneumonia: A single-arm, open-label clinical trial.

BACKGROUND: Nursing- and healthcare-associated pneumonia (NHCAP) constitutes most of the pneumonia in elderly patients including aspiration pneumonia in Japan. Lascufloxacin (LSFX) possesses broad antibacterial activity against respiratory pathogens, such as Streptococcus spp. And anaerobes inside the oral cavity. However, the efficacy and safety of LSFX in NHCAP treatment remains unknown. We aimed to evaluate the efficacy and safety of LSFX tablets in the treatment of patients with NHCAP. METHODS: In this single-arm, open-label, uncontrolled study, LSFX was administered to patients with NHCAP at 24 facilities. The study participants were orally administered 75 mg LSFX once daily for 7 days. The primary endpoint was the clinical efficacy at the time of test of cure (TOC). The secondary endpoints included clinical efficacy at the time of end of treatment (EOT), early clinical efficacy, microbiological efficacy, and safety analysis. RESULT: During the study period, 75 patients provided written informed consent to participate and were included. Finally, 56 and 71 patients were eligible for clinical efficacy and safety analyses, respectively. The median age of the patients was significantly high at 86 years. All patients were classified as having moderate disease severity using the A-DROP scoring system. LSFX tablets demonstrated high efficacy rates of 78.6 % at TOC and 89.3 % at EOT. The risk factors for resistant bacteria or aspiration pneumonia did not affect clinical efficacy. No severe adverse events associated with the study drugs were observed. CONCLUSION: Oral LSFX is an acceptable treatment option for moderate NHCAP in elderly patients who can take oral medications.

[Selected novelties for hospital based internal medicine]. / Nouveautés en médecine interne hospitalière.

In this selective overview of articles, we describe new concepts, therapeutic measures and pharmacological agents that may modify current practice in clinical internal medicine. Novelties for the management of cardiovascular disease, such as heart failure, hypoxemic respiratory failure, nosocomial pneumonia and certain allergies are discussed.

À travers quelques articles et études choisis, cet article décrit de nouveaux concepts, mesures thérapeutiques et agents pharmacologiques pouvant modifier les pratiques courantes en médecine interne. Des notions concernant la gestion de maladies cardiovasculaires telles que l'insuffisance cardiaque, les décompensations respiratoires hypoxémiques, les pneumonies nosocomiales et la gestion d'allergies y figurent au premier plan.

Respiratory metagenomics: route to routine service.

PURPOSE OF REVIEW: The coronavirus disease 2019 pandemic demonstrated broad utility of pathogen sequencing with rapid methodological progress alongside global distribution of sequencing infrastructure. This review considers implications for now moving clinical metagenomics into routine service, with respiratory metagenomics as the exemplar use-case. RECENT FINDINGS: Respiratory metagenomic workflows have completed proof-of-concept, providing organism identification and many genotypic antimicrobial resistance determinants from clinical samples in <6 h. This enables rapid escalation or de-escalation of empiric therapy for patient benefit and reducing selection of antimicrobial resistance, with genomic-typing available in the same time-frame. Attention is now focussed on demonstrating clinical, health-economic, accreditation, and regulatory requirements. More fundamentally, pathogen sequencing challenges the traditional culture-orientated time frame of microbiology laboratories, which through automation and centralisation risks becoming increasingly separated from the clinical setting. It presents an alternative future where infection experts are brought together around a single genetic output in an acute timeframe, aligning the microbiology target operating model with the wider human genomic and digital strategy. SUMMARY: Pathogen sequencing is a transformational proposition for microbiology laboratories and their infectious diseases, infection control, and public health partners. Healthcare systems that link output from routine clinical metagenomic sequencing, with pandemic and antimicrobial resistance surveillance, will create valuable tools for protecting their population against future infectious diseases threats.

In vivo pharmacokinetic/pharmacodynamic evaluation of cefepime/taniborbactam combination against cefepime-non-susceptible Enterobacterales and Pseudomonas aeruginosa in a murine pneumonia model.

BACKGROUND: Cefepime/taniborbactam is a cephalosporin/bicyclic boronate ß-lactamase inhibitor combination in clinical development for nosocomial pneumonia due to MDR Gram-negative bacteria. A murine pneumonia model was used to characterize cefepime/taniborbactam in vivo pharmacodynamics against Enterobacterales and Pseudomonas aeruginosa strains. METHODS: Clinical cefepime-non-susceptible Enterobacterales and P. aeruginosa strains expressing serine carbapenemases and/or other cefepime-hydrolysing ß-lactamases with cefepime/taniborbactam combination MICs of 0.12-16 mg/L were used. Cefepime and taniborbactam human-simulated regimens equivalent to clinical doses (i.e. 2/0.5 g q8h) were established in the pneumonia model. The in vivo activity of the cefepime human-simulated regimen given alone or concomitantly with escalating taniborbactam exposures against eight Enterobacterales and four P. aeruginosa strains was assessed. Taniborbactam pharmacokinetics were evaluated to determine systemic exposures of regimens used; taniborbactam fAUC0-24/MIC values required for efficacy were estimated using the Hill equation. In addition, the in vivo activity of the cefepime/taniborbactam combination human-simulated regimen was assessed against 18 strains. RESULTS: Among Enterobacterales, median taniborbactam fAUC0-24/MIC values associated with stasis and 1 log kill were 0.96 and 4.03, respectively, while for P. aeruginosa, requirements were 1.35 and 3.02 for stasis and 1 log kill, respectively. The cefepime/taniborbactam human-simulated regimen produced >2 log kill in 14/18 strains and >1 log kill in 18/18 strains. CONCLUSIONS: Cefepime/taniborbactam produced marked in vivo bactericidal activity against cefepime-non-susceptible Enterobacterales and P. aeruginosa isolates with cefepime/taniborbactam MICs up to and including 16 mg/L in the pneumonia model. Assessments of the probability of clinical attainment of the identified targets should be undertaken to support the selected cefepime/taniborbactam dose for treatment of nosocomial pneumonia.

A 600 mg of fixed-dose linezolid in renally impaired patients versus 15 mg/kg intermittent dose-optimized vancomycin in renally non-impaired patients: A single centre retrospective analysis for adult patients with hospital-acquired pneumonia due to methicillin-resistant Staphylococcus aureus.

OBJECTIVES: Both linezolid and vancomycin are approved by USFDA and IDSA guidelines for the management of nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) in clinical practice. Baseline creatinine clearance is the criterion for prescribing vancomycin or linezolid for hospital-acquired pneumonia in our institution. However, patients with renal function impairment are far more difficult to manage in intensive care. Thus, the objectives of the study were to compare the clinical efficacy and safety of 600 mg of fixed-dose linezolid with intermittent dose-optimised vancomycin in hospital-acquired pneumonia due to MRSA and to evaluate parameters of clinical cure. METHODS: Analysis of a review of patients' charts. Patients with creatinine clearance <80 ml/min received 600 mg linezolid/12 h (n = 139, LN cohort), and patients with creatinine clearance ≥80 ml/min received intravenous 15 mg/kg vancomycin/12 h for 1-2 weeks consecutively or 3 weeks in case of bacteremia (n = 152, VC cohort) for management of hospital-acquired pneumonia due to MRSA. RESULTS: A 59% of patients from the LN cohort and 47% of patients from the VC cohort were clinically cured. Administration of systemic steroids (p = 0.0412) and ≥ 80 ml/min creatinine clearance (p = 0.0498) were the independent parameters for the clinical cure of patients. Nephrotoxicity was higher among patients of the VC cohort than the LN cohort (p = 0.0464). Treatment failed in 41% of patients from the LN cohort and in 53% of patients from the VC cohort (p = 0.0200). CONCLUSIONS: A 600 mg of fixed-dose linezolid is an ideal alternative to intermittent dose-optimised vancomycin for better clinical outcomes for patients with hospital-acquired pneumonia due to MRSA, especially for patients with renal impairment.

Optimization of polymyxin B regimens for the treatment of carbapenem-resistant organism nosocomial pneumonia: a real-world prospective study.

BACKGROUND: Polymyxin B is the first-line therapy for Carbapenem-resistant organism (CRO) nosocomial pneumonia. However, clinical data for its pharmacokinetic/pharmacodynamic (PK/PD) relationship are limited. This study aimed to investigate the relationship between polymyxin B exposure and efficacy for the treatment of CRO pneumonia in critically ill patients, and to optimize the individual dosing regimens. METHODS: Patients treated with polymyxin B for CRO pneumonia were enrolled. Blood samples were assayed using a validated high-performance liquid chromatography-tandem mass spectrometry method. Population PK analysis and Monte Carlo simulation were performed using Phoenix NLME software. Logistic regression analyses and receiver operating characteristic (ROC) curve were employed to identify the significant predictors and PK/PD indices of polymyxin B efficacy. RESULTS: A total of 105 patients were included, and the population PK model was developed based on 295 plasma concentrations. AUCss,24 h/MIC (AOR = 0.97, 95% CI 0.95-0.99, p = 0.009), daily dose (AOR = 0.98, 95% CI 0.97-0.99, p = 0.028), and combination of inhaled polymyxin B (AOR = 0.32, 95% CI 0.11-0.94, p = 0.039) were independent risk factors for polymyxin B efficacy. ROC curve showed that AUCss,24 h/MIC is the most predictive PK/PD index of polymyxin B for the treatment of nosocomial pneumonia caused by CRO, and the optimal cutoff point value was 66.9 in patients receiving combination therapy with another antimicrobial. Model-based simulation suggests that the maintaining daily dose of 75 and 100 mg Q12 h could achieve ≥ 90% PTA of this clinical target at MIC values ≤ 0.5 and 1 mg/L, respectively. For patients unable to achieve the target concentration by intravenous administration, adjunctive inhalation of polymyxin B would be beneficial. CONCLUSIONS: For CRO pneumonia, daily dose of 75 and 100 mg Q12 h was recommended for clinical efficacy. Inhalation of polymyxin B is beneficial for patients who cannot achieve the target concentration by intravenous administration.

Non-ventilator-associated ICU-acquired pneumonia (NV-ICU-AP) in patients with acute exacerbation of COPD: From the French OUTCOMEREA cohort.

BACKGROUND: Non-ventilator-associated ICU-acquired pneumonia (NV-ICU-AP), a nosocomial pneumonia that is not related to invasive mechanical ventilation (IMV), has been less studied than ventilator-associated pneumonia, and never in the context of patients in an ICU for severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD), a common cause of ICU admission. This study aimed to determine the factors associated with NV-ICU-AP occurrence and assess the association between NV-ICU-AP and the outcomes of these patients. METHODS: Data were extracted from the French ICU database, OutcomeRea™. Using survival analyses with competing risk management, we sought the factors associated with the occurrence of NV-ICU-AP. Then we assessed the association between NV-ICU-AP and mortality, intubation rates, and length of stay in the ICU. RESULTS: Of the 844 COPD exacerbations managed in ICUs without immediate IMV, NV-ICU-AP occurred in 42 patients (5%) with an incidence density of 10.8 per 1,000 patient-days. In multivariate analysis, prescription of antibiotics at ICU admission (sHR, 0.45 [0.23; 0.86], p = 0.02) and no decrease in consciousness (sHR, 0.35 [0.16; 0.76]; p < 0.01) were associated with a lower risk of NV-ICU-AP. After adjusting for confounders, NV-ICU-AP was associated with increased 28-day mortality (HR = 3.03 [1.36; 6.73]; p < 0.01), an increased risk of intubation (csHR, 5.00 [2.54; 9.85]; p < 0.01) and with a 10-day increase in ICU length of stay (p < 0.01). CONCLUSION: We found that NV-ICU-AP incidence reached 10.8/1000 patient-days and was associated with increased risks of intubation, 28-day mortality, and longer stay for patients admitted with AECOPD.

Assessment of the pneumonia severity score in community-acquired and nursing and healthcare-associated pneumonia due to COVID-19.

INTRODUCTION: The Japanese Respiratory Society (JRS) pneumonia guidelines recommend simple predictive rules, the A-DROP scoring system, for assessment of the severity of community-acquired pneumonia (CAP) and nursing and healthcare-associated pneumonia (NHCAP). We evaluated whether the A-DROP system can be adapted for assessment of the severity of coronavirus disease 2019 (COVID-19) pneumonia. METHODS: Data from 1141 patients with COVID-19 pneumonia were analyzed, comprising 502 patients observed in the 1st to 3rd wave period, 338 patients in the 4th wave and 301 patients in the 5th wave in Japan. RESULTS: The mortality rate and mechanical ventilation rate were 0% and 1.4% in patients classified with mild disease (A-DROP score, 0 point), 3.2% and 46.7% in those with moderate disease (1 or 2 points), 20.8% and 78.3% with severe disease (3 points), and 55.0% and 100% with extremely severe disease (4 or 5 points), indicating an increase in the mortality and mechanical ventilation rates in accordance with severity (Cochran-Armitage trend test; p = <0.001). This significant relationship between the severity in the A-DROP scoring system and either the mortality rate or mechanical ventilation rate was observed in patients with COVID-19 CAP and NHCAP. In each of the five COVID-19 waves, the same significant relationship was observed. CONCLUSIONS: The mortality rate and mechanical ventilation rate in patients with COVID-19 pneumonia increased depending on severity classified according to the A-DROP scoring system. Our results suggest that the A-DROP scoring system can be adapted for the assessment of severity of COVID-19 CAP and NHCAP.

Clinically defined aspiration pneumonia is an independent risk factor associated with long-term hospital stay: a prospective cohort study.

BACKGROUND: Long-term hospital stay is associated with functional decline in patients with pneumonia, especially in the elderly. Among elderly patients with pneumonia, aspiration pneumonia is a major category. Clinical definition is usually used because it can occur without apparent aspiration episodes. It is still not clear whether a long-term hospital stay is due to aspiration pneumonia itself caused by underlying oropharyngeal dysfunction or simply due to functional decline in elderly patients with multiple comorbidities during acute infection. The aim of this study is to identify whether clinically defined aspiration pneumonia itself was associated with a long-term hospital stay. METHODS: A prospective observational study on community-acquired (CAP) or healthcare-associated pneumonia (HCAP) was conducted from January 2012 through January 2014. Aspiration pneumonia was clinically defined as pneumonia not only occurring in patients after documented aspiration episodes, but also occurring in those with underlying oropharyngeal dysfunction: chronic disturbances of consciousness and/or chronic neuromuscular diseases. We defined thirty-day hospital stay as a long-term hospital stay and compared it with logistic regression analysis. Potential confounders included age, sex, HCAP, body mass index (BMI), long-term bed-ridden state, heart failure, cerebrovascular disorders, dementia, antipsychotics use, hypnotics use, and CURB score which is a clinical prediction tool used to assess the severity, standing for; C (presence of Confusion), U (high blood Urea nitrogen level), R (high Respiratory rate), and B (low Blood pressure). In a sub-analysis, we also explored factors associated with long-term hospital stay in patients with aspiration pneumonia. RESULTS: Of 2,795 patients, 878 (31.4%) had aspiration pneumonia. After adjusting potential confounders, the aspiration pneumonia itself was significantly associated with long-term hospital stay (adjusted odds ratio 1.44; 95% confidence interval 1.09-1.89, p < 0.01), as were higher age, male sex, high CURB score, HCAP, low BMI, heart failure, cerebrovascular disease, and antipsychotics use. Sub-analysis revealed factors associated with long-term hospital stay in the aspiration pneumonia, which included male sex, and multi-lobar chest X-ray involvement. CONCLUSIONS: Clinically defined aspiration pneumonia itself was independently associated with long-term hospital stay. This result could potentially lead to specific rehabilitation strategies for pneumonia patients with underlying oropharyngeal dysfunction.

Can Neutrophils Prevent Nosocomial Pneumonia after Serious Injury?

Nosocomial pneumonia is a leading cause of critical illness and mortality among seriously injured trauma patients. However, the link between injury and the development of nosocomial pneumonia is still not well recognized. Our work strongly suggests that mitochondrial damage-associated molecular patterns (mtDAMPs), especially mitochondrial formyl peptides (mtFPs) released by tissue injury, play a significant role in developing nosocomial pneumonia after a serious injury. Polymorphonuclear leukocytes (neutrophils, PMN) migrate toward the injury site by detecting mtFPs through formyl peptide receptor 1 (FPR1) to fight/contain bacterial infection and clean up debris. Activation of FPR1 by mtFPs enables PMN to reach the injury site; however, at the same time it leads to homo- and heterologous desensitization/internalization of chemokine receptors. Thus, PMN are not responsive to secondary infections, including those from bacteria-infected lungs. This may enable a progression of bacterial growth in the lungs and nosocomial pneumonia. We propose that the intratracheal application of exogenously isolated PMN may prevent pneumonia coupled with a serious injury.

Rapid Point-of-Care PCR Testing of Drug-Resistant Strains on Endotracheal Aspirate Samples: A Repurposed Effective Tool in the Stepwise Approach of Healthcare-Acquired Pneumonia-A Pilot Study.

Healthcare-associated pneumonia (HCAP) is a common nosocomial infection with high morbidity and mortality. Culture-based detection of the etiologic agent and drug susceptibility is time-consuming, potentially leading to the inadequate use of broad-spectrum empirical antibiotic regimens. The aim was to evaluate the diagnostic capabilities of rapid point-of-care multiplex polymerase chain reaction (PCR) assays from the endotracheal aspirate of critically ill patients with HCAP. A consecutive series of 29 intensive care unit (ICU) patients with HCAP and a control group of 28 patients undergoing elective surgical procedures were enrolled in the study. The results of the PCR assays were compared to the culture-based gold standard. The overall accuracy of the PCR assays was 95.12%, with a sensitivity of 92.31% and a specificity of 97.67%. The median time was 90 min for the rapid PCR tests (p < 0.001), while for the first preliminary results of the cultures, it was 48 h (46-72). The overall accuracy for rapid PCR testing in suggesting an adequate antibiotic adjustment was 82.98% (95% CI 69.19-92.35%), with a specificity of 90% (95% CI 55.50-99.75%), a positive predictive value of 96.77% (95% CI 83.30-99.92%), and a negative predictive value of 56.25 (95% CII 29.88-80.25%). This method of rapid point-of-care PCR could effectively guide antimicrobial stewardship in patients with healthcare-acquired pneumonia.

A recalibrated prediction model can identify level-1 trauma patients at risk of nosocomial pneumonia.

INTRODUCTION: Nosocomial pneumonia has poor prognosis in hospitalized trauma patients. Croce et al. published a model to predict post-traumatic ventilator-associated pneumonia, which achieved high discrimination and reasonable sensitivity. We aimed to externally validate Croce's model to predict nosocomial pneumonia in patients admitted to a Dutch level-1 trauma center. MATERIALS AND METHODS: This retrospective study included all trauma patients (≥ 16y) admitted for > 24 h to our level-1 trauma center in 2017. Exclusion criteria were pneumonia or antibiotic treatment upon hospital admission, treatment elsewhere > 24 h, or death < 48 h. Croce's model used eight clinical variables-on trauma severity and treatment, available in the emergency department-to predict nosocomial pneumonia risk. The model's predictive performance was assessed through discrimination and calibration before and after re-estimating the model's coefficients. In sensitivity analysis, the model was updated using Ridge regression. RESULTS: 809 Patients were included (median age 51y, 67% male, 97% blunt trauma), of whom 86 (11%) developed nosocomial pneumonia. Pneumonia patients were older, more severely injured, and underwent more emergent interventions. Croce's model showed good discrimination (AUC 0.83, 95% CI 0.79-0.87), yet predicted probabilities were too low (mean predicted risk 6.4%), and calibration was suboptimal (calibration slope 0.63). After full model recalibration, discrimination (AUC 0.84, 95% CI 0.80-0.88) and calibration improved. Adding age to the model increased the AUC to 0.87 (95% CI 0.84-0.91). Prediction parameters were similar after the models were updated using Ridge regression. CONCLUSION: The externally validated and intercept-recalibrated models show good discrimination and have the potential to predict nosocomial pneumonia. At this time, clinicians could apply these models to identify high-risk patients, increase patient monitoring, and initiate preventative measures. Recalibration of Croce's model improved the predictive performance (discrimination and calibration). The recalibrated model provides a further basis for nosocomial pneumonia prediction in level-1 trauma patients. Several models are accessible via an online tool. LEVEL OF EVIDENCE: Level III, Prognostic/Epidemiological Study.

[Diagnosis and antibiotic therapy of nosocomial pneumonia in adults: from recommendations to real practice. A review].

Nosocomial pneumonia is a healthcare-associated infection with significant consequences for the patient and the healthcare system. The efficacy of treatment significantly depends on the timeliness and adequacy of the antibiotic therapy regimen. The growth of resistance of gram-negative pathogens of nosocomial pneumonia to antimicrobial agents increases the risk of prescribing inadequate empirical therapy, which worsens the results of patient treatment. Identification of risk factors for infection with multidrug-resistant microorganisms, careful local microbiological monitoring with detection of resistance mechanisms, implementation of antimicrobial therapy control strategy and use of rational combinations of antibacterial drugs are of great importance. In addition, the importance of using new drugs with activity against carbapenem-resistant strains, including ceftazidime/aviabactam, must be understood. This review outlines the current data on the etiology, features of diagnosis and antibacterial therapy of nosocomial pneumonia.

ORAL CARE TO REDUCE COSTS AND INCREASE CLINICAL EFFECTIVENESS IN PREVENTING NOSOCOMIAL PNEUMONIA: A SYSTEMATIC REVIEW.

BACKGROUND: Nosocomial pneumonia ranks among the top 5 diseases that lead to additional financial costs due to hospitalization. This study aimed to evaluate the cost of oral care and its clinical effectiveness in preventing pneumonia in a systematic review. METHODS: The search was conducted in the following databases: PubMed, Cochrane Library, Web of Sciences, Scopus, CINAHL, LILACS, complemented by gray literature and manual search, between January/2021 and August/2022. Two independent reviewers extracted data from the selected articles, individually analyzing each study's quality using the BMJ Drummond checklist. The data were tabulated by clinical or economic type. RESULTS: A total of 3,130 articles were identified; the eligibility criteria were verified, and 12 articles were selected for qualitative analysis. Only 2 achieved satisfactory quality assessment for economic analysis studies. There was heterogeneity between clinical and economic data. Eleven of the 12 studies reported a decrease in the incidence of nosocomial pneumonia following the application of oral care practices. Most authors reported a reduction in the estimate of individual costs, followed by a decrease in the need for antibiotic therapy. The costs of oral care were very low compared to other costs. CONCLUSIONS: Despite the low level of evidence in the literature, heterogeneity and poor quality of the selected studies, most studies concluded that oral care seemed to lead to reduced costs in hospital expenses for treating pneumonia.

Using Machine Learning To Define the Impact of Beta-Lactam Early and Cumulative Target Attainment on Outcomes in Intensive Care Unit Patients with Hospital-Acquired and Ventilator-Associated Pneumonia.

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common intensive care unit (ICU) infections. We aimed to evaluate the association of early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters with therapy outcomes in pneumonia. Adult ICU patients who received cefepime, meropenem, or piperacillin-tazobactam for HAP or VAP and had its concentration measured were included. Beta-lactam exposure was generated for every patient for the entire duration of therapy, and the time free concentration remained above the MIC (fT>MIC) and the time free concentration remained above four multiples of the MIC (fT>4×MIC) were calculated for time frames of 0 to 24 h, 0 to 10 days, and day 0 to end of therapy. Regression analyses and machine learning were performed to evaluate the impact of PK/PD on therapy outcomes. A total of 735 patients and 840 HAP/VAP episodes (47% HAP) were included. The mean age was 56 years, and the mean weight was 80 kg. Sequential organ failure assessment (SOFA), hemodialysis, age, and weight were significantly associated with the clinical outcomes and kept in the final model. In the full cohort including all pneumonia episodes, PK/PD parameters at different time windows were associated with a favorable composite outcome, clinical cure, and mechanical ventilation (MV)-free days. In patients who had positive cultures and reported MICs, almost all PK/PD parameters were significant predictors of therapy outcomes. In the machine learning analysis, PK/PD parameters ranked high and were the primary overall predictors of clinical cure. Early target attainment and cumulative target attainment have a great impact on pneumonia outcomes. Beta-lactam exposure should be optimized early and maintained through therapy duration.

Descriptive Epidemiology and Outcomes of Nonventilated Hospital-Acquired, Ventilated Hospital-Acquired, and Ventilator-Associated Bacterial Pneumonia in the United States, 2012-2019.

OBJECTIVES: Multiple randomized controlled trials exploring the outcomes of patients with ventilator-associated bacterial pneumonia and hospital-acquired bacterial pneumonia have noted that hospital-acquired bacterial pneumonia patients who require subsequent ventilated hospital-acquired bacterial pneumonia suffered higher mortality than either those who did not (nonventilated hospital-acquired bacterial pneumonia) or had ventilator-associated bacterial pneumonia. We examined the epidemiology and outcomes of all three conditions in a large U.S. database. DESIGN: Retrospective cohort. SETTING: Two hundred fifty-three acute-care hospitals, United States, contributing data (including microbiology) to Premier database, 2012-2019. PATIENTS: Patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia identified based on a slightly modified previously published International Classification of Diseases, 9th Edition/International Classification of Diseases, 10th Edition-Clinical Modification algorithm. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 17,819 patients who met enrollment criteria, 26.5% had nonventilated hospital-acquired bacterial pneumonia, 25.6% vHAPB, and 47.9% ventilator-associated bacterial pneumonia. Ventilator-associated bacterial pneumonia predominated in the Northeastern United States and in large urban teaching hospitals. Patients with nonventilated hospital-acquired bacterial pneumonia were oldest (mean 66.7 ± 15.1 yr) and most likely White (76.9%), whereas those with ventilator-associated bacterial pneumonia were youngest (59.7 ± 16.6 yr) and least likely White (70.3%). Ventilated hospital-acquired bacterial pneumonia was associated with the highest comorbidity burden (mean Charlson score 4.1 ± 2.8) and ventilator-associated bacterial pneumonia with the lowest (3.2 ± 2.5). Similarly, hospital mortality was highest among patients with ventilated hospital-acquired bacterial pneumonia (29.2%) and lowest in nonventilated hospital-acquired bacterial pneumonia (11.7%), with ventilator-associated bacterial pneumonia in-between (21.3%). Among survivors, 24.5% of nonventilated hospital-acquired bacterial pneumonia required a rehospitalization within 30 days of discharge, compared with 22.5% among ventilated hospital-acquired bacterial pneumonia and 18.8% ventilator-associated bacterial pneumonia. Unadjusted hospital length of stay after infection onset was longest among ventilator-associated bacterial pneumonia and shortest among nonventilated hospital-acquired bacterial pneumonia patients. Median total hospital costs mirrored length of stay: ventilator-associated bacterial pneumonia $77,657, ventilated hospital-acquired bacterial pneumonia $62,464, and nonventilated hospital-acquired bacterial pneumonia $39,911. CONCLUSIONS: Both hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia remain associated with significant mortality and cost in the United States. Our analyses confirm that of all three conditions, ventilated hospital-acquired bacterial pneumonia carries the highest risk of death. In contrast, ventilator-associated bacterial pneumonia remains most costly. Nonventilated hospital-acquired bacterial pneumonia survivors were most likely to require a readmission within 30 days of discharge.

Iron serum levels and iron homeostasis parameters in patients with nosocomial pneumonia treated with cefiderocol: post hoc analysis of the APEKS-NP study.

Critically ill patients often present with low serum iron levels or anemia. We evaluated the impact of iron levels and iron homeostasis on the efficacy and safety of cefiderocol, an iron-chelator siderophore cephalosporin, in patients with nosocomial pneumonia in a post hoc analysis of the randomized, double-blind, Phase 3 APEKS-NP study (NCT03032380). Patients with Gram-negative nosocomial pneumonia received cefiderocol 2 g, 3-h infusion, q8h, or high-dose, extended-infusion meropenem 2 g, 3-h infusion, q8h, for 7-14 days. Efficacy and safety parameters, including specific iron homeostasis parameters (i.e., hepcidin, iron, total iron binding capacity, transferrin saturation), were analyzed according to baseline iron levels. In the cefiderocol and meropenem arms, 79.1% (117/148) and 83.3% (125/150) randomized patients, respectively, had low baseline serum iron levels. Rates of 14-day (12.3% [14/114] vs 11.6% [14/121]) and 28-day all-cause mortality (20.5% [23/112] vs 19.0% [23/121]), clinical cure (63.2% [72/114] vs 67.2% [82/122]), and microbiological eradication (43.6% [41/94] vs 48.1% [51/106]) at test of cure were similar in cefiderocol vs meropenem arms, respectively. In the overall safety population, rates of anemia-related adverse events were similar (cefiderocol arm 18.2% [27/148], meropenem arm 18.7% [28/150]). Changes from baseline to test of cure in hepcidin, iron, total iron binding capacity, and transferrin saturation were similar between treatment arms. Cefiderocol treatment did not affect iron homeostasis, and its efficacy and safety were not influenced by baseline serum iron levels. Clinicaltrials.gov registration: NCT03032380. Date of registration: 26 January 2017.