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Nosocomial pneumonia due to multidrug-resistant Gram-negative pathogens poses an increasing challenge. We compared the efficacy and safety of cefiderocol versus high-dose, extended-infusion meropenem for adults with nosocomial pneumonia. We did a randomised, double-blind, parallel-group, phase 3, non-inferiority trial in 76 centres in 17 countries in Asia, Europe, and the USA (APEKS-NP). We enrolled adults aged 18 years and older with hospital-acquired, ventilator-associated, or health-care-associated Gram-negative pneumonia, and randomly assigned them (1:1 by interactive response technology) to 3-h intravenous infusions of either cefiderocol 2 g or meropenem 2 g every 8 h for 7–14 days. All patients also received open-label intravenous linezolid (600 mg every 12 h) for at least 5 days. An unmasked pharmacist prepared the assigned treatments; investigators and patients were masked to treatment assignment. Only the unmasked pharmacist was aware of the study drug assignment for the infusion bags, which were administered in generic infusion bags labelled with patient and study site identification numbers. Participants were stratified at randomisation by infection type and Acute Physiology and Chronic Health Evaluation II (APACHE II) score (≤15 and ≥16). The primary endpoint was all-cause mortality at day 14 in the modified intention-to-treat (ITT) population (ie, all patients receiving at least one dose of study drug, excluding patients with Gram-positive monomicrobial infections). The analysis was done for all patients with known vital status. Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference between cefiderocol and meropenem groups was less than 12·5%. Safety was investigated to the end of the study in the safety population, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03032380, and EudraCT, 2016-003020-23. Between Oct 23, 2017, and April 14, 2019, we randomly assigned 148 participants to cefiderocol and 152 to meropenem. Of 292 patients in the modified ITT population, 251 (86%) had a qualifying baseline Gram-negative pathogen, including Klebsiella pneumoniae (92 [32%]), Pseudomonas aeruginosa (48 [16%]), Acinetobacter baumannii (47 [16%]), and Escherichia coli (41 [14%]). 142 (49%) patients had an APACHE II score of 16 or more, 175 (60%) were mechanically ventilated, and 199 (68%) were in intensive care units at the time of randomisation. All-cause mortality at day 14 was 12·4% with cefiderocol (18 patients of 145) and 11·6% with meropenem (17 patients of 146; adjusted treatment difference 0·8%, 95% CI −6·6 to 8·2; p=0·002 for non-inferiority hypothesis). Treatment-emergent adverse events were reported in 130 (88%) of 148 participants in the cefiderocol group and 129 (86%) of 150 in the meropenem group. The most common treatment-emergent adverse event was urinary tract infection in the cefiderocol group (23 patients [16%] of 148) and hypokalaemia in the meropenem group (23 patients [15%] of 150). Two participants (1%) of 148 in the cefiderocol group and two (1%) of 150 in the meropenem group discontinued the study because of drug-related adverse events. Cefiderocol was non-inferior to high-dose, extended-infusion meropenem in terms of all-cause mortality on day 14 in patients with Gram-negative nosocomial pneumonia, with similar tolerability. The results suggest that cefiderocol is a potential option for the treatment of patients with nosocomial pneumonia, including those caused by multidrug-resistant Gram-negative bacteria. Shionogi.

This report compared plazomicin with colistin for the treatment of severe (bloodstream or pneumonia) infection with carbapenem-resistant Enterobacteriaceae. The trial was stopped early for futility, but a suggestion of activity of plazomicin was identified.

Background Augmented renal clearance (ARC) is recognized as a leading cause of β-lactam subexposure when conventional dosing regimens are used. The main objective was to compare the clinical outcome of ARC patients treated by conventional or increased β-lactam dosing regimens for a first episode of hospital or ventilator-acquired pneumonia (HAP-VAP). Methods In this single-center, retrospective study, every ARC patient treated by β-lactam for a first episode of HAP-VAP was included during two 15-month periods, before ( Control period ) and after ( Treatment period ) the modification of a local antibiotic therapy protocol. ARC was defined by a 24-h measured creatinine clearance ≥ 150 ml/min. The primary endpoint was defined as a therapeutic failure of the antimicrobial therapy or a HAP-VAP relapse within 28 days. Inverse probability of treatment weight (IPTW) was derived from a propensity score model. Cox proportional hazard models were used to evaluate the association between treatment period and clinical outcome. Results During the study period, 177 patients were included ( control period , N  = 88; treatment period , N  = 89). Therapeutic failure or HAP-VAP relapse was significantly lower in the treatment period (10 vs. 23%, p = 0.019 ). The IPTW-adjusted hazard ratio of poor clinical outcome in the treatment period was 0.35 (95% CI 0.15–0.81), p = 0.014 . No antibiotic side effect was reported during the treatment period. Conclusions Higher than licensed dosing regimens of β-lactams may be safe and effective in reducing the rate of therapeutic failure and HAP-VAP recurrence in critically ill augmented renal clearance (ARC) patients.

Purpose This executive summary of a German national guideline aims to provide the most relevant evidence-based recommendations on the diagnosis and treatment of nosocomial pneumonia. Methods The guideline made use of a systematic assessment and decision process using evidence to decision framework (GRADE). Recommendations were consented by an interdisciplinary panel. Evidence analysis and interpretation was supported by the German innovation fund providing extensive literature searches and (meta-) analyses by an independent methodologist. For this executive summary, selected key recommendations are presented including the quality of evidence and rationale for the level of recommendation. Results The original guideline contains 26 recommendations for the diagnosis and treatment of adults with nosocomial pneumonia, thirteen of which are based on systematic review and/or meta-analysis, while the other 13 represent consensus expert opinion. For this key summary, we present 11 most relevant for everyday clinical practice key recommendations with evidence overview and rationale, of which two are expert consensus and 9 evidence-based (4 strong, 5 weak and 2 open recommendations). For the management of nosocomial pneumonia patients should be divided in those with and without risk factors for multidrug-resistant pathogens and/or Pseudomonas aeruginosa . Bacterial multiplex-polymerase chain reaction (PCR) should not be used routinely. Bronchoscopic diagnosis is not considered superior to´non-bronchoscopic sampling in terms of main outcomes. Only patients with septic shock and the presence of an additional risk factor for multidrug-resistant pathogens (MDRP) should receive empiric combination therapy. In clinically stabilized patients, antibiotic therapy should be de-escalated and focused. In critically ill patients, prolonged application of suitable beta-lactam antibiotics should be preferred. Therapy duration is suggested for 7–8 days. Procalcitonin (PCT) based algorithm might be used to shorten the duration of antibiotic treatment. Patients on the intensive care unit (ICU) are at risk for invasive pulmonary aspergillosis (IPA). Diagnostics for Aspergillus should be performed with an antigen test from bronchial lavage fluid. Conclusion The current guideline focuses on German epidemiology and standards of care. It should be a guide for the current treatment and management of nosocomial pneumonia in Germany.

Intravenous cefiderocol (Fetroja ® ; Fetcroja ® ) is the first siderophore cephalosporin approved for the treatment of adults with serious Gram-negative bacterial infections. Cefiderocol is stable against all four Ambler classes of β-lactamases (including metallo-β-lactamases) and exhibits excellent in vitro activity against many clinically relevant Gram-negative pathogens, including multidrug resistant strains. In randomized, double-blind clinical trials, cefiderocol was noninferior to imipenem/cilastatin for the treatment of complicated urinary tract infections (cUTI) and to meropenem for nosocomial pneumonia. Furthermore, in a pathogen-focused clinical trial in patients with carbapenem-resistant (CR) infections, cefiderocol showed comparable efficacy to best available therapy (BAT), albeit all-cause mortality rate was higher in the cefiderocol arm, the cause of which has not been established. Cefiderocol had a good tolerability and safety profile in clinical trials. Thus cefiderocol is a novel, emerging, useful addition to the current treatment options for adults with susceptible Gram-negative bacterial infections (including cUTI and nosocomial pneumonia) for whom there are limited treatment options. Plain Language Summary Infections caused by carbapenem-resistant (CR) Enterobacterales and nonfermenters (such as Pseudomonas , Acinetobacter , Stenotrophomonas , Burkholderia ) are a major global health threat. Cefiderocol, a cephalosporin with activity against CR Enterobacterales and nonfermenters, uses the bacteria’s own iron uptake system to gain cell entry, like a Trojan horse. Once inside, the drug disrupts the formation of the bacterial cell wall, killing the bacteria. Cefiderocol is approved for the treatment of serious Gram-negative bacterial infections. In clinical trials, cefiderocol was effective versus carbapenems or best available therapy for complicated urinary tract infections, nosocomial pneumonia and bloodstream infections/sepsis, including those caused by CR bacteria. The drug had a good tolerability and safety profile. Thus, cefiderocol is a useful addition to the current treatment options for adults with cefiderocol-susceptible Gram-negative bacterial infections for whom there are limited treatment options.

To develop and evaluate a program to presvent hospital-acquired pneumonia (HAP). Prospective, observational, surveillance program to identify HAP before and after 7 interventions. An order set automatically triggered in programmatically identified high-risk patients. All 21 hospitals of an integrated healthcare system with 4.4 million members. All hospitalized patients. Interventions for high-risk patients included mobilization, upright feeding, swallowing evaluation, sedation restrictions, elevated head of bed, oral care and tube care. HAP rates decreased between 2012 and 2018: from 5.92 to 1.79 per 1,000 admissions (P = .0031) and from 24.57 to 6.49 per 100,000 members (P = .0014). HAP mortality decreased from 1.05 to 0.34 per 1,000 admissions and from 4.37 to 1.24 per 100,000 members. Concomitant antibiotic utilization demonstrated reductions of broad-spectrum antibiotics. Antibiotic therapy per 100,000 members was measured as follows: carbapenem days (694 to 463; P = .0020), aminoglycoside days (154 to 61; P = .0165), vancomycin days (2,087 to 1,783; P = .002), and quinolone days (2,162 to 1,287; P < .0001). Only cephalosporin use increased, driven by ceftriaxone days (264 to 460; P = .0009). Benzodiazepine use decreased between 2014 to 2016: 10.4% to 8.8% of inpatient days. Mortality for patients with HAP was 18% in 2012% and 19% in 2016 (P = .439). HAP rates, mortality, and broad-spectrum antibiotic use were all reduced significantly following these interventions, despite the absence of strong supportive literature for guidance. Most interventions augmented basic nursing care. None had risks of adverse consequences. These results support the need to examine practices to improve care despite limited literature and the need to further study these difficult areas of care.

To explore whether microbiology profiles and the impact of inappropriate empiric treatment differ in the setting of hospital-acquired bacterial pneumonia that requires subsequent mechanical ventilation (vHABP) versus one that does not (nvHABP) versus ventilator-associated bacterial pneumonia (VABP). Multicenter retrospective cohort study within Premier Research database, 2014-2019. We identified cases based on a previously published International Classification of Disease, Ninth Revision/Tenth Revision Clinical Modification (ICD-9/ICD-10-CM) algorithm, and we compared the 3 groups with respect to the bacterial pathogens isolated from their blood, sputum, or lower airway samples, and their respective rates of exposure to inappropriate empiric treatment. Using regression modeling we computed the effect of inappropriate empiric treatment on outcomes. Among 17,819 patients who met enrollment criteria, 26.5% had nvHABP, 25.6% vHAPB, and 47.9% VABP. S. aureus (majority methicillin-susceptible) was the most frequently isolated organism, followed P. aeruginosa, K. pneumoniae, and E. coli with variations across the conditions. Rates of carbapenem resistance were highest in VABP (9.1%) and to third-generation cephalosporins in vHABP (14.9%). Patients with nvHABP were most likely to receive inappropriate empiric treatment (8.5%). Although inappropriate empiric treatment was associated with an increase in adjusted postinfection-onset hospital length of stay (2.3 days) and cost ($12,142), its greatest magnitude was in the nvHABP group (4.9 days, $13,147). Substantial microbiologic differences exist among populations who suffer nvHABP, vHABP, and VABP, and inappropriate empiric treatment significantly worsens utilization outcomes. Given the moderate rates of carbapenem resistance and third-generation cephalosporin resistance, all patients require empiric coverage for a range of bacteria, including those targeting extended-spectrum β-lactamase and carbapenem resistance where appropriate.

IntroductionThe prevalence of carbapenem-resistant Enterobacteriaceae (CRE) infections is increasing worldwide. However, the evidence regarding the treatment of infections caused by CRE is either low or conditional.Methods and analysisThis multicentre, investigator-initiated, open-label, randomised controlled, non-inferiority trial compares colistin-based combination therapy with the best available therapy for treating CRE infections. This study is being conducted at 15 centres in China. We include participants with hospital-acquired pneumonia (HAP) or bloodstream infections (BSI) caused by CRE. Participants will be randomly assigned to a colistin-based combination therapy group or the best available therapy group. The primary outcome is the 14-day all-cause mortality. Secondary outcomes include 14-day clinical cure rate, 14-day efficacy rate, intensive care unit (ICU)-free days within 28 days after randomisation, 14-day microbiological cure rate, incidence of adverse events (AEs) and serious AEs within the first 28 days, hospital mortality, 28-day all-cause mortality and ICU mortality. A target sample size of 404, with 322 evaluable patients (161 in each group) allowed for at least 80% power (one-sided significance level of 0.025), assuming a 15% non-inferiority margin and a 14-day all-cause mortality rate of 35% in both groups. Primary outcome will be assessed based on the microbiologically modified intent-to-treat, and one interim analysis is planned when 50% of the participants have been enrolled.Ethics and disseminationThe study was approved by the Research Ethics Boards at Zhongda Hospital (file number: 2023ZDSYLL295-P03) and all participating centres. Informed consent will be obtained from all participants. The trial will be conducted under the oversight of an independent data and safety monitoring committee. Results will be disseminated in peer-reviewed journals.Trial registration numberNCT06051513.

Background Accurate microbiological documentation seems central for managing severe pneumonia. While the FilmArray ® Pneumonia + panel (FA-PP) offers rapid pathogen identification, its effectiveness during antibiotic treatment and in predicting clinical outcomes remains unclear. Methods We conducted a prospective observational study across four ICUs from April 2022 to June 2024, including patients with ventilator-associated pneumonia (VAP) or ventilated hospital-acquired pneumonia (vHAP). Bacterial loads were monitored on days 0, 1, 3, 7 and 10 and 3 days after stopping antibiotics, using endotracheal aspirates (ETAs) analyzed by FA-PP and standard cultures. The main objective was to assess the correlation between quantitative changes in FA-PP results and clinical success. Quantitative changes over time were analyzed using mixed ordinal logistic regression. Results Of the 93 patients enrolled, 60.2% ( n  = 56) achieved clinical success, while the ICU mortality rate was 25.8% ( n  = 24). Although FA-PP and culture quantification results declined over time ( p  < 0.0001), neither method consistently correlated with clinical success (non-significant for both). At diagnosis, FA-PP showed excellent diagnostic performance compared to culture, with a sensitivity of 94% [95% CI: 87–97] and a specificity of 98% [95% CI: 97–98]. Quantitative concordance improved with higher DNA copies, from 22.9% at the culture threshold at 10⁴ DNA copies/ml in FA-PP to 100% at ≥ 10⁷ DNA copies/ml. Diagnostic performance remained stable during antibiotic treatment with 94% sensitivity and 95% specificity in follow-up ETAs. Conclusions FA-PP provides rapid and accurate diagnostics, but repeated testing did not predict clinical outcomes during treatment, however our small sample size limited the study power.

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. AUC ss,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 AUC ss,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.