HAP-FAST: a feasibility study incorporating qualitative, mechanistic and costing sub-studies alongside a randomised pilot trial comparing chest x-ray to low-dose CT scan and empirical antibiotics to antibiotics guided by the BIOFIRE® FILM ARRAY® pneumonia plus panel in adults with suspected non-ventilator-associated hospital-cquired pneumonia.

INTRODUCTION: Non-ventilator-associated hospital-acquired pneumonia (nv-HAP) is the most common healthcare-associated infection (HCAI), is associated with high mortality and morbidity and places a major burden on healthcare systems. Diagnosis currently relies on chest x-rays to confirm pneumonia and sputum cultures to determine the microbiological cause. This approach leads to over-diagnosis of pneumonia, rarely identifies a causative pathogen and perpetuates unnecessary and imprecise antibiotic use. The HAP-FAST study aims to evaluate the feasibility of a randomised trial to evaluate the clinical impact of low-dose, non-contrast-enhanced thoracic CT scans and rapid molecular sputum analysis using the BIOFIRE® FILMARRAY® pneumonia plus panel (FAPP) for patients suspected with nv-HAP. METHODS AND ANALYSIS: The HAP-FAST feasibility study consists of a pilot randomised trial, a qualitative study, a costing analysis and exploratory analyses of clinical samples to investigate the immune-pathophysiology of HAP. Participants are identified and recruited from four acute hospitals in the Northwest of the UK. Using a Research Without Prior Consent model, the pilot trial will recruit 220 adult participants, with or without mental capacity, and with suspected HAP. HAP-FAST is a non-blinded, sequential, multiple assignment, randomised trial with two possible stages of randomisation: first, chest x-ray (CXR) or CT; second, if treated as nv-HAP, FAPP or standard microbiological processing alone (no FAPP). Pathogen-specific antibiotic guidance will be provided for FAPP results. Randomisation uses a web-based platform and followed up for 90 days. The feasibility of a future trial will be determined by assessing trial processes, outcome measures and patient and staff experiences. ETHICS AND DISSEMINATION: This study has undergone combined review by the UK NHS Research Ethics Committee and Health Research Authority. Results will be disseminated via peer-reviewed journals, via the funders' website and through a range of media to engage the public. TRIAL REGISTRATION NUMBER: NCT05483309.

Oral condition at admission predicts functional outcomes and hospital-acquired pneumonia development among acute ischemic stroke patients.

INTRODUCTION: Oral care is crucial for the prevention of cardiovascular events and pneumonia. However, few studies have evaluated the associations between multidimensional assessments of oral status or functional outcomes and hospital-acquired pneumonia (HAP). METHODS: Consecutive patients with acute ischemic stroke (AIS) were retrospectively analyzed. We evaluated the modified oral assessment grade (mOAG) and investigated its association with a modified Rankin scale (mRS) score of 0‒2 (good stroke outcome) and HAP. The mOAG was developed to evaluate 8 categories (lip, tongue, coated tongue, saliva, mucosa, gingiva, preservation, and gargling) on a 4-point scale ranging from 0 to 3. We analyzed the effectiveness of the mOAG score for predicting stroke outcome or HAP using receiver operating characteristic (ROC) curve analysis. RESULTS: In total, 247 patients with AIS were analyzed. The area under the ROC curve of the mOAG for predicting poor outcomes was 0.821 (cutoff value: 7), and that for HAP incidence was 0.783 (cutoff value: 8). mOAG (a one-point increase) was associated with poor stroke outcome (odds ratio [OR] 1.31, 95% confidence interval [CI] 1.17‒1.48, P < 0.001) and HAP (OR 1.21, 95% CI 1.07‒1.38, P = 0.003) after adjusting for baseline clinical characteristics, including age and stroke severity. CONCLUSIONS: Lower mOAG scores at admission were independently associated with good outcomes and a decreased incidence of HAP. Comprehensive oral assessments are essential for acute stroke patients in clinical settings.

Utility of pneumonia severity assessment tools for mortality prediction in healthcare-associated pneumonia: a systematic review and meta-analysis.

Accurate prognostic tools for mortality in patients with healthcare-associated pneumonia (HCAP) are needed to provide appropriate medical care, but the efficacy for mortality prediction of tools like PSI, A-DROP, I-ROAD, and CURB-65, widely used for predicting mortality in community-acquired and hospital-acquired pneumonia cases, remains controversial. In this study, we conducted a systematic review and meta-analysis using PubMed, Cochrane Library (trials), and Ichushi web database (accessed on August 22, 2022). We identified articles evaluating either PSI, A-DROP, I-ROAD, or CURB-65 and the mortality outcome in patients with HCAP, and calculated the pooled sensitivities, specificities, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the summary area under the curves (AUCs) for mortality prediction. Additionally, the differences in predicting prognosis among these four assessment tools were evaluated using overall AUCs pooled from AUC values reported in included studies. Eventually, 21 articles were included and these quality assessments were evaluated by QUADAS-2. Using a cut-off value of moderate in patients with HCAP, the range of pooled sensitivity, specificity, PLR, NLR, and DOR were found to be 0.91-0.97, 0.15-0.44, 1.14-1.66, 0.18-0.33, and 3.86-9.32, respectively. Upon using a cut-off value of severe in those patients, the range of pooled sensitivity, specificity, PLR, NLR, and DOR were 0.63-0.70, 0.54-0.66, 1.50-2.03, 0.47-0.58, and 2.66-4.32, respectively. Overall AUCs were 0.70 (0.68-0.72), 0.70 (0.63-0.76), 0.68 (0.64-0.73), and 0.67 (0.63-0.71), respectively, for PSI, A-DROP, I-ROAD, and CURB-65 (p = 0.66). In conclusion, these severity assessment tools do not have enough ability to predict mortality in HCAP patients. Furthermore, there are no significant differences in predictive performance among these four severity assessment tools.

Ventilator-Associated Pneumonia, Ventilator-Associated Events, and Nosocomial Respiratory Viral Infections on the Leeside of the Pandemic.

The COVID-19 pandemic has had an unprecedented impact on population health and hospital operations. Over 7 million patients have been hospitalized for COVID-19 thus far in the United States alone. Mortality rates for hospitalized patients during the first wave of the pandemic were > 30%, but as we enter the fifth year of the pandemic hospitalizations have fallen and mortality rates for hospitalized patients with COVID-19 have plummeted to 5% or less. These gains reflect lessons learned about how to optimize respiratory support for different kinds of patients, targeted use of therapeutics for patients with different manifestations of COVID-19 including immunosuppressants and antivirals as appropriate, and high levels of population immunity acquired through vaccines and natural infections. At the same time, the pandemic has helped highlight some longstanding sources of harm for hospitalized patients including hospital-acquired pneumonia, ventilator-associated events (VAEs), and hospital-acquired respiratory viral infections. We are, thankfully, on the leeside of the pandemic at present; but the large increases in ventilator-associated pneumonia (VAP), VAEs, bacterial superinfections, and nosocomial respiratory viral infections associated with the pandemic beg the question of how best to prevent these complications moving forward. This paper reviews the burden of hospitalization for COVID-19, the intersection between COVID-19 and both VAP and VAEs, the frequency and impact of hospital-acquired respiratory viral infections, new recommendations on how best to prevent VAP and VAEs, and current insights into effective strategies to prevent nosocomial spread of respiratory viruses.

Hospital-acquired bacterial pneumonia in critically ill patients: from research to clinical practice.

INTRODUCTION: Hospital-acquired pneumonia (HAP) represents a significant cause of mortality among critically ill patients admitted to Intensive Care Units (ICUs). Timely and precise diagnosis is imperative to enhance therapeutic efficacy and patient outcomes. However, the diagnostic process is challenged by test limitations and a wide-ranging list of differential diagnoses, particularly in patients exhibiting escalating oxygen requirements, leukocytosis, and increased secretions. AREAS COVERED: This narrative review aims to update diagnostic modalities, facilitating the prompt identification of nosocomial pneumonia while guiding, developing, and assessing therapeutic interventions. A comprehensive literature review was conducted utilizing the MEDLINE/PubMed database from 2013 to April 2024. EXPERT OPINION: An integrated approach that integrates clinical, microbiological, and imaging tools is paramount. Progress in diagnostic techniques, including novel molecular methods, the expanding utilization and accuracy of bedside ultrasound, and the emergence of Artificial Intelligence, coupled with an improved comprehension of lung microbiota and host-pathogen interactions, continues to enhance our capability to accurately and swiftly identify HAP and its causative agents. This advancement enables the refinement of treatment strategies and facilitates the implementation of precision medicine approaches.

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.

Clinical challenge of diagnosing non-ventilator hospital-acquired pneumonia and identifying causative pathogens: a narrative review.

Non-ventilated hospital-acquired pneumonia (NV-HAP) is associated with a significant healthcare burden, arising from high incidence and associated morbidity and mortality. However, accurate identification of cases remains challenging. At present, there is no gold-standard test for the diagnosis of NV-HAP, requiring instead the blending of non-specific signs and investigations. Causative organisms are only identified in a minority of cases. This has significant implications for surveillance, patient outcomes and antimicrobial stewardship. Much of the existing research in HAP has been conducted among ventilated patients. The paucity of dedicated NV-HAP research means that conclusions regarding diagnostic methods, pathology and interventions must largely be extrapolated from work in other settings. Progress is also limited by the lack of a widely agreed definition for NV-HAP. The diagnosis of NV-HAP has large scope for improvement. Consensus regarding a case definition will allow meaningful research to improve understanding of its aetiology and the heterogeneity of outcomes experienced by patients. There is potential to optimize the role of imaging and to incorporate novel techniques to identify likely causative pathogens. This would facilitate both antimicrobial stewardship and surveillance of an important healthcare-associated infection. This narrative review considers the utility of existing methods to diagnose NV-HAP, with a focus on the significance and challenge of identifying pathogens. It discusses the limitations in current techniques, and explores the potential of emergent molecular techniques to improve microbiological diagnosis and outcomes for patients.

Automated surveillance of non-ventilator-associated hospital-acquired pneumonia (nvHAP): a systematic literature review.

BACKGROUND: Hospital-acquired pneumonia (HAP) and its specific subset, non-ventilator hospital-acquired pneumonia (nvHAP) are significant contributors to patient morbidity and mortality. Automated surveillance systems for these healthcare-associated infections have emerged as a potentially beneficial replacement for manual surveillance. This systematic review aims to synthesise the existing literature on the characteristics and performance of automated nvHAP and HAP surveillance systems. METHODS: We conducted a systematic search of publications describing automated surveillance of nvHAP and HAP. Our inclusion criteria covered articles that described fully and semi-automated systems without limitations on patient demographics or healthcare settings. We detailed the algorithms in each study and reported the performance characteristics of automated systems that were validated against specific reference methods. Two published metrics were employed to assess the quality of the included studies. RESULTS: Our review identified 12 eligible studies that collectively describe 24 distinct candidate definitions, 23 for fully automated systems and one for a semi-automated system. These systems were employed exclusively in high-income countries and the majority were published after 2018. The algorithms commonly included radiology, leukocyte counts, temperature, antibiotic administration, and microbiology results. Validated surveillance systems' performance varied, with sensitivities for fully automated systems ranging from 40 to 99%, specificities from 58 and 98%, and positive predictive values from 8 to 71%. Validation was often carried out on small, pre-selected patient populations. CONCLUSIONS: Recent years have seen a steep increase in publications on automated surveillance systems for nvHAP and HAP, which increase efficiency and reduce manual workload. However, the performance of fully automated surveillance remains moderate when compared to manual surveillance. The considerable heterogeneity in candidate surveillance definitions and reference standards, as well as validation on small or pre-selected samples, limits the generalisability of the findings. Further research, involving larger and broader patient populations is required to better understand the performance and applicability of automated nvHAP surveillance.

Risk factors for hospital-acquired pneumonia in hip fracture patients: A systematic review and meta-analysis.

BACKGROUND: This study aimed to comprehensively assess the prevalence and risk factors for Hospital-acquired pneumonia (HAP) in hip fracture patients by meta-analysis. METHODS: Systematically searched 4 English databases and 4 Chinese databases from inception until October 20, 2022. All studies involving risk factors of HAP in patients with hip fractures will be considered. Newcastle-Ottawa Scale was used to evaluate the quality of the included studies. The results were presented through Review Manager 5.4 with the pooled odds ratio (OR) and 95% confidence interval. RESULTS: Of 35 articles included in this study, the incidence of HAP was 8.9%. 43 risk factors for HAP were initially included, 23 were eventually involved in the meta-analysis, and 21 risk factors were significant. Among them, the 4 most frequently mentioned risk factors were as follows: Advanced age (OR 1.07, 95% CI 1.05-1.10), chronic obstructive pulmonary disease (COPD) (OR 3.44, 95% CI 2.83-4.19), time from injury to operation (OR 1.09, 95% CI 1.07-1.12), time from injury to operation ≥ 48 hours (OR 3.59, 95% CI 2.88-4.48), and hypoalbuminemia < 3.5g/dL (OR 2.68, 95% CI 2.15-3.36). DISCUSSION: Hip fracture patients diagnosed with COPD have a 3.44 times higher risk of HAP compared to the general hip fracture patients. The risk of HAP also increases with age, with patients over 70 having a 2.34-fold higher risk and those over 80 having a 2.98-fold higher risk. These findings highlight the need for tailored preventive measures and timely interventions in vulnerable patient populations. Additionally, hip fracture patients who wait more than 48 hours for surgery have a 3.59-fold higher incidence of HAP. This emphasizes the importance of swift surgical intervention to minimize HAP risk. However, there are limitations to consider in this study, such as heterogeneity in selected studies, inclusion of only factors identified through multivariate logistic regression, and the focus on non-randomized controlled trial studies.

Application of a multiplex molecular pneumonia panel and real-world impact on antimicrobial stewardship among patients with hospital-acquired and ventilator-associated pneumonia in intensive care units.

BACKGROUND: The optimal timing for applying the BioFire FilmArray Pneumonia Panel (FAPP) in intensive care unit (ICU) patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) remains undefined, and there are limited data on its impact on antimicrobial stewardship. METHODS: This retrospective study was conducted at a referral hospital in Taiwan from November 2019 to October 2022. Adult ICU patients with HAP/VAP who underwent FAPP testing were enrolled. Patient data, FAPP results, conventional microbiological testing results, and the real-world impact of FAPP results on antimicrobial therapy adjustments were assessed. Logistic regression was used to determine the predictive factors for bacterial detection by FAPP. RESULTS: Among 592 respiratory specimens, including 564 (95.3%) endotracheal aspirate specimens, 19 (3.2%) expectorated sputum specimens and 9 (1.5%) bronchoalveolar lavage specimens, from 467 patients with HAP/VAP, FAPP testing yielded 368 (62.2%) positive results. Independent predictors for positive bacterial detection by FAPP included prolonged hospital stay (odds ratio [OR], 3.14), recent admissions (OR, 1.59), elevated C-reactive protein levels (OR, 1.85), Acute Physiology and Chronic Health Evaluation II scores (OR, 1.58), and septic shock (OR, 1.79). Approximately 50% of antimicrobial therapy for infections caused by Gram-negative bacteria and 58.4% for Gram-positive bacteria were adjusted or confirmed after obtaining FAPP results. CONCLUSIONS: This study identified several factors predicting bacterial detection by FAPP in critically ill patients with HAP/VAP. More than 50% real-world clinical practices were adjusted or confirmed based on the FAPP results. Clinical algorithms for the use of FAPP and antimicrobial stewardship guidelines may further enhance its benefits.

Exploration of a Potential DOOR Endpoint for Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia Using Six Registrational Trials for Antibacterial Drugs.

BACKGROUND: Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP). METHODS: Through comprehensive examination of data from nearly 4000 participants enrolled in six registrational trials for HABP/VABP submitted to the Food and Drug Administration (FDA) between 2005 and 2022, we derived and applied a HABP/VABP specific endpoint. We estimated the probability that a participant assigned to the study treatment arm would have a more favorable overall DOOR or component outcome than a participant assigned to comparator. RESULTS: DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 48.3% to 52.9% and were not statistically different. There were no significant differences between treatment arms in the component analyses. Although infectious complications and serious adverse events occurred more frequently in ventilated participants compared to non-ventilated participants, the types of events were similar. CONCLUSIONS: Through a data-driven approach, we constructed and applied a potential DOOR endpoint for HABP/VABP trials. The inclusion of syndrome-specific events may help to better delineate and evaluate participant experiences and outcomes in future HABP/VABP trials and could help inform data collection and trial design.

Clinical evaluation of the BioFire Respiratory Pathogen Panel for the guidance of empirical antimicrobial therapy in critically ill patients with hospital-acquired pneumonia: A multicenter, quality improvement project.

BACKGROUND: We aimed to determine whether implementing antimicrobial stewardship based on multiplex bacterial PCR examination of respiratory fluid can enhance outcomes of critically ill patients with hospital-acquired pneumonia (HAP). METHODS: We conducted a quality improvement study in two hospitals in France. Adult patients requiring invasive mechanical ventilation with a diagnosis of HAP were included. In the pre-intervention period (August 2019 to April 2020), antimicrobial therapy followed European guidelines. In the «intervention¼ phase (June 2020 to October 2021), treatment followed a multiplex PCR-guided protocol. The primary endpoint was a composite endpoint made of mortality on day 28, clinical cure between days 7 and 10, and duration of invasive mechanical ventilation on day 28. The primary outcome was analyzed with a DOOR strategy. RESULTS: A total of 443 patients were included in 3 ICUs from 2 hospitals (220 pre-intervention; 223 intervention). No difference in the ranking of the primary composite outcome was found (DOOR: 50.3%; 95%CI, 49.9%-50.8%). The number of invasive mechanical ventilation-free days at day 28 was 10.0 [0.0; 19.0] in the baseline period and 9.0 [0.0; 20.0] days during the intervention period (p = 0.95). The time-to-efficient antimicrobial treatment was 0.43 ± 1.29 days before versus 0.55 ± 1.13 days after the intervention (p = 0.56). CONCLUSION: Implementation of Rapid Multiplex PCR to guide empirical antimicrobial therapy for critically ill patients with HAP was not associated with better outcomes. However, adherence to stewardship was low, and the study may have had limited power to detect a clinically important difference.

[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.

Nursing and healthcare-associated pneumonia due to SARS-CoV-2 Omicron variant.

BACKGROUND: There were many differences in the clinical characteristics between nursing and healthcare-associated pneumonia (NHCAP) and community-acquired pneumonia (CAP) due to the SARS-CoV-2 ancestral strain, Alpha variant and Delta variant. With the replacement of the Delta variant by the Omicron variant, the Omicron variant showed decreased infectivity to lung and was less pathogenic. We investigated the clinical differences between NHCAP and CAP due to the Omicron variant. METHODS: We analyzed 516 NHCAP and 547 CAP patients with COVID-19 pneumonia. Of 516 patients with COVID-19 NHCAP, 330 cases were the Omicron variant (120 cases were BA.1, 53 cases were BA.2, and 157 cases were BA.5 subvariants) and 186 cases were non-Omicron variants. RESULTS: The median age, frequency of comorbid illness, rates of intensive care unit (ICU) stay, and mortality rate were significantly higher in Omicron patients with NHCAP than in those with CAP. Rates of ICU stay and in-hospital mortality were significantly higher in NHCAP patients with non-Omicron variants compared with those in the Omicron variant group. No clinical differences were observed in patients with NHCAP among the Omicron BA.1, BA.2, and BA.5 subvariant groups. CONCLUSIONS: The present study supported that the NHCAP category is necessary not only for bacterial pneumonia but also viral pneumonia. It is necessary to consider prevention and treatment strategies depending on the presence or absence of applicable criteria for NHCAP.

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.

Molecular pharmacodynamics of meropenem for nosocomial pneumonia caused by Pseudomonas aeruginosa.

Hospital-acquired pneumonia (HAP) is a leading cause of morbidity and mortality, commonly caused by Pseudomonas aeruginosa. Meropenem is a commonly used therapeutic agent, although emergent resistance occurs during treatment. We used a rabbit HAP infection model to assess the bacterial kill and resistance pharmacodynamics of meropenem. Meropenem 5 mg/kg administered subcutaneously (s.c.) q8h (±amikacin 3.33-5 mg/kg q8h administered intravenously[i.v.]) or meropenem 30 mg/kg s.c. q8h regimens were assessed in a rabbit lung infection model infected with P. aeruginosa, with bacterial quantification and phenotypic/genotypic characterization of emergent resistant isolates. The pharmacokinetic/pharmacodynamic output was fitted to a mathematical model, and human-like regimens were simulated to predict outcomes in a clinical context. Increasing meropenem monotherapy demonstrated a dose-response effect to bacterial kill and an inverted U relationship with emergent resistance. The addition of amikacin to meropenem suppressed the emergence of resistance. A network of porin loss, efflux upregulation, and increased expression of AmpC was identified as the mechanism of this emergent resistance. A bridging simulation using human pharmacokinetics identified meropenem 2 g i.v. q8h as the licensed clinical regimen most likely to suppress resistance. We demonstrate an innovative experimental platform to phenotypically and genotypically characterize bacterial emergent resistance pharmacodynamics in HAP. For meropenem, we have demonstrated the risk of resistance emergence during therapy and identified two mitigating strategies: (i) regimen intensification and (ii) use of combination therapy. This platform will allow pre-clinical assessment of emergent resistance risk during treatment of HAP for other antimicrobials, to allow construction of clinical regimens that mitigate this risk.IMPORTANCEThe emergence of antimicrobial resistance (AMR) during antimicrobial treatment for hospital-acquired pneumonia (HAP) is a well-documented problem (particularly in pneumonia caused by Pseudomonas aeruginosa) that contributes to the wider global antimicrobial resistance crisis. During drug development, regimens are typically determined by their sufficiency to achieve bactericidal effect. Prevention of the emergence of resistance pharmacodynamics is usually not characterized or used to determine the regimen. The innovative experimental platform described here allows characterization of the emergence of AMR during the treatment of HAP and the development of strategies to mitigate this. We have demonstrated this specifically for meropenem-a broad-spectrum antibiotic commonly used to treat HAP. We have characterized the antimicrobial resistance pharmacodynamics of meropenem when used to treat HAP, caused by initially meropenem-susceptible P. aeruginosa, phenotypically and genotypically. We have also shown that intensifying the regimen and using combination therapy are both strategies that can both treat HAP and suppress the emergence of resistance.

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.

Perspectives on the use of ceftolozane/tazobactam: a review of clinical trial data and real-world evidence.

Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are common healthcare-associated infections linked to high morbidity and mortality. Gram-negative pathogens, such as Pseudomonas aeruginosa, exhibit multidrug resistance and are recognized as major public health concerns, particularly among critically ill patients with HABP/VABP. Ceftolozane/tazobactam is a novel combination antibacterial agent comprising ceftolozane (a potent antipseudomonal cephalosporin) and tazobactam (a ß-lactamase inhibitor). Phase III trials have demonstrated non-inferiority of ceftolozane/tazobactam to comparators, leading to the approval of ceftolozane/tazobactam for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and nosocomial pneumonia. In this article, we review the clinical trial evidence and key real-world effectiveness data of ceftolozane/tazobactam for the treatment of serious healthcare-associated Gram-negative infections, focusing on patients with HABP/VABP.

Highlights from a review of ceftolozane/tazobactam for the treatment of serious infectionsSerious infections that can affect people in hospitals can cause serious illness or loss of life. Antibiotics are a type of medicine designed to kill the bacteria that cause these infections. However, bacteria have evolved over time, which means that antibiotics are not as effective at killing the bacteria and treating the infection. This is known as antibiotic resistance. To treat serious infections in hospital, there is a need for new antibiotics that can overcome this resistance and successfully fight off bacteria. This paper looks at an antibiotic known as ceftolozane/tazobactam (C/T), which can be used to treat people with serious infections that are picked up in hospitals. Clinical and laboratory studies have been reviewed to evaluate how effective, safe, and suitable C/T is for patients. The studies discussed in this paper highlight how well C/T works in people with serious infections, including those who are already ill and have been put on a ventilator to help with their breathing. Some of these studies showed that C/T worked well against lots of different types of bacteria that are known to cause serious infections in hospital and are linked to a high risk of death. Antibiotic resistance is a major problem all over the world. There is a need for effective antibiotics that can treat a range of infections caused by resistant bacteria. The results of this paper show that there is a lot of evidence to support the use of C/T in hospitals for people with serious bacterial infections.