Bacterial profile, and independent predictors for healthcare-associated pneumonia persistently caused by multidrug-resistant Gram-negative bacteria for patients with the preceding multidrug-resistant Gram-negative pneumonia in Taiwan.

OBJECTIVES: To understand the microbial profile and investigate the independent predictors for healthcare-associated pneumonia (HCAP) pertinaciously caused by isolates of multidrug-resistant (MDR) Gram-negative bacteria (GNB). METHODS: Multicenter ICU patients who received appropriate antibiotic treatments for preceding pneumonia due to MDR GNB isolates and subsequently developed HCAP caused by either MDR GNB (n = 126) or non-MDR GNB (n = 40) isolates in Taiwan between 2018 and 2023 were enrolled. Between the groups of patients with HCAP due to MDR GNB and non-MDR GNB, the proportions of the following variables, including demographic characteristics, important co-morbidities, nursing home residence, physiological severity, intervals between two hospitalizations, steroid use, the tracheostomy tube use alone, ventilator support, and the predominant GNB species involving HCAP, were analyzed using the chi-square test. Logistic regression was employed to explore the independent predictors for HCAP persistently caused by MDR GNB in the aforementioned variables with a P-value of <0.15 in the univariate analysis. RESULTS: MDR-Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii complex were the three predominant species causing HCAP. Chronic structural lung disorders, diabetes mellitus, intervals of ≤30 days between two hospitalizations, use of the tracheostomy tube alone, and prior pneumonia caused by MDR A. baumannii complex were shown to independently predict the HCAP tenaciously caused by MDR GNB. Conversely, the preceding pneumonia caused by MDR P. aeruginosa was a negative predictor. CONCLUSION: Identifying predictors for HCAP persistently caused by MDR GNB is crucial for prescribing appropriate antibiotics.

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.

Should we, and how to, optimize cefiderocol administration during severe nosocomial pneumonia due to carbapenem-resistant Acinetobacter baumanii? A viewpoint.

OBJECTIVES: Acinetobacter baumannii is classified by the centre for Disease Control and Prevention (CDC) as an "urgent threat" due to its ability to acquire and develop resistance to multiple classes of antibiotics. As a result, it is one of the most concerning pathogens in healthcare settings, with increasing incidence of infections due to carbapenem-resistant Acinetobacter baumannii (CRAB) associated with high morbidity and mortality rates. Therefore, there are ongoing efforts to find novel treatment options, one of which is cefiderocol. We aim to review available evidence on cefiderocol use for severe nosocomial pneumonia due to carbapenem-resistant Acinetobacter baumannii. METHODS: A comprehensive review was conducted from 2017 to 2023, covering articles from databases such as Pubmed, Scopus, and Embase, along with conference proceedings from ECCMID 2023. The primary focus was on severe nosocomial pneumonia due A. baumannii and cefiderocol. DISCUSSION: Cefiderocol, targeting periplasmic space Penicillin-Binding Proteins (PBPs) via siderophore transport pathways, exhibits promise against multi-drug resistant Gram-negative bacilli. Its effectiveness in treating CRAB pneumonia remains debated. The CREDIBLE trial reported higher mortality with cefiderocol compared to the best available treatment, while other cohort studies showed contrasting outcomes. Patient variations and pharmacokinetic factors may underlie these discrepancies. The recommended cefiderocol dosage regimen may fall short of desired pharmacokinetic targets, especially in critically ill patients and lung infections. Pulmonary factors hindering cefiderocol's entry into bacteria through iron transporters are overlooked in clinical breakpoints. Optimized dosing or combination regimens may enhance infection site exposure and outcomes. CONCLUSIONS: Further research is needed to determine the optimal cefiderocol dosage and administration (mono vs. dual therapy, continuous vs. intermittent infusion), in severe Acinetobacter baumannii nosocomial pneumonia.

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.

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.

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.

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.

Efficacy of combination therapy with standard-dose carbapenem for treating nosocomial pneumonia caused by carbapenem-resistant Acinetobacter baumannii in intensive care units: A multicentre retrospective propensity score-matched study.

Carbapenem-resistant Acinetobacter baumannii (CRAB) infection is common worldwide. Despite carbapenem resistance, standard-dose carbapenems are still used in clinical practice. Hence in this study, we aimed to compare the efficacy and outcomes of a regimen containing standard-dose carbapenems with those of a regimen lacking carbapenems during the treatment of critically ill patients with CRAB nosocomial pneumonia in the intensive care unit (ICU). Initially, 735 patients were recruited for this multicentre retrospective cohort study. After exclusion, time-window bias adjustment, and propensity score matching, multiple clinical outcomes were compared between the carbapenem-containing (CC) (n = 166) and no carbapenem-containing (NCC) (n = 166) groups. The CC group showed a higher risk of clinical failure on day 7 than the NCC group (44.6% vs. 33.1%, P = 0.043). The lengths of ICU stay (21 and 16 days, P = 0.024) and hospital stay (61 and 44 days, P = 0.003) were longer in the CC group than in the NCC group. Multivariate analysis showed that the CC regimen was associated with higher clinical failure (adjusted odds ratio (aOR) = 1.64, 95% CI = 1.05-2.56, P = 0.031) and lower microbiological eradication (aOR = 0.48, 95% CI = 0.23-1.00, P = 0.049) at day 7 than the NCC group. Thus, a regimen containing a standard dose of carbapenem should be prescribed with caution for treating CRAB nosocomial pneumonia in the ICU.

Which trial do we need? Combination antimicrobial therapy for hospital-acquired bacterial pneumonia caused by Pseudomonas aeruginosa.

Meropenem therapy will be open-label, while tobramycin or placebo will be administered in a double-blind fashion. The primary trial endpoint will be a composite hierarchical outcome of 1) 28-day all-cause mortality, 2) ventilator-free days, and 3) modified time to clinical stability, evaluated using a win ratio methodology (see below). Secondary trial outcomes will include frequency of safety events (acute kidney injury), resolution of circulatory shock, recurrent HABP, and emergence of meropenem resistance both during treatment and in cases of recurrent infection. Using simulation studies to inform sample size calculations, we estimate that recruitment of 130 patients per treatment arm would provide at least 80% power to detect a win ratio of 1.50 while preserving a two-sided type 1 error rate of 0.05.

[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.

Nosocomial pneumonia: Current etiology and impact on antimicrobial therapy.

Nosocomial pneumonia is an infection with high clinical impact and high morbimortality in which Pseudomonas aeruginosa plays a priority role, especially in the critically ill patient. Conventional antipseudomonal treatments, historically considered as standard, are currently facing important challenges due to the increase of antimicrobial resistance. In recent years, new antimicrobials have been developed with attractive sensitivity profiles and remarkable efficacy in clinical scenarios of nosocomial pneumonia including bacteremia, mechanical ventilation, infections with multidrug-resistant organisms or situations of therapeutic failure. This new evidence underscores the need to update current clinical guidelines for the antimicrobial treatment of nosocomial pneumonia, especially in the most critically ill patients.

Comparative study of the etiology of nosocomial bacteremic pneumonia in ventilated and non-ventilated patients: a 10-year experience in an institution.

IMPORTANCE: This study on bacteremic nosocomial pneumonia (bNP) demonstrates the importance of this condition both in patients undergoing and not undergoing mechanical ventilation. Staphylococcus aureus, Enterobacterales, and non-fermenting Gram-negative bacilli are all causative agents in ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP), with a predominance of S. aureus in HAP and of Pseudomonas aeruginosa in VAP. Mortality in this condition is very high. Therefore, new therapeutic and preventive approaches should be sought.

Changes in the prevalence of pathogens causing hospital-acquired bacterial pneumonia and the impact of their antimicrobial resistance patterns on clinical outcomes: A propensity-score-matched study.

BACKGROUND: This study aimed to evaluate changes in the prevalence of pathogens causing hospital-acquired bacterial pneumonia (HABP) and their antimicrobial resistance patterns in recent years, and to identify risk factors for 28-day all-cause mortality (ACM) in patients with HABP. METHODS: A propensity-score-matched study was performed by randomly allocating patients with ventilator-associated and non-ventilator-associated bacterial pneumonia admitted to two university hospitals between 2011 and 2021. RESULTS: In total, 17,250 patients with HABP were enrolled. The annual incidence of Staphylococcus aureus HABP decreased during the study period, while that of Klebsiella pneumoniae HABP increased significantly each year. Over the same period, the resistance rate of S. aureus to methicillin decreased from 88.4% to 64.4%, while the non-susceptibility rate of K. pneumoniae to carbapenems increased from 0% to 38%. HABP caused by A. baumannii [adjusted odds ratio (aOR) 1.50, 95% confidence interval (CI) 1.25-1.79], K. pneumoniae (aOR 1.28, 95% CI 1.16-1.40) and Stenotrophomonas maltophilia (aOR 1.32, 95% CI 1.05-1.66) was a risk factor for 28-day ACM. Patients with HABP caused by methicillin-resistant S. aureus and carbapenem-non-susceptible A. baumannii or K. pneumoniae had a significantly lower probability of survival. HABP with preceding coronavirus disease 2019 (COVID-19) was associated with high 28-day ACM (aOR 5.40, 955 CI 3.03-9.64) and high incidence of bacteraemic pneumonia (aOR 40.55, 95% CI 5.26-312.79). CONCLUSIONS: This study showed shifting trends in HABP-causing pathogens in terms of annual incidence and resistance rates to major therapeutic antimicrobial agents. HABP-causing bacterial pathogens, their antimicrobial resistance phenotypes, and preceding COVID-19 were significantly associated with progression of HABP to bloodstream infection and 28-day ACM in infected patients.

Comparative efficacy and safety of non-polymyxin antibiotics against nosocomial pneumonia, complicated intra-abdominal infection, or complicated urinary tract infection: A network meta-analysis of randomised clinical trials.

OBJECTIVES: The increasing epidemic of infections caused by drug-resistant Gram-negative bacteria has led to the development of several antibiotic therapies. Owing to the scarcity of head-to-head comparisons of current and emerging antibiotics, the present network meta-analysis aimed to compare the efficacy and safety of antibiotics in patients with nosocomial pneumonia, complicated intra-abdominal infection, or complicated urinary tract infection. METHODS: Two independent researchers systematically searched databases up to August 2022 and included 26 randomised controlled trials that fulfilled the inclusion criteria. The protocol was registered in the Prospective Register of Systematic Reviews, PROSPERO (CRD42021237798). The frequentist random effects model (R version 3.5.1, netmeta package) was utilized. The DerSimonian-Laird random effects model was used to estimate heterogeneity. The calculated P-score was applied to rank the interventions. Additionally, inconsistencies, publication bias, and subgroup effects were assessed in the present study to avoid bias. RESULTS: There was no significant difference among included antibiotics in terms of clinical response and mortality, probably because most antibiotic trials were designed to be non-inferior. In terms of P-score ranking, carbapenems may be the recommended choice considering both adverse events and clinical responses. On the other hand, for carbapenem-sparing options, ceftolozane-tazobactam was the preferred antibiotic for nosocomial pneumonia; eravacycline, for complicated intra-abdominal infection; and cefiderocol, for complicated urinary tract infection. CONCLUSION: Carbapenems may be preferable options in terms of safety and efficacy for the treatment of Gram-negative bacterial complicated infections. However, to preserve the effectiveness of carbapenems, it is important to consider carbapenem-sparing regimens.

Clinical outcomes and safety of intravenous polymyxin B-based treatment in critically ill patients with carbapenem-resistant Acinetobacter baumannii nosocomial pneumonia.

OBJECTIVES: Polymyxin B (PMB)-based therapy is one of the most important treatments for patients with nosocomial pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB). However, the optimal PMB-based combination regimen has not been well documented. METHODS: In this retrospective study, 111 critically ill patients in the intensive care unit with CRAB nosocomial pneumonia who received intravenous PMB-based therapy between 1 January 2018 and 1 June 2022 were included. The primary outcome was all-cause mortality within 28 days. Cox proportional hazards regression was used to explore risk factors for mortality in the enrolled patients treated with PMB-based regimens and the three most frequent combination regimens. RESULTS: PMB + sulbactam (SB) regimen was significantly associated with a decreased risk of mortality (aHR = 0.10, 95% CI 0.03-0.39; P = 0.001). The proportion of low-dose PMB in PMB + SB regimen (79.2%) was higher than in PMB + carbapenem (61.9%) or tigecycline (50.0%) regimens. In contrast, PMB + carbapenem regimen significantly increased mortality (aHR = 3.27, 95% CI 1.47-7.27; P = 0.004). Although the proportion of high-dose PMB in PMB + tigecycline (17.9%) was higher than in the other two regimens, mortality remained highest (42.9%) and serum creatinine increased significantly. CONCLUSIONS: PMB in combination with SB may be a promising treatment option for patients with CRAB-induced nosocomial pneumonia, as mortality was significantly reduced with low-dose PMB and no increased risk of nephrotoxicity was observed.

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.