Активность

Ceftazidime-avibactam (CZA), meropenem-vaborbactam (MVB) and imipenem-relebactam (I-R) are combinations of old ß-lactams with novel non-ß-lactam ß-lactamase inhibitors (BLBLIs) able to inhibit some carbapenemases, such as the KPC-type, thus are becoming the standard for difficult-to-treat carbapenemase-producing Enterobacterales (CPE); a practical question is whether these novel BLBLIs should be used as monotherapy or as part of a combination regimen with other antibiotics, and if so, with which ones, to reduce the emergence of resistant strains and to optimize their efficacy. In this short review, we assessed clinical outcomes in patients with CPE-infections treated with the novel BLBLIs as mono- or combo-regimens, and laboratory studies on the synergistic effects with other antimicrobials. Available evidence on combination therapy is scarce and mainly limited to retrospective studies involving 630 patients treated with CZA aminoglycosides were used in 39.6% of 336 patients treated with combo-regimens, followed by polymyxin B/colistin (24.4%), tigecycline (24.1%), carbapenems (13.4%) and fosfomycin (5.4%). Aminoglycosides could be useful in case of bloodstream and severe urinary infections. Pneumonia is a risk factor for CZA-resistance emergence fosfomycin, due to favorable lung pharmacokinetics/pharmacodynamics, could represent an interesting partner; fosfomycin could be added also for osteomyelitis. Tigecycline could be preferred for intrabdominal and skin-soft tissue infections. Due to nephrotoxicity and lack of in vitro synergy, the association CZA/colistin seems not optimal. MVB and I-R were mostly used as monotherapies. Currently, there is no definitive evidence whether combinations are more effective than monotherapies; further studies are warranted, and to date only personal opinions can be provided.Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with high heterogeneity but the common characterization of numerous autoantibodies and systemic inflammation which lead to the damage of multiple organs. Aberrance of B cells plays a pivotal role in the immunopathogenesis of SLE via both antibody-dependent and antibody-independent manners. Escape of autoreactive B cells from the central and peripheral tolerance checkpoints, over-activation of B cells and their excessive cytokines release which drive T cells and dendritic cells stimulation, and dysregulated surface molecules, as well as intracellular signal pathways involved in B cell biology, are all contributing to B cell aberrance and participating in the pathogenesis of SLE. Based on that rationale, targeting aberrance of B cells and relevant molecules and pathways is expected to be a promising strategy for lupus control. Multiple approaches targeting B cells through different mechanisms have been attempted, including B-cell depletion via monoclonal antibodies against B-cell-specific molecules, blockade of B-cell survival and activation factors, suppressing T-B crosstalk by interrupting costimulatory molecules and inhibiting intracellular activation signaling cascade by targeting pathway molecules in B cells. Though most attempts ended in failure, the efficacy of B-cell targeting has been encouraged by the FDA approval of belimumab that blocks B cell-activating factor (BAFF) and the recommended use of anti-CD20 as a remedial therapy in refractory lupus. find more Still, quantities of clinical trials targeting B cells or relevant molecules are ongoing and some of them have displayed promising preliminary results. Additionally, advances in multi-omics studies help deepen our understandings of B cell biology in lupus and may promote the discovery of novel potential therapeutic targets. The combination of real-world data with basic research achievements may pave the road to conquering lupus.A prodrome is a premonitory set of signs and symptoms indicating the onset of a disease. Prodromes are frequently reported by hereditary angioedema (HAE) patients, antedating attacks by a few hours or even longer. In some studies, high incidence of prodromes was reported by patients, with considerable number being able to predict oncoming attacks. Regrettably, prodromes have never received a consensual definition and have not been properly investigated in a systematic fashion. Therefore, their nature remains elusive and their contribution to the diagnosis and treatment of disorders is uncertain. The term “prodrome,” as used in various pathologies, denotes different meanings, timing, and duration, so it may not be equally suitable for all clinical situations. Perception of a prodrome is unique for each individual patient depending on self-experience. As modern drugs delegate the administration decision to the patients, early detection of a developing attack may help mitigate its severity and allow deployment of appropriate therapy. New diagnostic instruments were recently developed that can assist in defining the attributes of prodromes and their association with attacks. We will review the prodrome phenomenon as exhibited in certain clinical situations, with an emphasis on prodromes of HAE.Angioedema (AE), transient localized swelling due to extravasated fluid, is commonly classified as mast cell mediator-induced, bradykinin-mediated or of unknown cause. AE often occurs more than once, and it is these recurrent forms of AE that are challenging for patients and physicians, and they are the ones we focus on and refer to as AE in this review. Since effective treatment depends on the causative mediator, reliable and early diagnosis is essential. Although their clinical presentations bear similarities, many forms of angioedema exhibit specific patterns of clinical appearance or disease history that may aid in diagnosis. Here, we describe the most common differences and similarities in the mechanisms and clinical features of bradykinin-mediated and mast cell mediator-induced types of angioedema. We first provide an overview of the diseases that manifest with mast cell mediator-induced versus bradykinin-mediated angioedema as well as their respective underlying pathogenesis. We then compare these diseases for key clinical features, including angioedema location, course and duration of swelling, attack frequency, prevalence and relevance of prodromal signs and symptoms, triggers of angioedema attacks, and other signs and symptoms including wheals, age of onset, and duration.