The serine-rich repeat glycoprotein Srr2 mediates Streptococcus agalactiae interaction with host fibronectin.

BACKGROUND: Group B Streptococcus (GBS) is a commensal of healthy adults and an important pathogen in newborns, the elderly and immunocompromised individuals. GBS displays several virulence factors that promote colonisation and host infection, including the ST-17 strain-specific adhesin Srr2, previously characterised for its binding to fibrinogen. Another common target for bacterial adhesins and for host colonization is fibronectin, a multi-domain glycoprotein found ubiquitously in body fluids, in the extracellular matrix and on the surface of cells. RESULTS: In this study, fibronectin was identified as a novel ligand for the Srr2 adhesin of GBS. A derivative of the ST-17 strain BM110 overexpressing the srr2 gene showed an increased ability to bind fibrinogen and fibronectin, compared to the isogenic wild-type strain. Conversely, the deletion of srr2 impaired bacterial adhesion to both ligands. ELISA assays and surface plasmon resonance studies using the recombinant binding region (BR) form of Srr2 confirmed a direct interaction with fibronectin with an estimated Kd of 92 nM. Srr2-BR variants defective in fibrinogen binding also exhibited no interaction with fibronectin, suggesting that Srr2 binds this ligand through the dock-lock-latch mechanism, previously described for fibrinogen binding. The fibronectin site responsible for recombinant Srr2-BR binding was identified and localised in the central cell-binding domain of the protein. Finally, in the presence of fibronectin, the ability of a Δsrr2 mutant to adhere to human cervico-vaginal epithelial cells was significantly lower than that of the wild-type strain. CONCLUSION: By combining genetic and biochemical approaches, we demonstrate a new role for Srr2, namely interacting with fibronectin. We characterised the molecular mechanism of this interaction and demonstrated that it plays a role in promoting the adhesion of GBS to human cervico-vaginal epithelial cells, further substantiating the role of Srr2 as a factor responsible for the hypervirulence of GBS ST-17 strains. The discovery of the previously undescribed interaction between Srr2 and fibronectin establishes this adhesin as a key factor for GBS colonisation of host tissues.

Imipenem/Cilastatin/Relebactam for Complicated Infections: A Real-World Evidence.

(1) Background: Infections caused by multidrug-resistant (MDR) bacteria represent one of the major global public health problems of the 21st century. Beta-lactam antibacterial agents are commonly used to treat infections due to Gram-negative pathogens. New ß-lactam/ß-lactamase inhibitor combinations are urgently needed. Combining relebactam (REL) with imipenem (IMI) and cilastatin (CS) can restore its activity against many imipenem-nonsusceptible Gram-negative pathogens. (2) Methods: we performed a systematic review of the studies reporting on the use of in vivo REAL/IPM/CS. (3) Results: A total of eight studies were included in this review. The primary diagnosis was as follows: complicated urinary tract infection (n = 234), complicated intra-abdominal infections (n = 220), hospital-acquired pneumonia (n = 276), and ventilator-associated pneumonia (n = 157). Patients with normal renal function received REL/IPM/CS (250 mg/500 mg/500 mg). The most frequently reported AEs occurring in patients treated with imipenem/cilastatin plus REL/IPM/CS were nausea (11.5%), diarrhea (9.8%), vomiting (9.8%), and infusion site disorders (4.0%). Treatment outcomes in these high-risk patients receiving REL/IPM/CS were generally favorable. A total of 70.6% of patients treated with REL/IPM/CS reported a favorable clinical response at follow-up. (4) Conclusions: this review indicates that REL/IPM/CS is active against important MDR Gram-negative organisms.

Amyotrophic Lateral Sclerosis and Pain: A Narrative Review from Pain Assessment to Therapy.

Amyotrophic lateral sclerosis (ALS) is the most frequent neurodegenerative disease of the motor system that affects upper and lower motor neurons, leading to progressive muscle weakness, spasticity, atrophy, and respiratory failure, with a life expectancy of 2-5 years after symptom onset. In addition to motor symptoms, patients with ALS have a multitude of nonmotor symptoms; in fact, it is currently considered a multisystem disease. The purpose of our narrative review is to evaluate the different types of pain, the correlation between pain and the disease's stages, the pain assessment tools in ALS patients, and the available therapies focusing above all on the benefits of cannabis use. Pain is an underestimated and undertreated symptom that, in the last few years, has received more attention from research because it has a strong impact on the quality of life of these patients. The prevalence of pain is between 15% and 85% of ALS patients, and the studies on the type and intensity of pain are controversial. The absence of pain assessment tools validated in the ALS population and the dissimilar study designs influence the knowledge of ALS pain and consequently the pharmacological therapy. Several studies suggest that ALS is associated with changes in the endocannabinoid system, and the use of cannabis could slow the disease progression due to its neuroprotective action and act on pain, spasticity, cramps, sialorrhea, and depression. Our research has shown high patients' satisfaction with the use of cannabis for the treatment of spasticity and related pain. However, especially due to the ethical problems and the lack of interest of pharmaceutical companies, further studies are needed to ensure the most appropriate care for ALS patients.

Engagement of α3ß1 and α2ß1 integrins by hypervirulent Streptococcus agalactiae in invasion of polarized enterocytes.

The gut represents an important site of colonization of the commensal bacterium Streptococcus agalactiae (group B Streptococcus or GBS), which can also behave as a deadly pathogen in neonates and adults. Invasion of the intestinal epithelial barrier is likely a crucial step in the pathogenesis of neonatal infections caused by GBS belonging to clonal complex 17 (CC17). We have previously shown that the prototypical CC17 BM110 strain invades polarized enterocyte-like cells through their lateral surfaces using an endocytic pathway. By analyzing the cellular distribution of putative GBS receptors in human enterocyte-like Caco-2 cells, we find here that the alpha 3 (α3) and alpha 2 (α2) integrin subunits are selectively expressed on lateral enterocyte surfaces at equatorial and parabasal levels along the vertical axis of polarized cells, in an area corresponding to GBS entry sites. The α3ß1 and α2ß1 integrins were not readily accessible in fully differentiated Caco-2 monolayers but could be exposed to specific antibodies after weakening of intercellular junctions in calcium-free media. Under these conditions, anti-α3ß1 and anti-α2ß1 antibodies significantly reduced GBS adhesion to and invasion of enterocytes. After endocytosis, α3ß1 and α2ß1 integrins localized to areas of actin remodeling around GBS containing vacuoles. Taken together, these data indicate that GBS can invade enterocytes by binding to α3ß1 and α2ß1 integrins on the lateral membrane of polarized enterocytes, resulting in cytoskeletal remodeling and bacterial internalization. Blocking integrins might represent a viable strategy to prevent GBS invasion of gut epithelial tissues.

Comparison of McGrath Videolaryngoscope versus Macintosh Laryngoscope in Tracheal Intubation: An Updated Systematic Review.

(1) Background: In the last few years, many randomized controlled trials (RCTs) have compared direct Macintosh laryngoscopy with McGrath videolaryngoscopy in order to assess the potential benefits of the latter; the results were sometimes controversial. (2) Methods: We conducted a comprehensive literature search to identify our articles according to inclusion and exclusion criteria: to be included, each study had to be a prospective randomized trial or comparison between the McGrath videolaryngoscope and the Macintosh laryngoscope in an adult population. We did not include manikin trials or studies involving double-lumen tubes. (3) Results: 10 studies met the inclusion criteria necessary. In total, 655 patients were intubated with the McGrath and 629 with the Macintosh. In total, 1268 of 1284 patients were successfully intubated, showing equivalent results for the two devices: 648 of 655 patients with the McGrath videolaryngoscope and 620 of 629 patients with the Macintosh laryngoscope. No differences were noted in terms of hemodynamic changes or the incidence of adverse events. (4) Conclusions: We can assert that the McGrath videolaryngoscope and Macintosh laryngoscope, even if with equivalent tracheal intubation results, supplement each other.

An Unusual Case of a Double Tricuspid and Mitral Valves Infective Endocarditis Complicated by Multiple Septic Embolisms Secondary to an Atrial Septal Defect: A Case Report and Review of Literature.

Multivalvular endocarditis (MVE) is an uncommon infection that mostly involves mitral and aortic valves, and it is related to a higher risk of congestive heart failure and a higher mortality. We described a case of a bilateral MVE and performed a review of the literature on similar clinical cases. We reported an unusual case of a 68-year-old male patient with a tricuspid and mitral infective endocarditis due to a methicillin-resistant Staphylococcus aureus complicated by multiple right- and left-sided septic embolization (lungs, brain, spleen, L2-L3 vertebral bones) due to an unknown atrial septal defect identified and repaired during cardiac surgery. Despite the severity of the clinical case, the patient experienced a good clinical outcome also thanks to a multidisciplinary approach. We identified 21 case reports describing bilateral MVE. A multidisciplinary approach is essential in the management of valve diseases to improve the prognosis of patients, especially in bilateral MVE.

Caspase-8 inhibition improves the outcome of bacterial infections in mice by promoting neutrophil activation.

During differentiation, neutrophils undergo a spontaneous pro-inflammatory program that is hypothesized here to be under caspase-8 control. In mice, intraperitoneal administration of the caspase-8 inhibitor z-IETD-fmk is sufficient to unleash the production of pro-inflammatory cytokines and neutrophil influx in the absence of cell death. These effects are due to selective inhibition of caspase-8 and require tonic interferon-ß (IFN-ß) production and RIPK3 but not MLKL, the essential downstream executioner of necroptotic cell death. In vitro, stimulation with z-IETD-fmk is sufficient to induce significant cytokine production in murine neutrophils but not in macrophages. Therapeutic administration of z-IETD-fmk improves clinical outcome in models of lethal bacterial peritonitis and pneumonia by augmenting cytokine release, neutrophil influx, and bacterial clearance. Moreover, the inhibitor protects mice against high-dose endotoxin shock. Collectively, our data unveil a RIPK3- and IFN-ß-dependent pathway that is constitutively activated in neutrophils and can be harnessed therapeutically using caspase-8 inhibition.

Antimicrobial Resistance: Two-Component Regulatory Systems and Multidrug Efflux Pumps.

The number of multidrug-resistant bacteria is rapidly spreading worldwide. Among the various mechanisms determining resistance to antimicrobial agents, multidrug efflux pumps play a noteworthy role because they export extraneous and noxious substrates from the inside to the outside environment of the bacterial cell contributing to multidrug resistance (MDR) and, consequently, to the failure of anti-infective therapies. The expression of multidrug efflux pumps can be under the control of transcriptional regulators and two-component systems (TCS). TCS are a major mechanism by which microorganisms sense and reply to external and/or intramembrane stimuli by coordinating the expression of genes involved not only in pathogenic pathways but also in antibiotic resistance. In this review, we describe the influence of TCS on multidrug efflux pump expression and activity in some Gram-negative and Gram-positive bacteria. Taking into account the strict correlation between TCS and multidrug efflux pumps, the development of drugs targeting TCS, alone or together with already discovered efflux pump inhibitors, may represent a beneficial strategy to contribute to the fight against growing antibiotic resistance.

Pulsed Radiofrequency and Platelet Rich Plasma in Degenerative Joint Arthritis: Two Case Reports and Literature Analyses.

(1) Background: Osteoarthritis (OA) is a debilitating joint disease. The are several therapies available for OA. According to current knowledge, the combination of Platelet-Rich Plasma (PRP) and Pulsed Radiofrequency (PRF) can be applied in the treatment of pain of nociceptive origin due to peripheral tissue damage. (2) Methods: We performed a narrative review identifying the articles by searching electronic databases. A retrospective analysis of patients with OA treated with PRF and PRP in "Vito Fazzi" Hospital (Lecce, Italy) was performed. (3) Results: A total of four publications on the use of PRP and PRF in degenerative joint arthritis were included in our review. In our experience, two patients with OA were treated with PRP and PRF after unsuccessful conservative treatment. Patient pain score, daily activity ability, active range of activity, and muscle strength improved after treatment. Patients reported a higher level of satisfaction. No major adverse events were reported. (4) Conclusions: The goal of the combined application of the two treatments is to make full use of the analgesic effect of PRF and the repairing effect of PRP. At present, the therapeutic potential of PRP and PRF in OA remains unmet.

Current Views on Infective Endocarditis: Changing Epidemiology, Improving Diagnostic Tools and Centering the Patient for Up-to-Date Management.

Infective endocarditis (IE) is a rare but potentially life-threatening disease, sometimes with longstanding sequels among surviving patients. The population at high risk of IE is represented by patients with underlying structural heart disease and/or intravascular prosthetic material. Taking into account the increasing number of intravascular and intracardiac procedures associated with device implantation, the number of patients at risk is growing too. If bacteremia develops, infected vegetation on the native/prosthetic valve or any intracardiac/intravascular device may occur as the final result of invading microorganisms/host immune system interaction. In the case of IE suspicion, all efforts must be focused on the diagnosis as IE can spread to almost any organ in the body. Unfortunately, the diagnosis of IE might be difficult and require a combination of clinical examination, microbiological assessment and echocardiographic evaluation. There is a need of novel microbiological and imaging techniques, especially in cases of blood culture-negative. In the last few years, the management of IE has changed. A multidisciplinary care team, including experts in infectious diseases, cardiology and cardiac surgery, namely, the Endocarditis Team, is highly recommended by the current guidelines.

In Vivo Role of Two-Component Regulatory Systems in Models of Urinary Tract Infections.

Two-component signaling systems (TCSs) are finely regulated mechanisms by which bacteria adapt to environmental conditions by modifying the expression of target genes. In bacterial pathogenesis, TCSs play important roles in modulating adhesion to mucosal surfaces, resistance to antibiotics, and metabolic adaptation. In the context of urinary tract infections (UTI), one of the most common types infections causing significant health problems worldwide, uropathogens use TCSs for adaptation, survival, and establishment of pathogenicity. For example, uropathogens can exploit TCSs to survive inside bladder epithelial cells, sense osmolar variations in urine, promote their ascension along the urinary tract or even produce lytic enzymes resulting in exfoliation of the urothelium. Despite the usefulness of studying the function of TCSs in in vitro experimental models, it is of primary necessity to study bacterial gene regulation also in the context of host niches, each displaying its own biological, chemical, and physical features. In light of this, the aim of this review is to provide a concise description of several bacterial TCSs, whose activity has been described in mouse models of UTI.

Plazomicin against Multidrug-Resistant Bacteria: A Scoping Review.

Plazomicin is a next-generation semisynthetic aminoglycoside antibiotic that can be used to treat infections by multi-resistant bacteria. It is effective against many bacteria-producing carbapenemases or other specific hydrolases. This scoping review aims to define the role acquired by plazomicin from its approval by the FDA (US Food and Drug Administration) in 2018 to the present day. Furthermore, we aim to provide a base for a future meta-analysis. This project was conducted following the recommendations presented in the PRISMA extension for scoping reviews and the JBI Manual for Evidence Synthesis. Among 901 potentially engaging citations, 345 duplicates were removed, and only 81 articles were selected for the analysis. According to the data analysis, plazomicin has been used to treat urinary tract infections, bloodstream infections, and ventilation-associated pneumonia. The pathogens killed included multi-resistant E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, and S. aureus. Plazomicin can be a manageable, valid non-beta-lactam alternative for treating multi-resistant bacteria infections.

A Literature Overview of Secondary Peritonitis Due to Carbapenem-Resistant Enterobacterales (CRE) in Intensive Care Unit (ICU) Patients.

This comprehensive review of the recently published literature offers an overview of a very topical and complex healthcare problem: secondary peritonitis from multidrug-resistant pathogens, especially carbapenem-resistant Enterobacterales (CRE). Spontaneous secondary peritonitis and postsurgical secondary peritonitis are among the major causes of community- and healthcare- acquired sepsis, respectively. A large number of patients enter ICUs with a diagnosis of secondary peritonitis, and a high number of them reveal infection by CRE, P. aeruginosa or A. baumannii. For this reason, we conceived the idea to create a synthetic report on this topic including updated epidemiology data, a description of CRE resistance patterns, current strategies of antimicrobial treatment, and future perspectives. From this update it is clear that antimicrobial stewardship and precision medicine are becoming essential to fight the emergence of antimicrobial resistance and that even if there are new drugs effective against CRE causing secondary peritonitis, these drugs have to be used carefully especially in empirical therapy.

Comparative Efficacy of Tapentadol versus Tapentadol Plus Duloxetine in Patients with Chemotherapy-Induced Peripheral Neuropathy (CIPN): A Randomized Non-Inferiority Clinical Trial.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication due to treatment with many commonly used anti-cancer agents. CIPN is a mainly sensory neuropathy that can be characterized by the appearance of motor and autonomic alterations. Clinicians may offer duloxetine (DLX) for patients with cancer experiencing CIPN. Our aim was to assess the non-inferiority of the analgesic effect and safety of tapentadol (TP) alone compared to duloxetine plus tapentadol administered to patients with CIPN. METHODS: A total of 114 patients were enrolled in the study and randomized to receive tapentadol in a dosage of 50 to 500 mg/day (n = 56) or tapentadol plus duloxetine in a dosage of 60 to 120 mg/day (n = 58) for a period of 4 weeks. We evaluated the analgesia efficacy, defined as a decrease in pain on the NRS between the first administration and 28 days later. Secondary endpoints included analgesia efficacy at 28 and 42 days, defined by a decrease in DN4 and LEPs, decrease in quality of life, and the incidence of any serious or non-serious adverse events after the first administration. RESULTS: In this randomized, double-blind trial comparing TP and TP plus DLX for CIPN management, TP was feasible and non-inferior to the association with DLX as far as the reduction of pain after chemotherapy at 28 days is concerned. Scores on other rating scales evaluating the quality of life, anxiety and depression, and the characteristics of pain revealed similar improvements associated with tapentadol versus duloxetine at these time points. CONCLUSION: The use of TP is a safe and effective analgesic therapy in patients with CIPN. Positive effects of TP were noted on the patients' quality-of-life assessments.

Cefiderocol for Carbapenem-Resistant Bacteria: Handle with Care! A Review of the Real-World Evidence.

(1) Background: healthcare-associated infections are one of the most frequent adverse events in healthcare delivery worldwide. Several antibiotic resistance mechanisms have been developed, including those to carbapenemase. Cefiderocol (CFD) is a novel siderophore cephalosporin designed to treat carbapenem-resistant bacteria. (2) Methods: we performed a systematic review of all cases reported in the literature to outline the existing evidence. We evaluated real-world evidence studies of CFD in the treatment of carbapenem-resistant (CR) bacteria. (3) Results: a total of 19 publications treating cases of infection by CR bacteria were included. The three most frequent CR pathogens were Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. A regimen of 2 g every 8 h was most frequently adopted for CFD with a mean treatment duration of 25.6 days. CFD was generally well tolerated, with fewer side effects. The success rate of CFD therapy was satisfactory and almost 70% of patients showed clinical recovery; of these, nearly half showed negative blood cultures and infection-free status. (4) Conclusions: This review indicates that CFD is active against important GN organisms including Enterobacteriaceae, P. aeruginosa, and A. baumannii. CFD seems to have a safe profile.

Streptococcus pneumoniae binds collagens and C1q via the SSURE repeats of the PfbB adhesin.

The binding of Streptococcus pneumoniae to collagen is likely an important step in the pathogenesis of pneumococcal infections, but little is known of the underlying molecular mechanisms. Streptococcal surface repeats (SSURE) are highly conserved protein domains present in cell wall adhesins from different Streptococcus species. We find here that SSURE repeats of the pneumococcal adhesin plasminogen and fibronectin binding protein B (PfbB) bind to various types of collagen. Moreover, deletion of the pfbB gene resulted in a significant impairment of the ability of encapsulated or unencapsulated pneumococci to bind collagen. Notably, a PfbB SSURE domain is also bound to the complement component C1q that bears a collagen-like domain and promotes adherence of pneumococci to host cells by acting as a bridge between bacteria and epithelial cells. Accordingly, deletion of PfbB or pre-treatment with anti-SSURE antibodies markedly decreased pneumococcal binding to C1q as well as C1q-dependent adherence to epithelial and endothelial cells. Further data indicated that C1q promotes pneumococcal adherence by binding to integrin α2 ß1 . In conclusion, our results indicate that the SSURE domains of the PfbB protein promote interactions of pneumococci with various types of collagen and with C1q. These repeats may be useful targets in strategies to control S. pneumoniae infections.

Mechanisms of Action of Carbapenem Resistance.

Carbapenem antibiotics are the most effective antimicrobials for the treatment of infections caused by the most resistant bacteria. They belong to the category of ß-lactams that include the penicillins, cephalosporins, monobactams and carbapenems. This class of antimicrobials has a broader spectrum of activity than most other beta-lactams antibiotics and are the most effective against Gram-positive and Gram-negative bacteria. All ß-lactams antibiotics have a similar molecular structure: the carbapenems together with the ß-lactams. This combination gives an extraordinary stability to the molecule against the enzymes inactivating the ß-lactams. They are safe to use and therefore widespread use in many countries has given rise to carbapenem resistance which is a major global public health problem. The carbapenem resistance in some species is intrinsic and consists of the capacity to resist the action of antibiotics with several mechanisms: for the absence of a specific target, or an intrinsic difference in the composition of cytoplasmatic membrane or the inability to cross the outer membrane. In addition to intrinsic resistance, bacteria can develop resistance to antibiotics with several mechanisms that can be gathered in three main groups. The first group includes antibiotics with poor penetration into the outer membrane of bacterium or antibiotic efflux. The second includes bacteria that modify the target of the antibiotics through genetic mutations or post-translational modification of the target. The third includes bacteria that act with enzyme-catalyzed modification and this is due to the production of beta-lactamases, that are able to inactivate carbapenems and so called carbapenemases. In this review, we focus on the mode of action of carbapenem and the mechanisms of carbapenem resistance.

Pain in Intensive Care: A Narrative Review.

All critically ill adult patients in intensive care units (ICU) typically experience pain. Critically ill adults suffer pain of different intensities. It depends on individual characteristics, specific procedural interventions, and underlying diseases. Inadequate management of acute pain is a risk factor for the emergence of chronic pain, where the incidence is up to 33% into the ICU survivor population. For the management of pain, agitation, and delirium, several coexisting clinical practice guidelines have been published. The first problem is that the patient recovered in intensive care unit should not be able to communicate its pain state. Opioids are the analgesic drugs of choice in critically ill patients with non-neuropathic pain. All intravenous opioids have the same effects, respecting the equianalgesic table. Observational research has shown that opioids are the main analgesic treatment in over 80% of mechanically ventilated patients. It is interesting that opioid consumption in an ICU and the memory of painful experience are linked to the development of post-traumatic stress disorder after ICU discharge. In order to reduce the side effects and maintain analgesia, it is useful to associate adjuvant medications with opioids. An opportunity to improve patients' experience in an ICU is to manage pain through multimodal approaches.

Neutrophils discriminate live from dead bacteria by integrating signals initiated by Fprs and TLRs.

The mechanisms whereby neutrophils respond differentially to live and dead organisms are unknown. We show here that neutrophils produce 5- to 30-fold higher levels of the Cxcl2 chemokine in response to live bacteria, compared with killed bacteria or isolated bacterial components, despite producing similar levels of Cxcl1 or pro-inflammatory cytokines. Secretion of high levels of Cxcl2, which potently activates neutrophils by an autocrine mechanism, requires three signals. The first two signals are provided by two different sets of signal peptides released by live bacteria, which selectively activate formylated peptide receptor 1 (Fpr1) and Fpr2, respectively. Signal 3 originates from Toll-like receptor activation by microbial components present in both live and killed bacteria. Mechanistically, these signaling pathways converge at the level of the p38 MAP kinase, leading to activation of the AP-1 transcription factor and to Cxcl2 induction. Collectively, our data demonstrate that the simultaneous presence of agonists for Fpr1, Fpr2, and Toll-like receptors represents a unique signature associated with viable bacteria, which is sensed by neutrophils and induces Cxcl2-dependent autocrine cell activation.