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Since polymyxin B has a restricted therapeutic range and increased danger of both neurological damage and kidney damage, it is no longer the first choice for treating emerging gram-negative bacteria with multiple antibiotic resistance. The optimal dose schedule for patients with renal impairment regarding polymyxin B, it is provided as a chemically active formulation and primarily removed via methods other than kidney, is still up for debate. Similar to colistin, polymyxin-B effectively combats gram-negative aerobic bacterium that is resistant to several drugs such as Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli that produces carbapenemase, and Klebsiella pneumoniae. As a result, polymyxins cause cell apoptosis by inducing pan-caspase activation through many routes in a manner that is dependent on time and concentration. One of the most frequent and undesirable side effects of polymyxins is the development of AKI. A great deal of pharmacokinetic studies that have been published to far concur that creatinine clearance affects polymyxin B clearance; nevertheless, there is ongoing debate on the extent of this influence. [ABSTRACT FROM AUTHOR]

Neisseria meningitidis is a gram-negative organism primarily associated with invasive meningococcal disease. This case report presents a rare occurrence of Neisseria meningitidis pyelonephritis in a 24-year-old male with congenital urological abnormalities. We describe the diagnostic challenges and management of this unique case. Ultimately, the patient completed IV then oral antibiotics and recovered with no complications. This case emphasizes the importance of considering atypical pathogens in urinary tract infections and contributes valuable insights to diagnostic microbiology and clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Unique metabolic requirements accompany the development and functional fates of immune cells. How cellular metabolism is important in natural killer (NK) cells and their memory‐like differentiation in bacterial infections remains elusive. Methods: Here, we utilise our established NK cell memory assay to investigate the metabolic requirement for memory‐like NK cell formation and function in response to the Gram‐negative intracellular bacteria Burkholderia pseudomallei (BP), the causative agent of melioidosis. Results: We demonstrate that CD160+ memory‐like NK cells upon BP stimulation upregulate glucose and amino acid transporters in a cohort of recovered melioidosis patients which is maintained at least 3‐month post‐hospital admission. Using an in vitro assay, human BP‐specific CD160+ memory‐like NK cells show metabolic priming including increased expression of glucose and amino acid transporters with elevated glucose uptake, increased mTOR activation and mitochondrial membrane potential upon BP re‐stimulation. Antigen‐specific and cytokine‐induced IFN‐γ production of this memory‐like NK cell subset are highly dependent on oxidative phosphorylation (OXPHOS) with some dependency on glycolysis, whereas the formation of CD160+ memory‐like NK cells in vitro is dependent on fatty acid oxidation and OXPHOS and further increased by metformin. Conclusion: This study reveals the link between metabolism and cellular function of memory‐like NK cells, which can be exploited for vaccine design and for monitoring protection against Gram‐negative bacterial infection. [ABSTRACT FROM AUTHOR]

Introduction: Our objective is to determine whether prolonged infusion (PI) of beta-lactam antibiotics yields superior outcomes compared to intermittent infusion (II) in patients with Gram-Negative Bacterial (GNB) infections. Methods: We systematically searched papers from PubMed, the Cochrane Library, Embase, and Clinicaltrials.gov, targeting mortality as the primary outcome and looking at the clinical cure rate, hospital and intensive care unit (ICU) stay lengths, antibiotic treatment duration, and mechanical ventilation (MV) duration as secondary outcomes. Results: Our meta-analysis of 18 studies, including 5 randomized control trials and 13 observational studies, with a total of 3,035 patients—1,510 in the PI group and 1,525 in the II group, revealed significant findings. PI was associated with reduced mortality (RR, 0.67; 95% CI, 0.55–0.81; p = 0.001; I2 = 4.52%) and a shorter MV duration (SMD, −0.76; 95% CI, −1.37 to −0.16; p = 0.01; I2 = 87.81%) compared to II. However, no differences were found in clinical cure rates, antibiotic treatment duration, length of hospital stay, or length of ICU stay. Conclusions: The PI approach for administering beta-lactam antibiotics in patients with suspected or confirmed GNB infections may be advantageous in reducing mortality rates and the duration of MV when compared to the II strategy. [ABSTRACT FROM AUTHOR]

Objective To construct the prediction model for risk of Gram-negative bacterium (GNB) bloodstream infection (BSI) based on data of patients with blood flow infection from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, aiming to provide a new method for predicting the risk of GNB-BSI. Methods Clinical data and laboratory indexes [blood routine (red blood cells, white blood cells, platelets, etc.), blood biochemistry (potassium ions, calcium ions, chloride ions, bicarbonate, anion gap and urea nitrogen, etc.), coagulation function indicators (INR, PT, PTT) ] of 2 503 patients with bloodstream infection from MIMIC-IV database were collected. These data were divided into the training set (1 752 cases) and the validation set (751 cases) at a ratio of 7:3. The LASSO regression was employed to select the factors influencing the incidence of GNB-BSI in the training dataset. These factors were subjected to multivariate Logistic regression analysis in order to establish a nomogram prediction model for the risk of developing GNBBSI. The differentiation, consistency, and clinical practicality of the model was assessed using receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) in both the training and validation sets. Results Age, cancer, hepatobiliary disease, alcohol abuse, potassium, calcium, bicarbonate, anion gap, and urea nitrogen were independent factors influencing the risk of GNB-BSI. Logistic regression analysis was conducted to develop a risk prediction model for GNB-BSI (nomogram model) based on these factors. The area under ROC curve of the model was 0.711 (95%CI = 0.667-0.756) in the training set and 0. 705 (95%CI = 0. 678-0.733) in the validation set. The calibration curve exhibited satisfactory consistency between predicted and actual outcomes for GNB-BSI (P=0.764) . The DCA showed that the nomogram model had good clinical practicability. Conclusion A nomogram model for risk of GNB-BSI was established successfully, which had good predictive performance, and effectively identified high-risk patients. [ABSTRACT FROM AUTHOR]

Imipenem/cilastatin/relebactam is approved for the treatment of serious gram‐negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram‐negative bacterial infections receiving standard‐of‐care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration–time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax) across age cohorts were 56.5%‐93.7% and 32.2‐38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9‐21.3 mcg/mL and 26.1‐55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation. [ABSTRACT FROM AUTHOR]

Abstract Objective Unique metabolic requirements accompany the development and functional fates of immune cells. How cellular metabolism is important in natural killer (NK) cells and their memory‐like differentiation in bacterial infections remains elusive. Methods Here, we utilise our established NK cell memory assay to investigate the metabolic requirement for memory‐like NK cell formation and function in response to the Gram‐negative intracellular bacteria Burkholderia pseudomallei (BP), the causative agent of melioidosis. Results We demonstrate that CD160+ memory‐like NK cells upon BP stimulation upregulate glucose and amino acid transporters in a cohort of recovered melioidosis patients which is maintained at least 3‐month post‐hospital admission. Using an in vitro assay, human BP‐specific CD160+ memory‐like NK cells show metabolic priming including increased expression of glucose and amino acid transporters with elevated glucose uptake, increased mTOR activation and mitochondrial membrane potential upon BP re‐stimulation. Antigen‐specific and cytokine‐induced IFN‐γ production of this memory‐like NK cell subset are highly dependent on oxidative phosphorylation (OXPHOS) with some dependency on glycolysis, whereas the formation of CD160+ memory‐like NK cells in vitro is dependent on fatty acid oxidation and OXPHOS and further increased by metformin. Conclusion This study reveals the link between metabolism and cellular function of memory‐like NK cells, which can be exploited for vaccine design and for monitoring protection against Gram‐negative bacterial infection.

PurposeAlthough corticosteroids are recommended in the 2021 Surviving Sepsis Campaign (SSC) guidelines, evidence with respect to their effects on short-term mortality remains conflicting. We conducted this study to identify whether corticosteroids alter 28-day mortality in septic shock patients with gram-negative bacterial infection.Materials and methodsA total of 621 patients with septic shock and gram-negative bacterial culture results were identified from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Propensity score matching (PSM) was performed, and Kaplan–Meier survival curve analyses with log-rank tests were used to determine the relationship between corticosteroid use and the risk of 28-day mortality. Subgroup analyses were conducted to assess whether the conclusions were stable and reliable.ResultsCorticosteroid administration was associated with increased 28-day mortality in septic shock patients with gram-negative bacterial infection (log-rank test P = 0.028). The incidence of Stage 2 or 3 AKI and the rate of hospital mortality were higher among patients who received corticosteroids. The incidence of Stage 2 or 3 AKI in the early period significantly mediated the relationship between corticosteroid use and 28-day mortality [P =0.046 for the average causal mediation effect (ACME)]. Interaction tests indicated that the effect of corticosteroid use was maintained in patients with a neutrophil-to-lymphocyte ratio (NLR) of

Probability of target attainment (PTA) analyses were conducted to support the recommended ceftolozane/tazobactam dosing regimens, adjusted for renal function, in patients with hospital‐acquired/ventilator‐associated bacterial pneumonia (HABP/VABP). Previously published population pharmacokinetic models describing the disposition of ceftolozane and tazobactam in plasma and epithelial lining fluid (ELF) in patients with HABP/VABP were used to simulate ceftolozane and tazobactam concentration–time profiles in plasma and ELF over the course of 14 days. The simulations were conducted for patients with normal renal function and for patients receiving adjusted doses for mild, moderate, and severe renal impairment. PTA was calculated using established pharmacokinetic/pharmacodynamic targets for ceftolozane and tazobactam. Across renal function groups, plasma PTA was 100% for ceftolozane and >99% for tazobactam; ELF PTA was >99% for ceftolozane and >87% for tazobactam. These results provided support for the currently recommended ceftolozane/tazobactam dosing regimens for HABP/VABP, which were efficacious and well tolerated in the Ceftolozane–Tazobactam Versus Meropenem for Treatment of Nosocomial Pneumonia (ASPECT‐NP) trial. [ABSTRACT FROM AUTHOR]

Objective: The objective of this analysis was to evaluate the cost-effectiveness of imipenem/cilastatin/relebactam compared to colistin-imipenem in the treatment of hospitalized patients with Gram-negative bacterial infections caused by imipenem-resistant pathogens. The perspective was both that of the National Health Service (NHS) and the social one. Methodology: A mixed model was developed to simulate a cohort of patients capable of highlighting the impacts of the disease on the quality of life and the absorption of economic resources of the patients in analysis. Modelled patients were those with hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infection (cIAI) or complicated urinal tract infection (cUTI) caused by carbapenem-resistant Gram-negative (GN) pathogens. The model begins with a short-term decision tree describing possible treatment routes and outcomes for patients during the hospitalization period. Patients who are healed in the decision tree enter the long-term Markov model, designed to capture the follow-up costs and health-related quality of life (HRQL) of patients healed over their lifetime. Results: The analysis, conducted on a hypothetical cohort of 1,000 patients, highlights how the use of imipenem/cilastatin/relebactam is advantageous both in terms of diagnosis and treatment in the short term and in terms of cost-effectiveness. In fact, it is dominant compared to colistin-imipenem both in the NHS and in the social perspective since, compared to an average saving of € 2,800.15 and € 3,174.63 respectively, it would generate an increase of 4.76 years of life and of 4.12 QALYs per patient.

Objective: The objective of this analysis was to evaluate the cost-effectiveness of imipenem/cilastatin/relebactam compared to colistin-imipenem in the treatment of hospitalized patients with Gram-negative bacterial infections caused by imipenem-resistant pathogens. The perspective was both that of the National Health Service (NHS) and the social one. Methodology: A mixed model was developed to simulate a cohort of patients capable of highlighting the impacts of the disease on the quality of life and the absorption of economic resources of the patients in analysis. Modelled patients were those with hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infection (cIAI) or complicated urinal tract infection (cUTI) caused by carbapenem-resistant Gram-negative (GN) pathogens. The model begins with a short-term decision tree describing possible treatment routes and outcomes for patients during the hospitalization period. Patients who are healed in the decision tree enter the long-term Markov model, designed to capture the follow-up costs and health-related quality of life (HRQL) of patients healed over their lifetime. Results: The analysis, conducted on a hypothetical cohort of 1,000 patients, highlights how the use of imipenem/cilastatin/relebactam is advantageous both in terms of diagnosis and treatment in the short term and in terms of cost-effectiveness. In fact, it is dominant compared to colistin-imipenem both in the NHS and in the social perspective since, compared to an average saving of € 2,800.15 and € 3,174.63 respectively, it would generate an increase of 4.76 years of life and of 4.12 QALYs per patient. [ABSTRACT FROM AUTHOR]

BackgroundTo explore the diagnostic performance of interleukin (IL)-6 and IL-10 in discriminating Gram bacteria types and predicting disease severity in intensive care unit (ICU)-hospitalized pediatric sepsis patients.MethodWe retrospectively collected Th1/Th2 cytokine profiles of 146 microbiologically documented sepsis patients. Patients were categorized into Gram-positive (G+) or Gram-negative (G-) sepsis groups, and cytokine levels were compared. Subgroup analysis was designed to eliminate the influence of other inflammatory responses on cytokine levels.ResultsAfter propensity score matching, 78 patients were matched and categorized according to Gram bacteria types. Compared with G+ sepsis, IL-6 and IL-10 were significantly elevated in G- sepsis (p < 0.05). Spearman test proved the linear correlation between IL-6 and IL-10 (r = 0.654, p < 0.001), and their combination indicators (ratio and differences) were effective in identifying G- sepsis. In the subgroup analysis, such cytokine elevation was significant regardless of primary infection site. However, for patients with progressively deteriorating organ function [new or progressive multiple organ dysfunction syndrome (NPMODS)], differences in IL-6 and IL-10 levels were less significant between G+ and G- sepsis. In the receiver operating characteristic (ROC) curves of the G- sepsis group, the area under the curve (AUC) value for IL-6 and IL-10 was 0.679 (95% CI 0.561–0.798) and 0.637 (95% CI 0.512–0.762), respectively. The optimal cutoff value for diagnosing G- sepsis was 76.77 pg/ml and 18.90 pg/ml, respectively. While for the NPMODS group, the AUC for IL-6 and IL-10 was 0.834 (95% CI 0.766–0.902) and 0.781 (95% CI 0.701–0.860), respectively.ConclusionIL-6 and IL-10 are comparably effective in discriminating G+/G- sepsis in pediatric intensive care unit (PICU) patients. The deteriorated organ function observed in ICU patients reveals that complex inflammatory responses might have contributed to the cytokine pattern observed in severe sepsis patients, therefore confounding the discriminating efficacy of Th1/Th2 cytokines in predicting Gram bacteria types.

We report the first case of chronic endophthalmitis following uncomplicated cataract surgery secondary to the bacterium Aquamicrobium terrae. Recurrent inflammation secondary to infection persisted after intraocular lens removal and total capsulectomy, but resolved after adherent residual capsule fragments were ablated using endoscopic vitrectomy. Purpose: Chronic postoperative endophthalmitis is a known complication of cataract surgery. Here, we report a case of chronic endophthalmitis following uncomplicated cataract surgery secondary to the atypical bacterium Aquamicrobium terrae. Methods: Retrospective case report of a single patient with endophthalmitis secondary to A. terrae. Results: A 61-year-old healthy patient presented with recurrent iridocyclitis following uncomplicated cataract surgery. Repeated attempts to taper off topical steroid eyedrops were unsuccessful. Anterior chamber paracentesis cultures and vitrectomy cultures grew the same gram-negative bacillus, A. terrae , on six different occasions. The patient was treated initially with a series of intravitreal ceftazidime injections and adjuvant oral minocycline with recurrence of inflammation necessitating pars plana vitrectomy with intraocular lens removal and total capsulectomy. Inflammatory episodes recurred until residual capsule fragments were ablated using endoscopic vitrectomy. Since ablation over 18 months ago, no further recurrences have occurred and the patient has excellent visual outcome. Conclusion: A. terrae is a gram-negative bacillus recovered from polluted soil. This is the first case of postoperative endophthalmitis secondary to A. terrae and the first description of human infection caused by this newly identified microbe. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies (mAbs) are gaining significant momentum as novel therapeutics for infections caused by antibiotic-resistant bacteria. We evaluated the mechanism by which antibacterial mAb therapy protects against Acinetobacter baumannii infections. Anticapsular mAb enhanced macrophage opsonophagocytosis and rescued mice from lethal infections by harnessing complement, macrophages, and neutrophils; however, the degree of bacterial burden did not correlate with survival. Furthermore, mAb therapy reduced proinflammatory (interleukin-1β [IL-1β], IL-6, tumor necrosis factor-α [TNF-α]) and anti-inflammatory (IL-10) cytokines, which correlated inversely with survival. Although disrupting IL-10 abrogated the survival advantage conferred by the mAb, IL-10-knockout mice treated with mAb could still survive if TNF-α production was suppressed directly (via anti-TNF-α neutralizing antibody) or indirectly (via macrophage depletion). Thus, even for a mAb that enhances microbial clearance via opsonophagocytosis, clinical efficacy required modulation of pro- and anti-inflammatory cytokines. These findings may inform future mAb development targeting bacteria that trigger the sepsis cascade. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to delineate the characteristics and outcomes of gram-negative bacteremia (GNB) in oncology patients; analyze the risk factors for multi-drug-resistant (MDR) GNB; and assess its impact on the recurrence of bloodstream infection (BSI), hospital stay, and 30-day mortality., Methods: Data, including demographics, clinical features, common cancers, and microbiologic findings, were collected retrospectively from electronic medical records of patients admitted with solid tumors and BSI episodes between January and December 2022. Fisher's exact tests were used to determine the effect of MDR-GNB on 30-day mortality and BSI recurrence. The Wilcoxon rank-sum test assessed the differences in the length of hospital stay. Logistic regression models identified the risk factors for MDR-GNB., Results: Among 1074 patients, 77 episodes of GNB bacteremia occurred in 59 individuals (47% male, median age 57.4 years). Of these, 37 (48%) were MDR-GNB. Carbapenem resistance was noted in 9.1% of GNB episodes. Previous antibiotic use was significantly associated with MDR-GNB (odds ratio 7.82; 95% confidence interval 2.52-24). MDR-GNB was linked to longer hospital stays (median 23 vs 10.5 days, P = 0.003) and higher recurrence rates than non-MDR-GNB (35.13% vs 5.0%, P <0.001). However, 30-day mortality did not significantly differ between the groups (35.14% vs 32.5%, P = 0.81)., Conclusion: Previous antibiotic use predicted MDR-GNB in patients with solid tumor. MDR-GNB bacteremia increased the length of hospital stay and risk of recurrence compared with non-MDR-GNB bacteremia., Competing Interests: The authors have no competing interests to declare., (© 2024 The Author(s).)

Objective: Neonatal sepsis is a clinical condition that results in serious morbidity and mortality unless urgently diagnosed and treated. Obtaining the results of blood cultures to determine the causative agent in sepsis is a time-consuming process. The CRP/albumin ratio is an inflammatory marker that has started to be used in recent years. The aim of our study was to investigate the relationship between CRP/albumin and Gram-negative bacterial sepsis in neonates. Material and Methods: This study was conducted on 112 premature neonates with sepsis. The patients were divided into two groups according to culture results as Gram-negative and Gram-positive bacterial sepsis. The laboratory and demographic features of the patients were obtained from the hospital records. A receiver operating characteristic curve was plotted to evaluate the predictive value of the CRP/albumin ratio for Gram-negative sepsis. Results: CRP/albumin was significantly higher in the Gram-negative group (p<0.001). According to the receiver operating characteristic curve, the optimal cut-off value of CRP/albumin for the prediction of Gram-negative sepsis was >35.17, which had a specificity of 97% and sensitivity of 56% (AUC=0.839; 95% CI: 0.743-0.944; p<0.001). A multivariate logistic regression analysis revealed that CRP/albumin (OR=1.082, 95% CI: 1.033-1.134, p=0.001) and absolute neutrophil count (OR=1.145, 95% CI: 1.000-1.312, p=0.049) were still associated with Gram-negative sepsis after adjustment for variables found to be statistically significant in univariate analysis and correlated with Gram-negative sepsis. Conclusion: The CRP/albumin ratio is independently related to Gram-negative sepsis in neonatal sepsis and may be useful in predicting Gram-negative bacteremia. INSET: 32. [ABSTRACT FROM AUTHOR]

Introduction Neisseria elongata, which is part of the normal oropharyngeal bacterial flora, can be an aggressive organism causing serious infections including infective endocarditis. N. elongata infective endocarditis is rare and no current guidelines exist to direct antibiotic selection and/or duration of treatment. Case report We report a case of infective endocarditis due to N. elongata and a review of the literature. Our patient is a healthy young woman, who was found to have an aortic root abscess with valve perforation requiring valve replacement. Discussion N. elongata infective endocarditis typically affects the left cardiac chambers and is associated with high risk of embolization. A transesophageal echocardiogram should be performed as part of the initial workup to assess the extent of infection, as a high percentage of patients develop perivalvular abscess formation and/or valve perforation. Most patients require prolonged antibiotic therapy and early surgical intervention. Conclusions This case demonstrates the potential severity of N. elongata endocarditis. Further studies are needed to establish management guidance. [ABSTRACT FROM AUTHOR]

Caspase-11 is a pro-inflammatory enzyme that is stringently regulated during its expression and activation. As caspase-11 is not constitutively expressed in cells, it requires a priming step for its upregulation, which occurs following the stimulation of pathogen and cytokine receptors. Once expressed, caspase-11 activation is triggered by its interaction with lipopolysaccharide (LPS) from Gram-negative bacteria. Being an initiator caspase, activated caspase-11 functions primarily through its cleavage of key substrates. Gasdermin D (GSDMD) is the primary substrate of caspase-11, and the GSDMD cleavage fragment generated is responsible for the inflammatory form of cell death, pyroptosis, via its formation of pores in the plasma membrane. Thus, caspase-11 functions as an intracellular sensor for LPS and an immune effector. This review provides an overview of caspase-11—describing its structure and the transcriptional mechanisms that govern its expression, in addition to its activation, which is reported to be regulated by factors such as guanylate-binding proteins (GBPs), high mobility group box 1 (HMGB1) protein, and oxidized phospholipids. We also discuss the functional outcomes of caspase-11 activation, which include the non-canonical inflammasome, modulation of actin dynamics, and the initiation of blood coagulation, highlighting the importance of inflammatory caspase-11 during infection and disease.

Cystic fibrosis (CF) patients with Burkholderia cepacia complex (Bcc) pulmonary infections have high morbidity and mortality. The aim of this study was to compare different methods for identification of Bcc species isolated from paediatric CF patients. Oropharyngeal swabs from children with CF were used to obtain isolates of Bcc samples to evaluate six different tests for strain identification. Conventional (CPT) and automatised (APT) phenotypic tests, polymerase chain reaction (PCR)-recA, restriction fragment length polymorphism-recA, recAsequencing, and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) were applied. Bacterial isolates were also tested for antimicrobial susceptibility. PCR-recA analysis showed that 36 out of the 54 isolates were Bcc. Kappa index data indicated almost perfect agreement between CPT and APT, CPT and PCR-recA, and APT and PCR-recA to identify Bcc, and MALDI-TOF and recAsequencing to identify Bcc species. The recAsequencing data and the MALDI-TOF data agreed in 97.2% of the isolates. Based on recA sequencing, the most common species identified were Burkholderia cenocepacia IIIA (33.4%),Burkholderia vietnamiensis (30.6%), B. cenocepaciaIIIB (27.8%), Burkholderia multivorans (5.5%), and B. cepacia (2.7%). MALDI-TOF proved to be a useful tool for identification of Bcc species obtained from CF patients, although it was not able to identify B. cenocepacia subtypes.

Purpose: Although corticosteroids are recommended in the 2021 Surviving Sepsis Campaign (SSC) guidelines, evidence with respect to their effects on short-term mortality remains conflicting. We conducted this study to identify whether corticosteroids alter 28-day mortality in septic shock patients with gram-negative bacterial infection., Materials and Methods: A total of 621 patients with septic shock and gram-negative bacterial culture results were identified from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Propensity score matching (PSM) was performed, and Kaplan-Meier survival curve analyses with log-rank tests were used to determine the relationship between corticosteroid use and the risk of 28-day mortality. Subgroup analyses were conducted to assess whether the conclusions were stable and reliable., Results: Corticosteroid administration was associated with increased 28-day mortality in septic shock patients with gram-negative bacterial infection (log-rank test P = 0.028). The incidence of Stage 2 or 3 AKI and the rate of hospital mortality were higher among patients who received corticosteroids. The incidence of Stage 2 or 3 AKI in the early period significantly mediated the relationship between corticosteroid use and 28-day mortality [ P =0.046 for the average causal mediation effect (ACME)]. Interaction tests indicated that the effect of corticosteroid use was maintained in patients with a neutrophil-to-lymphocyte ratio (NLR) of <20 ( P -value for interaction = 0.027)., Conclusion: Systemic corticosteroid use could be harmful in septic shock patients with gram-negative bacterial infection, especially in patients with relatively low NLR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dong, Heng, Zhang, Shen, Lan, Wei and Jin.)

Background & objectives: Sepsis due to multidrug-resistant Gram-negative pathogens is a challenge for clinicians and microbiologists and has led to use of parenteral colistin. There is a paucity of data regarding safety and efficacy of intravenous colistin use in neonates. The objective of this retrospective analysis was to study the efficacy and safety of intravenous colistin in the treatment of neonatal sepsis. Methods: An audit of the data from neonates, admitted to a neonatal intensive care unit of a tertiary care hospital during January 2012 to December 2012, and who received intravenous colistin was carried out. Results: Sixty two neonates received intravenous colistin (52 preterm and 10 term) for the treatment of pneumonia, bloodstream infections and meningitis. The isolated pathogens in decreasing order of frequency were Acinetobacter baumannii, Klebsiella pneumonia and Pseudomonas aeruginosa. Of the total 62 neonates, 41 (66.12%) survived and 21 (33.87%) died. Significantly higher mortality was observed in neonates with lower body weights (P < 0.05). A significant association of mortality was found in those with sepsis due to Klebsiella species. Only one of seven with this infection survived as against 15 of the 23 who grew other organisms [P = 0.03; crude odds ratio = 11.25 (1.2, 110.5)]. None of the neonates developed neurotoxicity or nephrotoxicity. Interpretation & conclusions: This retrospective study in neonates with sepsis showed that intravenous colistin was safe and effective in the treatment of neonatal sepsis. Further, well-controlled, prospective clinical trials need to be done to corroborate these findings. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to report an unusual case of chronic postoperative endophthalmitis following cataract surgery, secondary to Ochrobactrum anthropi that was found to be resistant to vancomycin. Findings: Anterior chamber paracentesis cultures grew gram negative bacilli Ochrobactrum anthropi. The patient was treated with a series of intracameral injections of moxifloxacin, with adjuvant oral moxifloxacin. Posterior sub-Tenon and oral corticosteroids were used to treat cystoid macular edema. Explantation of the intraocular lens (IOL)-capsular bag complex was avoided. Conclusions: Chronic postoperative endophthalmitis is a rare entity, often due to indolent pathogens that sequester in the capsular bag. Aggressive surgical intervention may be avoided with the use of adequate intraocular antibiotic, provided that the offending organism demonstrates appropriate antibiotic susceptibilities. [ABSTRACT FROM AUTHOR]

Background Human toll-like receptor 4 (TLR4) is an important receptor in innate immunity, particularly against gram-negative bacterial infection (GNBI). In our study, we evaluated associations of TLR4 single nucleotide polymorphisms (SNPs) with GNBI in Han Chinese neonates. Patients and Methods Polymorphisms in TLR4 were genotyped in 201 neonates with GNBI and 279 gestational age and birth weight-matched controls without GNBI. Polymorphism analyses were applied to allele frequencies of the detected TLR4 SNPs and their associations with various clinical entities, including premature birth and GNBI were assessed. Results A total of six SNPs with more than 5% frequency were found in several promoter sequences, including rs10759931, rs2737190, rs10116253, rs10983755, rs1927914, and rs10759932. Mutation allele frequencies ranged from 23 to 41%. There were no SNPs with a frequency greater than 5% in exon analyses. Allele G rs2737190 mutations and GGCGGC haplotypes weremore frequent among preterm GNBI neonates (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.02-1.71 and OR, 1.89; 95% CI, 1.19-3.00, respectively). No specific alleles or haplotypes were associated with GNBI status among term neonates. Conclusion In this study population of Han Chinese, there was a significant association between an ethnical unique SNP in the TLR4 promoter region and preterm neonatal GNBIs. [ABSTRACT FROM AUTHOR]

Background: To explore the diagnostic performance of interleukin (IL)-6 and IL-10 in discriminating Gram bacteria types and predicting disease severity in intensive care unit (ICU)-hospitalized pediatric sepsis patients., Method: We retrospectively collected Th1/Th2 cytokine profiles of 146 microbiologically documented sepsis patients. Patients were categorized into Gram-positive (G+) or Gram-negative (G-) sepsis groups, and cytokine levels were compared. Subgroup analysis was designed to eliminate the influence of other inflammatory responses on cytokine levels., Results: After propensity score matching, 78 patients were matched and categorized according to Gram bacteria types. Compared with G+ sepsis, IL-6 and IL-10 were significantly elevated in G- sepsis (p < 0.05). Spearman test proved the linear correlation between IL-6 and IL-10 (r = 0.654, p < 0.001), and their combination indicators (ratio and differences) were effective in identifying G- sepsis. In the subgroup analysis, such cytokine elevation was significant regardless of primary infection site. However, for patients with progressively deteriorating organ function [new or progressive multiple organ dysfunction syndrome (NPMODS)], differences in IL-6 and IL-10 levels were less significant between G+ and G- sepsis. In the receiver operating characteristic (ROC) curves of the G- sepsis group, the area under the curve (AUC) value for IL-6 and IL-10 was 0.679 (95% CI 0.561-0.798) and 0.637 (95% CI 0.512-0.762), respectively. The optimal cutoff value for diagnosing G- sepsis was 76.77 pg/ml and 18.90 pg/ml, respectively. While for the NPMODS group, the AUC for IL-6 and IL-10 was 0.834 (95% CI 0.766-0.902) and 0.781 (95% CI 0.701-0.860), respectively., Conclusion: IL-6 and IL-10 are comparably effective in discriminating G+/G- sepsis in pediatric intensive care unit (PICU) patients. The deteriorated organ function observed in ICU patients reveals that complex inflammatory responses might have contributed to the cytokine pattern observed in severe sepsis patients, therefore confounding the discriminating efficacy of Th1/Th2 cytokines in predicting Gram bacteria types., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Li and Ning.)

Klebsiella pneumoniae (Kp) is a Gram-negative bacterium that can cause serious infections in humans. Autophagy-related gene 7 (Atg7) has been implicated in certain bacterial infections; however, the role of Atg7 in macrophage-mediated immunity against Kp infection has not been elucidated. Here we showed that Atg7 expression was significantly increased in murine alveolar macrophages (MH-S) upon Kp infection, indicating that Atg7 participated in host defense. Knocking down Atg7 with small-interfering RNA increased bacterial burdens in MH-S cells. Using cell biology assays and whole animal imaging analysis, we found that compared with wild-type mice atg7 knockout (KO) mice exhibited increased susceptibility to Kp infection, with decreased survival rates, decreased bacterial clearance, and intensified lung injury. Moreover, Kp infection induced excessive proinflammatory cytokines and superoxide in the lung of atg7 KO mice. Similarly, silencing Atg7 in MH-S cells markedly increased expression levels of proinflammatory cytokines. Collectively, these findings reveal that Atg7 offers critical resistance to Kp infection by modulating both systemic and local production of proinflammatory cytokines. [ABSTRACT FROM AUTHOR]

Caveolin-1 ( Cav1) is a structural protein of caveolae. Although Cav1 is associated with certain bacterial infections, it is unknown whether Cav1 is involved in host immunity against Klebsiella pneumoniae, the third most commonly isolated microorganism from bacterial sepsis patients. Here, we showed that cav1 knockout mice succumbed to K. pneumoniae infection with markedly decreased survival rates, increased bacterial burdens, intensified tissue injury, hyperactive proinflammatory cytokines, and systemic bacterial dissemination as compared with WT mice. Knocking down Cav1 by a dominant negative approach in lung epithelial MLE-12 cells resulted in similar outcomes (decreased bacterial clearance and increased proinflammatory cytokine production). Furthermore, we revealed that STAT5 influences the GSK3β−β-catenin− Akt pathway, which contributes to the intensive inflammatory response and rapid infection dissemination seen in Cav1 deficiency. Collectively, our findings indicate that Cav1 may offer resistance to K. pneumoniae infection, by affecting both systemic and local production of proinflammatory cytokines via the actions of STAT5 and the GSK3β−β-catenin− Akt pathway. [ABSTRACT FROM AUTHOR]

Background: Although hospital-acquired infections presumably may have a poorer prognosis than community-onset infections because of unanticipated antimicrobial resistance, little data are available on the clinical and microbiological characteristics of hospital-acquired versus community-onset urinary tract–related bacteremia cases. Methods: Data were collected from a nationwide database of surveillance for bacteremia. Data from patients with hospital-acquired urinary tract–related bacteremia were compared with those with community-onset bacteremia. Results: Of 398 patients with urinary tract–related bacteremia, 71 (17.8%) had hospital-acquired infection, and the remaining 327 (82.2%) had community-onset infection. Although Escherichia coli was the most common isolate identified, pathogens other than E coli were more frequently isolated in hospital-acquired infections than in community-onset infections (46.5% vs 19.3%). Among E coli isolates causing hospital-acquired infections, 26.3% (10 of 38) were resistant to extended-spectrum cephalosporins (ESCs), whereas among E coli isolates causing community-onset infections, only 6.1% (16 of 264) were ESC-resistant. Hospital-acquired infection had a significantly higher mortality rate than community-onset infection (21.1% [15 of 71] vs 8.3% [27 of 327]; P = .004). Multivariate analysis identified nosocomial acquisition as a significant independent risk factor for mortality, along with severe sepsis, underlying solid tumor, ESC resistance, and high Pitt bacteremia score (all P < .05). Conclusion: Hospital-acquired urinary tract–related bacteremia has a poorer prognosis than community-onset bacteremia. The ESC-resistant nature of gram-negative bacilli, which may be more common in nosocomial isolates than in community isolates, adversely affects the outcome of urinary tract–related bacteremia. [Copyright &y& Elsevier]

Abstract: This study aimed (i) to assess the ability of electronic nose (e-nose) technology to differentiate between blood samples of experimentally infected and non-infected subjects and (ii) to evaluate e-nose responses given by volatile organic compounds in relation to the acute phase reaction generated in the host. In an animal model of gram-negative bacterial infection (20 calves; intratracheal inoculation of Mannheimia haemolytica A1), the concentrations of the acute phase proteins (APPs; i.e. lipopolysaccharide binding protein and haptoglobin) were measured in serum samples before and after challenge, and headspaces of pre- and post-inoculation serum samples were analysed using a conducting polymer-based e-nose. Significant changes of certain e-nose sensor responses allowed discrimination between samples before and after challenge. The maximal changes in responses of sensitive e-nose sensors corresponded to the peak of clinical signs. Significant correlations linked decreasing responses of multiple e-nose sensors to increasing concentrations of APPs in the peripheral blood. [Copyright &y& Elsevier]

Objective: To investigate lipopolysaccharide (LPS)-induced DNA damage in preimplanting embryonic and uterine cells during preimplantation period of pregnancy that may ultimately inhibit the process of implantation in mouse. Design: Animal study. Setting: Academic research environment. Animal(s): Sixty four Park strain female mice. Intervention(s): The “minimum dose” (MD) of LPS was injected intraperitoneally in the pregnant females on day 0.5 of pregnancy, and individual embryos and uterine cells were assessed by comet assay on days 1.5, 2.5, 3.5, and 4.375 of the preimplantation period of pregnancy. Main Outcome Measure(s): Percentage of embryos and uterine cells with tail, mean comet tail length, percentage of fragmented DNA in tail. Result(s): Significantly higher numbers of embryos with higher mean comet tail length and percentage of fragmented DNA in tail were observed in the LPS-treated compared with control animals as the period of pregnancy approaches the stage of implantation. At the same time, DNA damage was also significantly higher in the uterine cells of LPS-treated compared with control animals. Conclusion(s): The MD of LPS can induce DNA damage in the preimplantation-stage embryos and uterine cells, which causes poor embryonic development and improper preparation of uterine horns during the preimplantation period of pregnancy, which may ultimately inhibit the process of implantation in mouse. [Copyright &y& Elsevier]

Problem Lipopolysaccharide (LPS) has been postulated to exert harmful biologic effects during pregnancy. The objective of present investigation is to measure the vaginal electrical resistance (VER) in LPS-treated normal cycling and pregnant female mice. Method of study Minimum dose (MD) of LPS (250 μg/kg body weight) was injected in pregnant female mice through i.p. route on day 0.5 of pregnancy. VER was measured during different phases of reproductive cycle in female mice, which were pre-exposed to LPS and in untreated cycling female mice. VER was also measured in control pregnant female mice (saline-treated mice) through whole pregnancy and LPS-treated female mice in early stages of pregnancy. Results Vaginal electrical resistance was significantly higher during proestrous or early estrous stage as compared with any other stages of reproductive cycle in mouse. One peak of VER was observed during peri-implantation period of pregnancy in control female mice. The significant differences in the pattern of VER were found between LPS-treated and control female mice during peri-implantation period of pregnancy, and between cycling female mice, which were pre-exposed to LPS and untreated cycling female mice during proestrus. Conclusion The presented results demonstrate, for the first time, that LPS exposure during pregnancy may be determined by measuring VER in mothers without any adverse effect on ongoing pregnancy and may help in refining the assisted reproduction techniques. [ABSTRACT FROM AUTHOR]

[Display omitted] Novel cyclic peptide derivatives based on ogipeptins A, B, C, and D were synthesized. Starting with a mixture of ogipeptins A–D, a practical four-step synthetic procedure was followed to prepare novel derivatives with various kinds of acyl side chains. Among the 45 new synthetic derivatives identified, the antibacterial activities of compounds 8 - 3 and 8 - 38 were comparable with those of ogipeptin A. In in vitro nephrotoxicity screening using LLC-PK1 cells, compounds 8 - 3 and 8 - 38 showed significantly lower cytotoxicity (LD 20 > 480 μM) than colistin (LD 20 = 44.2 μM). [ABSTRACT FROM AUTHOR]

Introduction: Neisseria elongata (NE), a Gram-negative, rod-shaped organism, was previously thought to be non-pathogenic. However, in recent years it has become increasingly recognized as a rare cause of infective endocarditis. In this paper, we report a case of NE infective endocarditis and provide a review of the literature., Objectives: To describe a case of NE endocarditis, and to review the literature in search of any similar cases of this rare condition., Case Report: Our patient is a 77-year-old, otherwise healthy female patient who was found to have mitral valve endocarditis with valve regurgitation., Discussion: NE endocarditis is a rare condition that typically affects the left cardiac chambers and is associated with high risk of embolization. A literature review retrieved 35 other cases., Conclusions: Our report underlines the rarity of NE endocarditis, insofar as relatively few cases have been reported. The bacterium presents similarities with HACEK organisms and can potentially cause infective endocarditis., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Caspase-11 is a pro-inflammatory enzyme that is stringently regulated during its expression and activation. As caspase-11 is not constitutively expressed in cells, it requires a priming step for its upregulation, which occurs following the stimulation of pathogen and cytokine receptors. Once expressed, caspase-11 activation is triggered by its interaction with lipopolysaccharide (LPS) from Gram-negative bacteria. Being an initiator caspase, activated caspase-11 functions primarily through its cleavage of key substrates. Gasdermin D (GSDMD) is the primary substrate of caspase-11, and the GSDMD cleavage fragment generated is responsible for the inflammatory form of cell death, pyroptosis, via its formation of pores in the plasma membrane. Thus, caspase-11 functions as an intracellular sensor for LPS and an immune effector. This review provides an overview of caspase-11—describing its structure and the transcriptional mechanisms that govern its expression, in addition to its activation, which is reported to be regulated by factors such as guanylate-binding proteins (GBPs), high mobility group box 1 (HMGB1) protein, and oxidized phospholipids. We also discuss the functional outcomes of caspase-11 activation, which include the non-canonical inflammasome, modulation of actin dynamics, and the initiation of blood coagulation, highlighting the importance of inflammatory caspase-11 during infection and disease. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance is an important global issue that impacts the efficacy of established antimicrobial therapy. This is true globally and within the Arab countries of the Middle East, where a range of key Gram-negative pathogens pose challenges to effective therapy. There is a need to establish effective treatment recommendations for this region given specific challenges to antimicrobial therapy, including variations in the availability of antimicrobials, infrastructure and specialist expertise. This consensus provides regional recommendations for the first-line treatment of hospitalized patients with serious infections caused by World Health Organization critical priority Gram-negative pathogens Acinetobacter baumannii and Pseudomonas aeruginosa resistant to carbapenems, and Enterobacteriaceae resistant to carbapenems and third-generation cephalosporins. A working group comprising experts in infectious disease across the region was assembled to review contemporary literature and provide additional consensus on the treatment of key pathogens. Detailed therapeutic recommendations are formulated for these pathogens with a focus on bacteraemia, nosocomial pneumonia, urinary tract infections, skin and soft tissue infections, and intra-abdominal infections. First-line treatment options are provided, along with alternative agents that may be used where variations in antimicrobial availability exist or where local preferences and resistance patterns should be considered. These recommendations take into consideration the diverse social and healthcare structures of the Arab countries of the Middle East, meeting a need that is not filled by international guidelines. There is a need for these recommendations to be updated continually to reflect changes in antimicrobial resistance in the region, as well as drug availability and emerging data from clinical trials. [ABSTRACT FROM AUTHOR]

Cefiderocol is a novel siderophore cephalosporin with potent activity against gram-negative bacteria, including multidrug-resistant strains. This Phase I study was conducted to assess the tolerability of single-ascending doses of cefiderocol (part 1) and the effect of cefiderocol on cardiac repolarization, assessed using the electrocardiographic corrected QT interval (QTcF) and other ECG parameters (part 2), in healthy adult subjects. Part 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy adult male and female subjects. Part 2 was a 4-period crossover study in which subjects received a single 2-g dose of cefiderocol (therapeutic dose), a single 4-g dose of cefiderocol (supratherapeutic dose), or saline (placebo), each infused over 3 hours, and a single oral 400-mg dose of moxifloxacin. In each treatment period, continuous cardiac monitoring was used to assess the effects of cefiderocol on ECG parameters. The QT interval corrected using the Fridericia formula (QTcF) was the primary ECG parameter; the time-matched placebo- and baseline-adjusted (dd)-QTcF interval was the primary end point. The plasma pharmacokinetic properties of cefiderocol were calculated on the basis of concentration–time profiles in all evaluable subjects. All point estimates for the ddQTcF interval were <5 ms and the upper bound of the 90% CIs were <10 ms at each timepoint after the initiation of the cefiderocol 3-hour infusion. Concentration-effect modeling showed a slightly negative slope and predicted modestly negative values of the ddQTcF interval at the C max of cefiderocol. Both doses of cefiderocol were well tolerated. All adverse events were mild in severity, with no deaths or serious adverse events reported. Overall, therapeutic and supratherapeutic doses of cefiderocol had no apparent clinically significant effect on the QTcF. [ABSTRACT FROM AUTHOR]