CAR Immunotherapy for the treatment of infectious diseases: a systematic review.

Immunotherapy treatments aim to modulate the host's immune response to either mitigate it in inflammatory/autoimmune disease or enhance it against infection or cancer. Among different immunotherapies reaching clinical application during the last years, chimeric antigen receptor (CAR) immunotherapy has emerged as an effective treatment for cancer where different CAR T cells have already been approved. Yet their use against infectious diseases is an area still relatively poorly explored, albeit with tremendous potential for research and clinical application. Infectious diseases represent a global health challenge, with the escalating threat of antimicrobial resistance underscoring the need for alternative therapeutic approaches. This review aims to systematically evaluate the current applications of CAR immunotherapy in infectious diseases and discuss its potential for future applications. Notably, CAR cell therapies, initially developed for cancer treatment, are gaining recognition as potential remedies for infectious diseases. The review sheds light on significant progress in CAR T cell therapy directed at viral and opportunistic fungal infections.

Executive summary of the consensus document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) on the diagnosis and antimicrobial treatment of infections due to carbapenem-resistant Gram-negative bacteria.

Infections caused by multidrug resistant Gram-negative bacteria are becoming a worldwide problem due to their increasing incidence and associated high mortality. Carbapenem-resistant bacteria such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii are the most important in clinical practice. The objective of these guidelines is to update the recommendations for the diagnosis and treatment of infections caused by these multidrug resistant bacteria. Although 'old' antibiotics such as aminoglycosides, colistin, or tigecycline are frequently used for therapy of these bacteria, the 'new' beta-lactams such as ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam or cefiderocol are progressively becoming the first-line therapy for most of these microorganisms. The Spanish Society of Infectious Diseases and Clinical Microbiology (Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica) designated a panel of experts in the field to provide evidence-based recommendations in response to common clinical questions. This document is primarily focused on microbiological diagnosis, clinical management, and targeted antimicrobial therapy of these infections, with special attention to defining the role of the new antimicrobials in the treatment of these bacteria.

A Large Multicenter Prospective Study of Community-Onset Healthcare Associated Bacteremic Urinary Tract Infections in the Era of Multidrug Resistance: Even Worse than Hospital Acquired Infections?

INTRODUCTION: Healthcare-associated (HCA) infections represent a growing public health problem. The aim of this study was to compare community-onset healthcare associated (CO-HCA) bacteremic urinary tract infections (BUTI) and hospital-acquired (HA)-BUTI with special focus on multidrug resistances (MDR) and outcomes. METHODS: ITUBRAS-project is a prospective multicenter cohort study of patients with HCA-BUTI. All consecutive hospitalized adult patients with CO-HCA-BUTI or HA-BUTI episode were included in the study. Exclusion criteria were: patients < 18 years old, non-hospitalized patients, bacteremia from another source or primary bacteremia, non-healthcare-related infections and infections caused by unusual pathogens of the urinary tract. The main outcome variable was 30-day all-cause mortality with day 1 as the first day of positive blood culture. Logistic regression was used to analyze factors associated with clinical cure at hospital discharge and with receiving inappropriate initial antibiotic treatment. Cox regression was used to evaluate 30-day all-cause mortality. RESULTS: Four hundred forty-three episodes were included, 223 CO-HCA-BUTI. Patients with CO-HCA-BUTI were older (p < 0.001) and had more underlying diseases (p = 0.029) than those with HA-BUTI. The severity of the acute illness (Pitt score) was also higher in CO-HCA-BUTI (p = 0.026). Overall, a very high rate of MDR profiles (271/443, 61.2%) was observed, with no statistical differences between groups. In multivariable analysis, inadequate empirical treatment was associated with MDR profile (aOR 3.35; 95% CI 1.77-6.35), Pseudomonas aeruginosa (aOR 2.86; 95% CI 1.27-6.44) and Charlson index (aOR 1.11; 95% CI 1.01-1.23). Mortality was not associated with the site of acquisition of the infection or the presence of MDR profile. However, in the logistic regression analyses patients with CO-HCA-BUTI (aOR 0.61; 95% CI 0.40-0.93) were less likely to present clinical cure. CONCLUSION: The rate of MDR infections was worryingly high in our study. No differences in MDR rates were found between CO-HCA-BUTI and HA-BUTI, in the probability of receiving inappropriate empirical treatment or in 30-day mortality. However, CO-HCA-BUTIs were associated with worse clinical cure.

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis.

Aims: Peritonitis is one of the most common causes of sepsis, a serious syndrome characterized by a dysregulated systemic inflammatory response. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role and the therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis. Methods: The level of extracellular GzmA as well as GzmA activity were analyzed in serum from healthy volunteers and patients with confirmed peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (WT) and GzmA-/- mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics alone or in combination serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days, levels of some proinflammatory cytokines were measured in serum and bacterial load and diversity was analyzed in blood and spleen at different times. Results: Clinically, elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen and GzmA did not affect bacterial replication in macrophages in vitro, indicating that GzmA has no role in bacterial control. Analysis of GzmA in lymphoid cells following CLP showed that it was mainly expressed by NK cells. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFα. Conclusions: Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis and provide solid evidences about its therapeutic potential for the treatment of this severe pathology.

The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover.

Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem.

Performance Assessment of Software to Detect and Assist Prescribers with Antimicrobial Drug Interactions: Are all of them Created Equal?

BACKGROUND: Detecting and managing antimicrobial drug interactions (ADIs) is one of the facets of prudent antimicrobial prescribing. Our aim is to compare the capability of several electronic drug-drug interaction (DDI) checkers to detect and report ADIs. METHODS: Six electronic DDI checking platforms were evaluated: Drugs.com®, Medscape®, Epocrates®, Medimecum®, iDoctus®, and Guía IF®. Lexicomp® Drug Interactions was selected as the gold standard. Ten ADIs addressing different mechanisms were evaluated with every electronic DDI checker. For each ADI, we assessed five dimensions and calculated an overall performance score (maximum possible score: 10 points). The explored dimensions were sensitivity (capability to detect ADI), clinical effect (type and severity), mechanism of interaction, recommended action(s), and documentation (quality of evidence and availability of references). RESULTS: The electronic DDI checkers did not detect a significant proportion of the ADI assessed. The overall performance score ranged between 4.4 (Medimecum) and 8.8 (Drugs.com). Drugs.com was the highest ranked platform in four out of five dimensions (sensitivity, effect, mechanism, and recommended action). CONCLUSIONS: There is significant variability in the performance of the available platforms in detecting and assessing ADI. Although some ADI checkers have proven to be very accurate, others missed almost half of the explored interactions.