Efficacy of EBL-1003 (apramycin) against Acinetobacter baumannii lung infections in mice.
Becker Katja,Aranzana-Climent Vincent,Cao Sha,Nilsson Anna,Shariatgorji Reza,Haldimann Klara,Platzack Björn,Hughes Diarmaid,Andrén Per E,Böttger Erik C,Friberg Lena E,Hobbie Sven N,
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
OBJECTIVES:Novel therapeutics are urgently required for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) causing critical infections with high mortality. Here we assessed the therapeutic potential of the clinical-stage drug candidate EBL-1003 (crystalline free base of apramycin) in the treatment of CRAB lung infections. METHODS:The genotypic and phenotypic susceptibility of CRAB clinical isolates to aminoglycosides and colistin was assessed by database mining and broth microdilution. The therapeutic potential was assessed by target attainment simulations on the basis of time-kill kinetics, a murine lung infection model, comparative pharmacokinetic analysis in plasma, epithelial lining fluid (ELF) and lung tissue, and pharmacokinetic/pharmacodynamic (PKPD) modelling. RESULTS:Resistance gene annotations of 5451 CRAB genomes deposited in the National Database of Antibiotic Resistant Organisms (NDARO) suggested >99.9% of genotypic susceptibility to apramycin. Low susceptibility to standard-of-care aminoglycosides and high susceptibility to EBL-1003 were confirmed by antimicrobial susceptibility testing of 100 A. baumannii isolates. Time-kill experiments and a mouse lung infection model with the extremely drug-resistant CRAB strain AR Bank #0282 resulted in rapid 4-log CFU reduction both in vitro and in vivo. A single dose of 125 mg/kg EBL-1003 in CRAB-infected mice resulted in an AUC of 339 h × μg/mL in plasma and 299 h × μg/mL in ELF, suggesting a lung penetration of 88%. PKPD simulations suggested a previously predicted dose of 30 mg/kg in patients (creatinine clearance (CLCr) = 80 mL/min) to result in >99% probability of -2 log target attainment for MICs up to 16 μg/mL. CONCLUSIONS:This study provides proof of concept for the efficacy of EBL-1003 in the treatment of CRAB lung infections. Broad in vitro coverage, rapid killing, potent in vivo efficacy, and a high probability of target attainment render EBL-1003 a strong therapeutic candidate for a priority pathogen for which treatment options are very limited.
Risk factors for lung infection in stroke patients: a meta-analysis of observational studies.
Yuan Mei-zhen,Li Feng,Tian Xin,Wang Wei,Jia Man,Wang Xue-feng,Liu Guang-wei
Expert review of anti-infective therapy
BACKGROUND:The aims of this meta-analysis were to evaluate the risk factors associated with lung infections in stroke patients and to provide evidence for prevention decisions. METHODS:We searched the Embase, PubMed, EBSCO and Web of Science databases to collect studies from January 2000 to July 2015. RESULTS:The meta-analysis identified 23 risk factors for lung infections in stroke patients, and the top 5, ranked by order according to odds ratio values (95% confidence interval), were as follows: multiple vertebrobasilar stroke, 22.99 (4.04, 130.83); National Institutes of Health Stroke Scale score >15 points, 14.63 (8.54, 25.08); mechanical ventilation, 10.20 (7.15, 14.57); nasogastric tube use, 9.87 (6.21, 15.70); and dysphagia, 7.50 (2.60, 21.65). CONCLUSION:Preventive measures should be taken against these risk factors to reduce the incidence of lung infection.
Risk Factors for Stroke in Patients With Sepsis and Bloodstream Infections.
Shao Iris Yuefan,Elkind Mitchell S V,Boehme Amelia K
Background and Purpose- Sepsis has been identified as a trigger for stroke, but the underlying mechanisms and risk factors that predispose patients with sepsis to increased stroke risk remain unclear. We sought to identify predictors of stroke after sepsis and bloodstream infections. Methods- The 2007-2009 California State Inpatient Database from the Health Care Utilization Project was used to identify patients over the age of 18 years and hospitalized with sepsis or bloodstream infection defined by International Classification of Diseases, Ninth Revision codes. Patients who died during their sepsis hospitalization were excluded. The primary outcome was a primary diagnosis of ischemic or hemorrhagic stroke on a subsequent hospitalization within 1 year. Associations between risk factors, also defined by International Classification of Diseases, Ninth Revision codes, and stroke were analyzed using multivariable logistic regression. A composite risk score was generated to predict stroke risk. Results- Of 121 947 patients with sepsis, 0.5% (n=613) had a primary diagnosis of stroke within a year of their sepsis hospitalization. Significant predictors for stroke were identified. A score was generated from these risk factors with points assigned based on regression coefficients: valvular heart diseases (1 point), congestive heart failure (1), renal failure (1), lymphoma (2), peripheral vascular diseases (2), pulmonary circulation disorders (2), and coagulopathy (3). The C statistic for the receiver operating characteristic curve for the score was 0.68. The risk of stroke increased 43% (odds ratio, 1.43; 95% CI, 1.37-1.48) per-point increase in the score. The effect of increase in score was greater among younger patients. Conclusions- Risk factors and a composite risk score for stroke may help identify a subpopulation of sepsis patients that could be targeted to reduce the short-term risk of stroke after serious infections.
Stroke Severity, and Not Cerebral Infarct Location, Increases the Risk of Infection.
Shim Raymond,Wen Shu Wen,Wanrooy Brooke J,Rank Michelle,Thirugnanachandran Tharani,Ho Luke,Sepehrizadeh Tara,de Veer Michael,Srikanth Velandai K,Ma Henry,Phan Thanh G,Sobey Christopher G,Wong Connie H Y
Translational stroke research
Infection is a leading cause of death in patients with stroke; however, the impact of cerebral infarct size or location on infectious outcome is unclear. To examine the effect of infarct size on post-stroke infection, we utilised the intraluminal middle-cerebral artery occlusion (MCAO) mouse model of ischemic stroke and adjusted the duration of arterial occlusion. At 1 day following stroke onset, the proportion of mice with infection was significantly greater in mice that had larger infarct sizes. Additionally, the presence of lung infection in these mice with severe strokes extended past 2 days, suggestive of long-term immune impairment. At the acute phase, our data demonstrated an inverse relationship between infarct volume and the number of circulating leukocytes, indicating the elevated risk of infection in more severe stroke is associated with reduced cellularity in peripheral blood, owing predominately to markedly decreased lymphocyte numbers. In addition, the stroke-induced reduction of lymphocyte-to-neutrophil ratio was also evident in the lung of all post-stroke animals. To investigate the effect of infarct location on post-stroke infection, we additionally performed a photothrombotic (PT) model of stroke and using an innovative systematic approach of analysis, we found the location of cerebral infarct does not impact on the susceptibility of post-stroke infection, confirming the greater role of infarct volume over infarct location in the susceptibility to infection. Our experimental findings were validated in a clinical setting and reinforced that stroke severity, and not infarct location, influences the risk of infection after stroke.
Stroke and death risk in ventricular assist device patients varies by ISHLT infection category: An INTERMACS analysis.
Shah Palak,Birk Sarah E,Cooper Lauren B,Psotka Mitchell A,Kirklin James K,Barnett Scott D,Katugaha Shalika B,Phillips Sheila,Looby Mary M,Pagani Francis D,Cowger Jennifer A
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
BACKGROUND:Ventricular assist device (VAD) patients often experience infections, which increase the risk of stroke and mortality. Using the definitions of the International Society for Heart and Lung Transplantation (ISHLT), we have characterized differences in clinical outcomes for categories of infection: VAD-specific (e.g., pump component related); VAD-related (e.g., bloodstream infection, BSI); and non-VAD infections (e.g., pneumonia). METHODS:Querying of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) identified 16,597 continuous-flow VAD recipients. Categories of infection were tested in multivariate models to determine the risk of stroke and death. RESULTS:After implant, 7,046 patients (42%) developed an infection at a median of 69 (interquartile range 12 to 272) days. A majority were non-VAD infections (49%), followed by VAD-related (26%) and VAD-specific infections (25%). BSIs were the most common form of VAD-related infection (92%), and the majority (59%) had no associated infection, that is, idiopathic bacteremia. Internal pump component infections were rare (0.003 event per patient-year [EPPY]). Infected VAD patients had a higher prevalence of stroke compared to patients without an infection (18% vs 11%, p < 0.001). The lowest stroke rate occurred after a VAD-specific infection (0.11 EPPY) compared with VAD-related (0.17 EPPY) and non-VAD infections (0.15 EPPY, p < 0.001). Hemorrhagic strokes were more common than ischemic strokes in all infection groups and highest after a VAD-related infection (0.13 EPPY). One-year survival after an infection was 87% in VAD-specific infections, as compared with VAD-related (71%) and non-VAD infections (72%, p < 0.001). CONCLUSIONS:The ISHLT categorization of VAD infections unveils notable differences in associated risk of stroke and mortality. A re-assessment of transplant prioritization for eligible infected VAD patients may be useful to increase transplant-related survival benefit.
Advanced age promotes colonic dysfunction and gut-derived lung infection after stroke.
Wen Shu Wen,Shim Raymond,Ho Luke,Wanrooy Brooke J,Srikhanta Yogitha N,Prame Kumar Kathryn,Nicholls Alyce J,Shen S J,Sepehrizadeh Tara,de Veer Michael,Srikanth Velandai K,Ma Henry,Phan Thanh G,Lyras Dena,Wong Connie H Y
Bacterial infection a leading cause of death among patients with stroke, with elderly patients often presenting with more debilitating outcomes. The findings from our retrospective study, supported by previous clinical reports, showed that increasing age is an early predictor for developing fatal infectious complications after stroke. However, exactly how and why older individuals are more susceptible to infection after stroke remains unclear. Using a mouse model of transient ischaemic stroke, we demonstrate that older mice (>12 months) present with greater spontaneous bacterial lung infections compared to their younger counterparts (7-10 weeks) after stroke. Importantly, we provide evidence that older poststroke mice exhibited elevated intestinal inflammation and disruption in gut barriers critical in maintaining colonic integrity following stroke, including reduced expression of mucin and tight junction proteins. In addition, our data support the notion that the localized pro-inflammatory microenvironment driven by increased tumour necrosis factor-α production in the colon of older mice facilitates the translocation and dissemination of orally inoculated bacteria to the lung following stroke onset. Therefore, findings of this study demonstrate that exacerbated dysfunction of the intestinal barrier in advanced age promotes translocation of gut-derived bacteria and contributes to the increased risk to poststroke bacterial infection.
Analysis of risk factors and prognosis of post-stroke pulmonary infection in integrated ICU.
Xu C-Y,Ye H-W,Chen B,Wu Y-F,Cao Z,Ding Z,Yao Y-P,Gao Y,Li J,Zhu J-J,He S
European review for medical and pharmacological sciences
OBJECTIVE:The incidence of SAP (stroke-associated pneumonia) is high in integrated ICU (Intensive Care Unit), and it might result in sepsis, which exacerbates the clinical outcome and increases mortality. It is necessary to investigate the epidemiological features of post-stroke infection and sepsis, identify the risk factors and analyze the prognosis. PATIENTS AND METHODS:We retrospectively analyzed the data of 329 patients with cerebral infarction or cerebral hemorrhage, from seven tertiary university hospitals in Suzhou, Jiangsu Province, between January 1, 2016, and December 31, 2016. Basic demographic and clinical data including common health evaluation, stroke severity, microbiological parameters, surgical interventions and treatments were recorded for the analysis. SAP was diagnosed according to the criteria and recommendation from American Heart Association (AHA). RESULTS:188 (66.4%) patients suffered pneumonia, 124 patients were diagnosed as SAP. Compared with SAP, patients with non-SAP pulmonary infection had prolonged mechanical ventilation time, prolonged central venous catheter indwelling time, and higher incidence of sepsis (17.7% vs. 48.4%). 53 patients (18.7%) developed sepsis during hospitalization, whose mortality rate during hospitalization and the occurrence of neurologic dysfunction at 3 months were significantly increased (p<0.05). 130 positive results of sputum cultures were found. The detected pathogens were mainly gram-negative bacteria. The pathogenic detection rate of non-SAP patients with pulmonary infection was higher (78.1%). The in-hospital mortality was 16.3% and the related risk factors were higher NIHSS score at admission, lower GCS score at admission, pulmonary infection (especially non-SAP pulmonary infection) and sepsis during hospitalization. CONCLUSIONS:The incidence of pulmonary infection after stroke in the integrated ICU is high, and it is easy to be complicated with sepsis, prolonging the mechanical ventilation time, central venous catheter indwelling time and hospitalization time, and the prognosis of long-term neurological function is relatively poor. The definition of stroke-associated pneumonia has implications for the classification of clinical infections, the prediction of possible pathogenic pathogens, and the guidance of anti-infective treatment.
Lung Imaging Reveals Stroke-Induced Impairment in Pulmonary Intravascular Neutrophil Function, a Response Exacerbated with Aging.
Journal of immunology (Baltimore, Md. : 1950)
In stroke patients, infection is a significant contributor to morbidity and mortality. Moreover, older stroke patients show an increased risk of developing stroke-associated infection, although the mechanisms underlying this increased susceptibility to infection are unknown. In this study, using an experimental mouse model of ischemic stroke, we showed that older (12-15 mo of age) mice had elevated lung bacterial infection and inflammatory damage after stroke when compared with young (8-10 wk of age) counterparts, despite undergoing the same degree of brain injury. Intravital microscopy of the lung microvasculature revealed that in younger mice, stroke promoted neutrophil arrest in pulmonary microvessels, but this response was not seen in older poststroke mice. In addition, bacterial phagocytosis by neutrophils in the lung microvasculature was reduced by both aging and stroke, such that neutrophils in aged poststroke mice showed the greatest impairment in this function. Analysis of neutrophil migration in vitro and in the cremaster muscle demonstrated that stroke alone did not negatively impact neutrophil migration, but that the combination of increased age and stroke led to reduced effectiveness of neutrophil chemotaxis. Transcriptomic analysis of pulmonary neutrophils using RNA sequencing identified 79 genes that were selectively altered in the context of combined aging and stroke, and they were associated with pathways that control neutrophil chemotaxis. Taken together, the findings of this study show that stroke in older animals results in worsening of neutrophil antibacterial responses and changes in neutrophil gene expression that have the potential to underpin elevated risk of stroke-associated infection in the context of increased age.
Dynamic Process of Secondary Pulmonary Infection in Mice With Intracerebral Hemorrhage.
Zhang Hanyu,Huang Yingying,Li Xiaojin,Han Xu,Hu Jing,Wang Bin,Zhang Lin,Zhuang Pengwei,Zhang Yanjun
Frontiers in immunology
Stroke is a common central nervous system disease in clinical practice. Stroke patients often have infectious complications, such as pneumonia and infections of the urinary tract and gastrointestinal tract. Although it has been shown that translocation of the host gut microbiota to the lungs and immune dysfunction plays a vital role in the development of infection after ischemic stroke, the occurrence and mechanism of pulmonary infection at different time points after hemorrhagic cerebral remain unclear. In this study, the changes in the immune system and intestinal barrier function in mice during disease development were investigated at 1 day (M 1 d), 3 days (M 3 d) and 7 days (M 7 d) following hemorrhagic stroke to clarify the mechanism of secondary pulmonary infection. The experimental results revealed that after hemorrhagic stroke, model mice showed increased brain damage from day 1 to 3, followed by a trend of brain recovery from day 3 to 7 . After hemorrhagic stroke, the immune system was disturbed in model mice. Significant immunosuppression of the peripheral immune system was observed in the M 3 d group but improved in the M 7 d group. Staining of lung tissues with hematoxylin and eosin (H&E) and for inflammatory factors revealed considerable disease and immune disorders in the M 7 d group. Stroke seriously impaired intestinal barrier function in mice and significantly changed the small intestine structure. From 1 to 7 d after stroke, intestinal permeability was increased, whereas the levels of markers for intestinal tight junctions, mucus and immunoglobulin A were decreased. Analysis based on 16S rRNA suggested that the microflora in the lung and ileum was significantly altered after stroke. The composition of microflora in lung and ileum tissue was similar in the M 7d group, suggesting that intestinal bacteria had migrated to lung tissue and caused lung infection at this time point after hemorrhagic stroke. In stroke mice, the aggravation of intestinal barrier dysfunction and immune disorders after intracerebral hemorrhage, promoted the migration of enteric bacteria, and increased the risk of pneumonia poststroke. Our findings reveal the dynamic process of infection after hemorrhagic stroke and provide clues for the optimal timing of intervention for secondary pulmonary infection in stroke patients.
Signs of Pulmonary Infection on Admission Chest Computed Tomography Are Associated With Pneumonia or Death in Patients With Acute Stroke.
de Jonge Jeroen C,Takx Richard A P,Kauw Frans,de Jong Pim A,Dankbaar Jan W,van der Worp H Bart
Background and Purpose- In patients with acute stroke, the occurrence of pneumonia has been associated with poor functional outcomes and an increased risk of death. We assessed the presence and consequences of signs of pulmonary infection on chest computed tomography (CT) before the development of clinically overt pneumonia. Methods- In 200 consecutive patients with acute ischemic stroke who had CT angiography from skull to diaphragm (including CT of the chest) within 24 hours of symptom onset, we assessed the presence of consolidation, ground-glass-opacity and the tree-in-bud sign as CT signs of pulmonary infection and assessed the association with the development of clinically overt pneumonia and death in the first 7 days and functional outcome after 90 days with logistic regression. Results- The median time from stroke onset to CT was 151 minutes (interquartile range, 84-372). Thirty patients (15%) had radiological signs of infection on admission, and 22 (11.0%) had a clinical diagnosis of pneumonia in the first 7 days. Patients with radiological signs of infection had a higher risk of developing clinically overt pneumonia (30% versus 7.6%; adjusted odds ratios, 4.2 [95% CI, 1.5-11.7]; =0.006) and had a higher risk of death at 7 days (adjusted odds ratios, 3.7 [95% CI, 1.2-11.6]; =0.02), but not at 90 days. Conclusions- About 1 in 7 patients with acute ischemic stroke had radiological signs of pulmonary infection within hours of stroke onset. These patients had a higher risk of clinically overt pneumonia or death. Early administration of antibiotics in these patients may lead to better outcomes.