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New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections. We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7–14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23). Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8–66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9–75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2–65·5) of 23 patients in the cefiderocol group and six (43%, 17·7–71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8–77·0) of 17 patients in the cefiderocol group and one (20%, 0·5–71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug. Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options. Shionogi.

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.

Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) can be caused by a wide variety of bacteria that originate from the patient flora or the health care environment. We review the medical and microbiology literature and the results of the SENTRY Antimicrobial Surveillance Program (1997-2008) to establish the pathogens most likely to cause HABP or VABP. In all studies, a consistent 6 organisms (Staphylococcus aureus [28.0%], Pseudomonas aeruginosa [21.8%], Klebsiella species [9.8%], Escherichia coli [6.9%], Acinetobacter species [6.8%], and Enterobacter species [6.3%]) caused ∼80% of episodes, with lower prevalences of Serratia species, Stenotrophomonas maltophilia, and community-acquired pathogens, such as pneumococci and Haemophilus influenzae. Slight changes in the pathogen order were noted among geographic regions; Latin America had an increased incidence of nonfermentative gram-negative bacilli. In addition, VABP isolates of the same species had a mean of 5%-10% less susceptibility to frequently used extended-spectrum antimicrobials, and the rate of drug resistance among HABP and VABP pathogens has been increasing by 1% per year (2004-2008). In conclusion, the empirical treatment of HABP and VABP due to prevailing bacterial causes and emerging drug resistance has become more challenging and requires use of multidrug empirical treatment regimens for routine clinical practice. These facts have profound impact on the choices of comparison therapies to be applied in contemporary new drug clinical trials for pneumonia.

Background: Stroke-associated pneumonia (SAP) has been implicated in the morbidity, mortality and increased medical cost after acute ischemic stroke. The annual cost of SAP during hospitalization in the United States approaches USD 459 million. The incidence and prognosis of SAP among intensive care unit (ICU) patients have not been thoroughly investigated. We reviewed the pathophysiology, microbiology, incidence, risk factors, outcomes and prophylaxis of SAP with special attention to ICU studies. Methods: To determine the incidence, risk factors and prognosis of acute SAP, PubMed was searched using the terms ‘pneumonia' AND ‘neurology intensive unit' and the MeSH terms ‘stroke' AND ‘pneumonia'. Non-English literature, case reports and chronic SAP studies were excluded. Studies were classified into 5 categories according to the setting they were performed in: neurological intensive care units (NICUs), medical intensive care units (MICUs), stroke units, mixed studies combining more than one setting or when the settings were not specified and rehabilitation studies. Results: The incidences of SAP in the following settings were: NICUs 4.1-56.6%, MICUs 17-50%, stroke units 3.9-44%, mixed studies 3.9-23.8% and rehabilitation 3.2-11%. The majority of NICU and MICU studies were heterogeneous including different neurovascular diseases, which partly explains the wide range of SAP incidence. The higher incidence in the majority of ICU studies compared to stroke units or acute floor studies is likely explained by the presence of mechanical ventilation, higher stroke severity causing higher rates of aspiration and stroke-induced immunodepression among ICU patients. The short-term mortality of SAP was increased among the mixed and stroke unit studies ranging between 10.1 and 37.3%. SAP was associated with worse functional outcome in the majority of stroke unit and floor studies. Mortality was less consistent among NICU and MICU studies. This difference could be due to the heterogeneity of ICU studies and the effect of small sample size or other independent risk factors for mortality such as the larger neurological deficit, mechanical ventilation, and age, which may simultaneously increase the risk of SAP and mortality confounding the outcomes of SAP itself. The pathophysiology of SAP is likely explained by aspiration combined with stroke-induced immunodepression through complex humeral and neural pathways that include the hypothalamic-pituitary-adrenal axis, parasympathetic and sympathetic systems. Conclusions: A unified definition of SAP, strict inclusion criteria, and the presence of a long-term follow-up need to be applied to the future prospective studies to better identify the incidence and prognosis of SAP, especially among ICU patients.

Nosocomial pneumonia due to antimicrobial-resistant pathogens is associated with high mortality. We assessed the efficacy and safety of the combination antibacterial drug ceftolozane–tazobactam versus meropenem for treatment of Gram-negative nosocomial pneumonia. We conducted a randomised, controlled, double-blind, non-inferiority trial at 263 hospitals in 34 countries. Eligible patients were aged 18 years or older, were undergoing mechanical ventilation, and had nosocomial pneumonia (either ventilator-associated pneumonia or ventilated hospital-acquired pneumonia). Patients were randomly assigned (1:1) with block randomisation (block size four), stratified by type of nosocomial pneumonia and age (<65 years vs ≥65 years), to receive either 3 g ceftolozane–tazobactam or 1 g meropenem intravenously every 8 h for 8–14 days. The primary endpoint was 28-day all-cause mortality (at a 10% non-inferiority margin). The key secondary endpoint was clinical response at the test-of-cure visit (7–14 days after the end of therapy; 12·5% non-inferiority margin). Both endpoints were assessed in the intention-to-treat population. Investigators, study staff, patients, and patients' representatives were masked to treatment assignment. Safety was assessed in all randomly assigned patients who received study treatment. This trial was registered with ClinicalTrials.gov, NCT02070757. Between Jan 16, 2015, and April 27, 2018, 726 patients were enrolled and randomly assigned, 362 to the ceftolozane–tazobactam group and 364 to the meropenem group. Overall, 519 (71%) patients had ventilator-associated pneumonia, 239 (33%) had Acute Physiology and Chronic Health Evaluation II scores of at least 20, and 668 (92%) were in the intensive care unit. At 28 days, 87 (24·0%) patients in the ceftolozane–tazobactam group and 92 (25·3%) in the meropenem group had died (weighted treatment difference 1·1% [95% CI −5·1 to 7·4]). At the test-of-cure visit 197 (54%) patients in the ceftolozane–tazobactam group and 194 (53%) in the meropenem group were clinically cured (weighted treatment difference 1·1% [95% CI −6·2 to 8·3]). Ceftolozane–tazobactam was thus non-inferior to meropenem in terms of both 28-day all-cause mortality and clinical cure at test of cure. Treatment-related adverse events occurred in 38 (11%) of 361 patients in the ceftolozane–tazobactam group and 27 (8%) of 359 in the meropenem group. Eight (2%) patients in the ceftolozane–tazobactam group and two (1%) in the meropenem group had serious treatment-related adverse events. There were no treatment-related deaths. High-dose ceftolozane–tazobactam is an efficacious and well tolerated treatment for Gram-negative nosocomial pneumonia in mechanically ventilated patients, a high-risk, critically ill population. Merck & Co.

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease such as cystic fibrosis (CF). Pulmonary disease caused by NTM has emerged as a major threat to the health of individuals with CF but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened an expert panel of specialists to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM pulmonary disease in individuals with CF. Nineteen experts were invited to participate in the recommendation development process. Population, Intervention, Comparison, Outcome (PICO) methodology and systematic literature reviews were employed to inform draft recommendations. An anonymous voting process was used by the committee to reach consensus. All committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or more of scores between 7 and 9 being considered ‘good’ agreement. Additionally, the committee solicited feedback from the CF communities in the USA and Europe and considered the feedback in the development of the final recommendation statements. Three rounds of voting were conducted to achieve 80% consensus for each recommendation statement. Through this process, we have generated a series of pragmatic, evidence-based recommendations for the screening, investigation, diagnosis and treatment of NTM infection in individuals with CF as an initial step in optimising management for this challenging condition.

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) remain important causes of morbidity and mortality. Increasing antimicrobial resistance has aroused the concern of the failure of antibiotic treatment. To determine the distribution of the bacterial isolates of HAP and VAP, their antimicrobial resistance patterns, and impact of discordant antibiotic therapy on clinical outcome in Asian countries A prospective surveillance study was conducted in 73 hospitals in 10 Asian countries from 2008-2009. A total of 2,554 cases with HAP or VAP in adults were enrolled and 2,445 bacterial isolates were collected from 1,897 cases. Clinical characteristics and antimicrobial resistance profiles were analyzed. Major bacterial isolates from HAP and VAP cases in Asian countries were Acinetobacter spp., Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae. Imipenem resistance rates of Acinetobacter and P. aeruginosa were 67.3% and 27.2%, respectively. Multidrug-resistant rates were 82% and 42.8%, and extensively drug-resistant rates were 51.1% and 4.9%. Multidrug-resistant rate of K. pneumoniae was 44.7%. Oxacillin resistance rate of S. aureus was 82.1%. All-cause mortality rate was 38.9%. Discordant initial empirical antimicrobial therapy increased the likelihood of pneumonia-related mortality (odds ratio, 1.542; 95% confidence interval, 1.127-2.110). Acinetobacter spp., P. aeruginosa, S. aureus, and K. pneumoniae are the most frequent isolates from adults with HAP or VAP in Asian countries. These isolates are highly resistant to major antimicrobial agents, which could limit the therapeutic options in the clinical practice. Discordant initial empirical antimicrobial therapy significantly increases the likelihood of pneumonia-related mortality.

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.

Bioinspired microrobots capable of actively moving in biological fluids have attracted considerable attention for biomedical applications because of their unique dynamic features that are otherwise difficult to achieve by their static counterparts. Here we use click chemistry to attach antibiotic-loaded neutrophil membrane-coated polymeric nanoparticles to natural microalgae, thus creating hybrid microrobots for the active delivery of antibiotics in the lungs in vivo. The microrobots show fast speed (>110 µm s −1 ) in simulated lung fluid and uniform distribution into deep lung tissues, low clearance by alveolar macrophages and superb tissue retention time (>2 days) after intratracheal administration to test animals. In a mouse model of acute Pseudomonas aeruginosa pneumonia, the microrobots effectively reduce bacterial burden and substantially lessen animal mortality, with negligible toxicity. Overall, these findings highlight the attractive functions of algae–nanoparticle hybrid microrobots for the active in vivo delivery of therapeutics to the lungs in intensive care unit settings. Biohybrid microrobots consisting of nanoparticle-modified microalgae are constructed for active drug delivery in the lungs. In an acute bacterial pneumonia model, the microrobots effectively reduce bacterial burden and lessen animal mortality.

Community-acquired pneumonia (CAP) is a common disease in children, and its aetiological and clinical diagnosis are challenging for physicians in both private practice and hospitals. Over the past three decades, conjugate vaccines have successfully reduced the burden of the former main causes of CAP, Streptococcus pneumoniae and Haemophilus influenzae type b. Today, viruses are by far the most commonly detected pathogens in children with CAP.   Conclusion : New insights into the aetiology and treatment of CAP in children in recent years have influenced management and are the focus of this review. In addition to reducing diagnostic uncertainty, there is an urgent need to reduce antibiotic overuse and antimicrobial resistance in children with CAP. What is Known: • Conjugate vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b have shifted the epidemiology of childhood CAP to predominantly viral pathogens and Mycoplasma pneumoniae. • Clinical, laboratory, and radiological criteria cannot reliably distinguish between bacterial and viral aetiology in children with CAP. What is New: • Test results and epidemiological data must be carefully interpreted, as no single diagnostic method applied to non-pulmonary specimens has both high sensitivity and high specificity for determining pneumonia aetiology in childhood CAP. • This review provides a simple and pragmatic management algorithm for children with CAP to aid physicians in providing optimal and safe care and reducing antibiotic prescribing.