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Toll‐like receptors (TLRs) play an important role in innate immunity. Previous studies have shown that single nucleotide polymorphisms (SNPs) in the genes coding for these innate immune molecules can affect susceptibility to and the outcome of certain diseases. The aim of the present study was to examine the clinical relevance of well‐studied TLR1–4 SNPs in individuals who are prone to infections. Four functional SNPs, TLR1 rs5743618 (1805C > A, Ser602Ile), TLR2 rs5743708 (2258G > A, Arg753Gln), TLR3 rs3775291 (1234C > T, Leu412Phe) and TLR4 rs4986790 (896A > G, Asp299Gly), were analysed in 155 patients with recurrent respiratory infections (n = 84), severe infections (n = 15) or common variable immunodeficiency (n = 56), and in 262 healthy controls, using the High Resolution Melting Analysis method. Polymorphisms of TLR2 rs5743708 (odds ratio [OR] 3.16; 95% confidence interval [CI] 1.45–6.83, p =.004, ap =.016) and TLR4 rs4986790 (OR 1.8; 95% CI 1.05–3.12, p =.028, ap =.112) were more frequent in patients with recurrent or severe infections than in controls. Interestingly, seven patients were found to carry both variant genotypes of TLR2 and TLR4, whereas none of the control group carried such genotypes (p ≤.0001). Moreover, TLR2 polymorphism was associated with increased risk for acute otitis media episodes (OR, 3.02; 95% CI 1.41–6.47; p =.012). This study indicates that children and adults who are more prone to recurrent or severe respiratory infections carry one or both variant types of TLR2 and TLR4 more often than control subjects. Genetic variations of TLRs help explain why some children are more susceptible to respiratory infections. [ABSTRACT FROM AUTHOR]

Las infecciones en pacientes con vasculitis sistémica representan una de las principales causas de mortalidad. Son factores de riesgo conocidos la edad, el compromiso orgánico asociado, el uso de corticoides y de inmunosupresores, asi como el requerimiento de diálisis, entre otros. Determinar la prevalencia de infección grave y factores asociados en pacientes diagnosticados de vasculitis asociada a ANCA poliarteritis nudosa (PAN). Estudio retrospectivo realizado en un único centro de reumatología entre los años 2000 y 2018. Se incluyó a pacientes con granulomatosis con poliangitis, granulomatosis eosinofílica con poliangitis, poliangitis microscópica y PAN. Se registraron episodios infecciosos graves que requirieron hospitalización o tratamiento antibiótico/antiviral prolongado, infección recurrente por virus del herpes zóster o infecciones oportunistas. Se incluyó a 105 pacientes, la mediana del tiempo de seguimiento fue de 18 meses; el 58,7% eran mujeres, con una mediana de edad de 52 años; el 41,9% presentaban poliangitis microscópica, el 16,2% granulomatosis eosinofílica con poliangitis, el 40% granulomatosis con poliangitis y el 1,9% PAN. Los compromisos constitucional, pulmonar, renal y otorrinolaringológico fueron los más frecuentes. fue del 34,2% con una mediana de 3 meses desde el diagnóstico de vasculitis. Las infecciones de vías respiratorias bajas (42,8%), la sepsis (31,4%) y el tracto urinario (14,3%) fueron los sitios de infección más comunes. Predominó la etiología bacteriana (67,7%). La mortalidad en el primer episodio fue del 14,3%. Se encontraban en fase de inducción de tratamiento el 72,2%. Las infecciones se asociaron significativamente con edad > 65 años (p = 0,030), compromiso pulmonar (p = 0,016), renal (p = 0,001), BVAS3 >15 y mortalidad (p = 0,0002). La prevalencia de infecciones graves fue del 34,2%. Las infecciones pulmonares, septicemia y las urinarias fueron las más frecuentes y se asociaron a compromiso renal y pulmonar, así como a mortalidad, especialmente en pacientes de edad avanzada. Infections in patients with systemic vasculitis represent one of the main causes of mortality. Corticosteroid use, immunosuppressive therapy, age, associated organic involvement and dialysis dependence are risk factors of infection. To determine the prevalence of severe infection and associated factors in patients diagnosed with ANCA-associated vasculitis and polyarteritis nodosa (PAN). Retrospective study was conduced in a single rheumatology center (2000-2018). We included patients diagnosed with ANCA-associated vasculitis (granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and microscopic polyangiitis and PAN. Serious infectious events requiring hospitalization or prolonged antibiotic/antiviral treatment, recurrent infection of herpes zoster virus or opportunistic infections were evaluated. Sites of infection, isolated microorganisms and mortality related were analyzed. A total of 105 patients were analyzed, follow-up time median 18 months, 58.7% were women and median age was 52 years. Types of vasculitis: 41.9% microscopic polyangiitis, 16.2% eosinophilic granulomatosis with polyangiitis, 40% granulomatosis with polyangiitis, 1.9% PAN. Constitutional, pulmonary, renal and otorhinolaryngology manifestations were the most frequent. was 34,2%, with a median of 3 months from diagnosis of vasculitis to the infectious event. Low respiratory tract (42.8%), sepsis (31.4%), and urinary tract (14.3%) were the most common sites of infections. Bacterial etiology was the most prevalent (67.7%). Mortality at the first event was 14.3% and a 72.2% of patients were in the induction phase of treatment. Infectious events were significantly associated with age > 65 years (P = 0.030), presence of lung (P = 0.016) and renal involvement (P = 0.001), BVASv3 > 15 and mortality (P = 0.0002). The prevalence of infection was 34.2%. Lower airway infections, septicemia and urinary tract infections were the most prevalent. Infections were associated with renal and pulmonary involvement, age older than 65 years and score BVAS >15. Severe infections were associated with mortality, especially in elderly patients. [ABSTRACT FROM AUTHOR]

The COVID-19 epidemic we have experienced is unprecedented in scale and duration. The interaction of multiple factors has led to a complex pattern in the development of the epidemic, which has also brought significant challenges to the control of the epidemic. We focus on age heterogeneity, the dynamics of individual behavioural changes, and vaccinations during the spread of COVID-19 and propose a multi-scale age structure model to explore the impact of the interaction of these factors on disease transmission. We use game theory to depictwhether individuals take normal behaviours or protective measures due to changes in fear of disease infection. Taking the cross-infection of two age groups as an example, we calculated the explicit expression of the reproductive number to explore the threshold of disease outbreak and extinction. Our results reveal that dynamic switching of behavioural changes result in multi-wave patterns. Under the interaction of multiple factors, we found several interesting phenomenon by exploring the disease dynamics. Thresholds for behavioural change in old people and young people have opposite effects on reducing the peak number of disease infections. Older people's high alertness to diseases may increase the peak infection rate for each age group. Whilst fixing other parameters, we found a critical value of the old people's attention to infective cases, at which the infection peak of the elderly can be minimised. If the vaccine is ineffective in reducing the infection rate, as the ratio of vaccination increases, the cumulative number of mild infections will increase instead. [ABSTRACT FROM AUTHOR]

Background: This study aims to assess the effectiveness and safety of cefiderocol in treating severe infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) in critically ill patients, particularly those in intensive care units (ICUs). Methods: A meta-analysis of studies, including randomized clinical trials and observational studies in adult patients, was performed. Studies with at least 50% of critically ill patients were included. Studies with small sample size or without comparison groups were excluded. Sources included PubMed, Scopus, or Google Scholar, up to 14 August 2024. Risk of bias was assessed according to the Cochrane tool. The main outcome examined was 30-day mortality, while secondary outcomes assessed included clinical cure rates and adverse effects. Results were expressed with odds ratios. No funding was received for this study. It was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with reference CRD42024563041. Results: eight studies, with 1339 patients were included in the meta-analysis. Cefiderocol treatment was associated with a lower 30-day mortality rate than other available therapies (pooled OR 0.47; 95% CI: 0.23–0.97, p = 0.04), particularly in cases of carbapenem-resistant A. baumannii infections (pooled OR 0.29; 95% CI: 0.14–0.60, p < 0.001). Although there was a non-significant trend toward higher clinical cure rates in the cefiderocol group (OR 1.59; 95% CI: 0.96–2.62, p = 0.07), the drug demonstrated at least non-inferiority when compared to other treatment options. Study limitations included moderate heterogeneity between studies, and a high risk of bias in non-RCT studies. (Five cohort studies were included). Another limitation is that five of the eight studies compared cefiderocol versus colistine, an antibiotic with known toxicity. Conclusions: The findings suggest that cefiderocol is a promising therapeutic option for managing severe MDR-GNB infections in critically ill patients, offering a potential global benefit on mortality and at least non-inferiority in the cure rate when compared with other therapies.

Objectives: Systemic lupus erythematosus (SLE) is a complicated autoimmune disease, in which infection is a leading cause of death. Some SLE patients clinically presented with recurrent and refractory infections, which manifested as adult-onset immunodeficiency syndrome due to the production of anti-interferon-γ (anti-IFN-γ) autoantibodies. This study aimed to investigate the role of anti-IFN-γ autoantibodies concerning severe infections in SLE patients. Methods: We detected serum levels of anti-IFN-γ IgG/IgM isotypes in SLE patients with severe infections (n = 55), SLE patients without severe infections (n = 120), rheumatoid arthritis (n = 24), ankylosing spondylitis (n = 24), and healthy controls (n = 60). The relationship between anti-IFN-γ autoantibodies and clinical characteristics and laboratory parameters were analyzed. We further evaluated the neutralizing ability of anti-IFN-γ IgG. Results: The level of anti-IFN-γ IgG was significantly elevated in SLE patients with severe infections compared with the other groups (all p < 0.01), and the positive rates of anti-IFN-γ IgG in SLE patients with and without severe infections were 29.1% and 10.8%, respectively. Further analysis indicated that the levels of anti-IFN-γ IgG were positively associated with the SLEDAI score (r = 0.6420, p < 0.001), and it could predict the susceptibility to severe infections in SLE patients. Moreover, the inhibition and function assay showed that purified IgG from anti-IFN-γ IgG-positive SLE patients could neutralize IFN-γ, and further impair IFN-γ-induced STAT1 phosphorylation. Conclusions: The neutralizing anti-IFN-γ IgG might increase the susceptibility to infection in SLE patients, which has important implications for the treatment. Key Points • The role of anti-IFN-γ autoantibodies concerning severe infections in SLE patients remains unknown. • The results of this study reveals that anti-IFN-γ IgG levels were significantly elevated in SLE patients with severe infections. • This study suggests that neutralizing anti-IFN-γ IgG might increase the susceptibility to infection in SLE patients. [ABSTRACT FROM AUTHOR]

Objectives To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections. Methods We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine–Gray model to assess the association between low IgG (the minimum IgG levels <500 mg/dl) and severe infections. In addition, the association was expressed as a restricted cubic spline (RCS) and analysed by treatment subgroups. Results Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03–3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens. Conclusion Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation. [ABSTRACT FROM AUTHOR]

A review of the literature concerning the efficacy and safety of combined anti-pseudomonas protected ureidopenicillin piperacillin/tazobactam usage. Randomized clinical trials and their meta-analysis have demonstrated that piperacillin/ tazobactam among non-carbapenem β-lactams is an equally effective alternative to carbapenems in the treatment of severe infections, including those caused by extended-spectrum β-lactamase producing strains, regardless of the infection locus. It can be used in cases of carbapenem de-escalation if it is necessary. The use of this antimicrobial therapy strategy is justified not only from a clinical, but also from an economic point of view.

Murine typhus is a febrile, fleaborne disease caused by infection with Rickettsia typhi bacteria. Cases can range from mild and nonspecific to fatal. We report 2 cases of murine typhus in Costa Rica, confirming the presence and circulation of R. typhi causing severe disease in the country.

Objectives Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab. Methods This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centres. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months. Results The study included 227 patients. IgG levels at 6 months were lower than baseline (P  < 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (P  = 0.004). Age [β (95% CI): −0.23 (−0.38, −0.08) per 10 years, P  = 0.003], oral glucocorticoid dose at induction [β (95% CI): −0.37 (−0.51, −0.24) per sqrt-transformed mg prednisone, P  < 0.001] and concomitant use of intravenous glucocorticoid pulses [β (95% CI): −0.88 (−1.73, −0.02), P  = 0.044] were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age [OR (95% CI): 1.46 (1.15, 1.86) per 10 years, P  = 0.002] and oral glucocorticoid dose at induction [OR (95% CI): 1.52 (1.23, 1.89) per 10 mg prednisone, P  < 0.001]. Conclusions In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses. [ABSTRACT FROM AUTHOR]

As a synergistic treatment approach with systemic antimicrobial therapy or a systemic antibiotic-sparing strategy, the local administration of antimicrobial agents has been proposed as an alternative route for complicated infections. With the rationale of concentrating the active principle in the desired target site, avoiding potentially toxic systemic levels and bypassing anatomical and physiological barriers, local irrigation or infusion of antibiotics may effectively shorten the antimicrobial therapy course and reduce both infection-related and systemic therapy-related complications. Although evidence from the adult population supports its use in selected patients with an acceptable safety profile, data specifically focused on the pediatric population are limited. To provide a rapid and easily accessible tool for clinical practice, we synthesized the most relevant evidence on the use of local antimicrobial agents in common severe infections in children: meningitis, mediastinitis, pleural infections, recurrent urinary infections, and peritonitis. A literature search was performed using predefined combined keywords through an electronic research database (PubMed). Described molecules, dosages, routes, treated age groups, and related efficacy have been summarized for prompt application to clinical practice. It should, however, be noted that the evidence for the pediatric population remains limited, and the local administration of several molecules remains off-label. A careful multidisciplinary and patient-tailored evaluation, as well as a rational use of available guidelines, should always be the basis of clinical decision making in settings where local administration of antibiotics may be considered. [ABSTRACT FROM AUTHOR]

Abstract Background Sepsis is a heterogeneous syndrome due to a variable range of dysregulated processes in the host immune response. Efforts are made to stratify patients for personalized immune-based treatments and better prognostic prediction. Using gene expression data, different inflammatory profiles have been identified. However, it remains unknown whether these endotypes mirror inflammatory proteome profiling, which would be more feasible to assess in clinical practice. We aim to identify different inflammatory endotypes based on circulating proteins in a cohort of moderately ill patients with severe infection (Sepsis-2 criteria). Methods In this prospective study, 92 inflammatory plasma markers were profiled using a targeted proteome platform and compared between patients with severe infection (Sepsis-2 criteria) and healthy controls. To identify endotypes with different inflammatory profiles, we performed hierarchical clustering of patients based on the differentially expressed proteins, followed by clinical and demographic characterization of the observed endotypes. Results In a cohort of 167 patients with severe infection and 192 healthy individuals, we found 62 differentially expressed proteins. Inflammatory proteins such as TNFSF14, OSM, CCL23, IL-6, and HGF were upregulated, while TRANCE, DNER and SCF were downregulated in patients. Unsupervised clustering identified two different inflammatory profiles. One endotype showed significantly higher inflammatory protein abundance, and patients with this endotype were older and showed lower lymphocyte counts compared to the low inflammatory endotype. Conclusions By identifying endotypes based on inflammatory proteins in moderately ill patients with severe infection, our study suggests that inflammatory proteome profiling can be useful for patient stratification.

A new carbapenem antibiotic — biapenem — previously used only in Japan and Southeast Asia, was registered in Russia in 2021. The article analyzes the antimicrobial, pharmacokinetic, and clinical characteristics of biapenem in detail, provides pharmacodynamic justifications for antibiotic dosing. The most important properties and advantages of biapenem related to antimicrobial action (higher activity and eradication potential against Pseudomonas aeruginosa), the highest stability among carbapenems to carbapenemases of classes D (OXA-48-type) and B (NDM-type) are emphasized, which determines a new option for the treatment of infections caused by carbapenem-resistant Enterobacterales (biapenem in combination with polymyxin/colistin and/or tigecycline). Among the features of pharmacokinetics, it is necessary to highlight low albumin binding (3.7%), good tissue penetration, as well as stable pharmacokinetics of biapenem in patients in critical condition, septic shock, and those requiring renal replacement therapy. Pharmacodynamic modeling has established the most optimal dosage of biapenem in sepsis and septic shock: 300 mg (3-hour infusion) every 6 hours or 600 mg every 12 hours. A dosage regimen of 300 mg QID is preferable in patients undergoing continuous renal replacement therapy. The effectiveness of biapenem has been documented in numerous studies, which also show good antibiotic tolerability and safety: the frequency of side effects averaged 2% and was lower than that of other carbapenems. Biapenem can be effectively and safely prescribed to the most problematic elderly patients with serious comorbid conditions and impaired kidney and liver function.

Objective: This study aimed to describe severe infections in patients treated with tocilizumab for systemic diseases other than rheumatoid arthritis. Methods: Data from patients receiving at least 2 doses of tocilizumab for systemic diseases other than rheumatoid arthritis between January 1, 2012, and July 1, 2020, in the region Poitou-Charentes (France) were retrospectively collected from medical records. Psoriatic arthritis and systemic juvenile idiopathic arthritis were also excluded as usually treated with similar modalities to rheumatoid arthritis. Results: Of 37 patients, mainly suffering from giant cell arteritis, 25 patients (68%) had at least 1 infectious event and 15 severe infections occurred in 6 patients (3.2/100 patient-years), mainly bacterial. Lower respiratory tract and skin were the main sites. Severe bacterial infections were associated with a marked biological inflammatory syndrome, even under a cycle of administration of tocilizumab. Two severe zonas and 1 severe diverticulitis occurred. No tuberculosis or viral hepatitis reactivation was observed. Conclusion: The incidence rate of severe infections was 3.2/100 patient-years and seems lower than that reported in rheumatoid arthritis. C-reactive protein dosage could be helpful for the diagnosis of bacterial infectious adverse events in patients on tocilizumab. Further larger studies are needed to confirm these results to assess potential risk factors for severe infections. [ABSTRACT FROM AUTHOR]

Background: Sepsis is a heterogeneous syndrome due to a variable range of dysregulated processes in the host immune response. Efforts are made to stratify patients for personalized immune-based treatments and better prognostic prediction. Using gene expression data, different inflammatory profiles have been identified. However, it remains unknown whether these endotypes mirror inflammatory proteome profiling, which would be more feasible to assess in clinical practice. We aim to identify different inflammatory endotypes based on circulating proteins in a cohort of moderately ill patients with severe infection (Sepsis-2 criteria).Methods: In this prospective study, 92 inflammatory plasma markers were profiled using a targeted proteome platform and compared between patients with severe infection (Sepsis-2 criteria) and healthy controls. To identify endotypes with different inflammatory profiles, we performed hierarchical clustering of patients based on the differentially expressed proteins, followed by clinical and demographic characterization of the observed endotypes.Results: In a cohort of 167 patients with severe infection and 192 healthy individuals, we found 62 differentially expressed proteins. Inflammatory proteins such as TNFSF14, OSM, CCL23, IL-6, and HGF were upregulated, while TRANCE, DNER and SCF were downregulated in patients. Unsupervised clustering identified two different inflammatory profiles. One endotype showed significantly higher inflammatory protein abundance, and patients with this endotype were older and showed lower lymphocyte counts compared to the low inflammatory endotype.Conclusions: By identifying endotypes based on inflammatory proteins in moderately ill patients with severe infection, our study suggests that inflammatory proteome profiling can be useful for patient stratification. [ABSTRACT FROM AUTHOR]

BackgroundStaphylococcus aureus is a well-known bacterium associated with carriage and responsible for different types of infections. The Panton-Valentine leucocidin (PVL) is a key virulence factor causing tissue necrosis. PVL can, however, be present in both benign and life-threatening infections.Case reports and managementWe present three pediatric severe infections occurring over a period of only three weeks, in February 2021, and caused by genetically unrelated methicillin-sensitive Staphylococcus aureus producing PVL in a tertiary children’s hospital in Belgium. The first one presented with necrotizing pneumonia, the second one with a neck abscess extended to the mediastinum, and the last one had sacral osteomyelitis complicated by endocarditis. The management of these infections is mostly based on expert opinions. The most appropriate treatment seems to be the combination of early surgical drainage of infected collections with an antibiotic regimen associating two antibiotics; beta-lactams and either clindamycin or linezolid. Human immunoglobulins also appear to be useful as adjunctive therapy.ConclusionPVL-producing Staphylococcus aureus is associated with life-threatening infections in children. Prompt management is needed including surgery and appropriate antibiotic regimens.

As a synergistic treatment approach with systemic antimicrobial therapy or a systemic antibiotic-sparing strategy, the local administration of antimicrobial agents has been proposed as an alternative route for complicated infections. With the rationale of concentrating the active principle in the desired target site, avoiding potentially toxic systemic levels and bypassing anatomical and physiological barriers, local irrigation or infusion of antibiotics may effectively shorten the antimicrobial therapy course and reduce both infection-related and systemic therapy-related complications. Although evidence from the adult population supports its use in selected patients with an acceptable safety profile, data specifically focused on the pediatric population are limited. To provide a rapid and easily accessible tool for clinical practice, we synthesized the most relevant evidence on the use of local antimicrobial agents in common severe infections in children: meningitis, mediastinitis, pleural infections, recurrent urinary infections, and peritonitis. A literature search was performed using predefined combined keywords through an electronic research database (PubMed). Described molecules, dosages, routes, treated age groups, and related efficacy have been summarized for prompt application to clinical practice. It should, however, be noted that the evidence for the pediatric population remains limited, and the local administration of several molecules remains off-label. A careful multidisciplinary and patient-tailored evaluation, as well as a rational use of available guidelines, should always be the basis of clinical decision making in settings where local administration of antibiotics may be considered.

B cell chronic lymphoproliferative diseases (B-CLPD) are associated with secondary antibody deficiency and other innate and adaptive immune defects, whose impact on infectious risk has not been systematically addressed. We performed an immunological analysis of a cohort of 83 B-CLPD patients with recurrent and/or severe infections to ascertain the clinical relevance of the immune deficiency expression. B-cell defects were present in all patients. Patients with combined immune defect had a 3.69-fold higher risk for severe infection (p = 0.001) than those with predominantly antibody defect. Interestingly, by Kaplan–Meier analysis, combined immune defect showed an earlier progression of cancer with a hazard ratio of 3.21, than predominantly antibody defect (p = 0.005). When B-CLPD were classified in low-degree, high-degree, and plasma cell dyscrasias, risk of severe disease and cancer progression significantly diverged in combined immune defect, compared with predominantly antibody defect (p = 0.001). Remarkably, an underlying primary immunodeficiency (PID) was suspected in 12 patients (14%), due to prior history of infections, autoimmune and granulomatous conditions, atypical or variegated course and compatible biological data. This first proposed SID classification might have relevant clinical implications, in terms of predicting severe infections and cancer progression, and might be applied to different B-CLPD entities. [ABSTRACT FROM AUTHOR]

Background: People living with HIV (PLWH) have been shown to have an increased risk of autoimmune diseases. Corticosteroids are the cornerstone of autoimmune diseases treatment, but their use is associated with an increased risk of infections. It is unclear how HIV status affects the risk of infection associated with corticosteroids use.Methods: We conducted a retrospective cohort study from 1991 to 2011, using a medico-administrative database from Quebec. Medical billing codes were used to identify PLWH, and we matched them on age, sex, and index date with up to 4 HIV-negative controls. The exposure of interest was the use of corticosteroids, defined as a systemic corticosteroid dispensation lasting at least 20 days. The outcome of interest was hospitalization for severe infection. Crude and adjusted incidence rates ratios of infection were obtained using a random effect Poisson model, and results were stratified by HIV status.Results: In total, 4798 PLWH were matched to 17 644 HIV-negative controls, among which 1083 (22.6%) PLWH and 1854 (10.5%) HIV-negative controls received at least one course of corticosteroid. The mean duration of corticosteroids use was 4 ± 4.4 months in PLWH and 1.6 ± 5.5 months in HIV-negative controls. The incidence rate ratio (IRR) for infections associated with corticosteroids use was 2.49[1.71-3.60] in PLWH and 1.32[0.71-2.47] in HIV-negative controls (P value for interaction 0.18). The most frequent infections were pulmonary infections (50.4%), followed by urinary tract infections (26%) and opportunistic infections (10.5%).Conclusion: Although our interaction term did not reach significance, the increased risk of infection associated with corticosteroids use was more pronounced in PLWH. However, further research with contemporary data is warranted to confirm if the risk associated with corticosteroids use remains high in PLWH with well-controlled HIV infection. [ABSTRACT FROM AUTHOR]

Objectives Rituximab (RTX) is an anti-CD20 antibody that selectively depletes B cells and has emerged as a therapy for ANCA-associated vasculitis (AAV) during the past decade. This study sought to quantify and determine potential risk factors for severe infections in AAV patients treated with RTX at rheumatology clinics in Mexico City, Mexico and Lund, Sweden. Methods The study consisted of a retrospective case-record review (2005–15) with standardized data collection related to the occurrence of severe infection in 46 patients with AAV in Mexico City (n  = 20) and Lund (n  = 26) treated with RTX during their disease course. Median duration of follow-up from first RTX dose to death or end of study was 26 months. Results Eleven (24%) patients suffered a total of 18 severe infections (infection rate of 11.5/100 patient-years). Thirteen of the 18 infections (72%) occurred within the first year of treatment. Risk factors for severe infection were older age at RTX initiation and absence of ENT involvement at diagnosis. In multivariate analyses, age at RTX infusion was the only independent factor predicting severe infection. Four patients (9%) died during follow-up, all as a result of infection. Conclusion Severe infections are common following RTX treatment, and mortality due to infection is a major concern. Most severe infections occur within the first year of RTX treatment. The negative correlation of ENT involvement with severe infection might reflect granulomatosis with polyangiitis phenotype heterogeneity. Older age at time of RTX treatment independently predicts severe infections. [ABSTRACT FROM AUTHOR]

Abstract Background In critically ill patients, the use of high tigecycline dosages (HD TGC) (200 mg/day) has been recently increasing but few pharmacokinetic/pharmacodynamic (PK/PD) data are available. We designed a prospective observational study to describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of HD TGC in a cohort of critically ill patients with severe infections. Results This was a single centre, prospective, observational study that was conducted in the 20-bed mixed ICU of a 1500-bed teaching hospital in Rome, Italy. In all patients admitted to the ICU between 2015 and 2018, who received TGC (200 mg loading dose, then 100 mg q12) for the treatment of documented infections, serial blood samples were collected to measure steady-state TGC concentrations. Moreover, epithelial lining fluid (ELF) concentrations were determined in patients with nosocomial pneumonia. Amongst the 32 non-obese patients included, 11 had a treatment failure, whilst the other 21 subjects successfully eradicated the infection. There were no between-group differences in terms of demographic aspects and main comorbidities. In nosocomial pneumonia, for a target AUC0-24/MIC of 4.5, 75% of the patients would be successfully treated in presence of 0.5 mcg/mL MIC value and all the patients obtained the PK target with MIC ≤ 0.12 mcg/mL. In intra-abdominal infections (IAI), for a target AUC0-24/MIC of 6.96, at least 50% of the patients would be adequately treated against bacteria with MIC ≤ 0.5 mcg/mL. Finally, in skin and soft-tissue infections (SSTI), for a target AUC0-24/MIC of 17.9 only 25% of the patients obtained the PK target at MIC values of 0.5 mcg/mL and less than 10% were adequately treated against germs with MIC value ≥ 1 mcg/mL. HD TGC showed a relevant pulmonary penetration with a median and IQR ELF/plasma ratio (%) of 152.9 [73.5–386.8]. Conclusions The use of HD TGC is associated with satisfactory plasmatic and pulmonary concentrations for the treatment of severe infections due to fully susceptible bacteria (MIC

Severe infections are a major public health problem responsible for about 40-65% of hospitalizations in intensive care units (ICU). The high mortality (30-50%) of persons diagnosed with severe infection is caused by largely unknown mechanisms of sepsis-induced immune system response. Severe infections with dynamic progress are accompanied with SIRS (systemic inflammatory reaction syndrome) and CARS (compensatory anti-inflammatory response syndrome), and require a biological treatment appropriate to the phase of immune response. The mechanisms responsible for severe infection related to immune system response particularly attract extensive interest of non-specific defense mechanisms, including signaling pathways of Toll-like receptors (mainly TLR4 and TLR2) that recognize distinct pathogen-associated molecular patterns (PAMP) and play a critical role in innate immune response. There are attempts of treatment, followed by blocking ligand binding with TLR or modulation of intracellular signaling pathways, to inhibit signal transduction. Moreover, researches regarding new and more efficient diagnostics biomarkers were mostly focused on indicators related to innate response to infection as well as connections of pro-inflammatory response with anti-inflammatory response. According to these studies, in case of ICU septic patients with high-risk of mortality, the solution for the problem will require mainly early immune and genetic diagnostics (e.g. cytokines, microRNA, cluster of differentiation-64 [CD64], triggering receptor expressed on myeloid cells-1 [TREM-1], and high mobility group box 1 protein [HMGB1]).

Vitamin C, a key nutrient with potent antioxidant and immunomodulatory properties, has been explored for its therapeutic potential in treating severe infections, particularly sepsis. This systematic review aims to evaluate the effectiveness of parenteral vitamin C in improving clinical outcomes in patients with severe infections. A comprehensive search of several databases, including PubMed, EMBASE, and the Cochrane Library, was conducted for studies published between January 2000 and June 2024. Included were randomized controlled trials, observational studies, and case reports that examined the use of parenteral vitamin C in adult patients with severe infections. Data extracted included study design, sample size, intervention specifics, and clinical outcomes. Quality was assessed using tools appropriate to each study design, such as the Cochrane Risk of Bias Tool and the Newcastle-Ottawa Scale. The review included nine studies with diverse methodologies. While individual studies reported benefits such as improved immune function and reduced oxidative stress, larger systematic reviews and meta-analyses did not demonstrate a significant reduction in mortality. The results indicate that while parenteral vitamin C may improve certain biochemical and physiological parameters, these improvements do not consistently translate into enhanced survival or substantial clinical benefits. Parenteral vitamin C shows potential in modulating immune response and reducing oxidative damage in severe infections. However, its impact on key clinical outcomes like mortality and long-term recovery remains uncertain. This review highlights the need for further high-quality, randomized controlled trials to clarify vitamin C's role in managing severe infections and define optimal therapeutic protocols., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Thakare et al.)

Copyright of Cirugía y Cirujanos is the property of Publicidad Permanyer SLU and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

B cell chronic lymphoproliferative diseases (B-CLPD) are associated with secondary antibody deficiency and other innate and adaptive immune defects, whose impact on infectious risk has not been systematically addressed. We performed an immunological analysis of a cohort of 83 B-CLPD patients with recurrent and/or severe infections to ascertain the clinical relevance of the immune deficiency expression. B-cell defects were present in all patients. Patients with combined immune defect had a 3.69-fold higher risk for severe infection (p = 0.001) than those with predominantly antibody defect. Interestingly, by Kaplan–Meier analysis, combined immune defect showed an earlier progression of cancer with a hazard ratio of 3.21, than predominantly antibody defect (p = 0.005). When B-CLPD were classified in low-degree, high-degree, and plasma cell dyscrasias, risk of severe disease and cancer progression significantly diverged in combined immune defect, compared with predominantly antibody defect (p = 0.001). Remarkably, an underlying primary immunodeficiency (PID) was suspected in 12 patients (14%), due to prior history of infections, autoimmune and granulomatous conditions, atypical or variegated course and compatible biological data. This first proposed SID classification might have relevant clinical implications, in terms of predicting severe infections and cancer progression, and might be applied to different B-CLPD entities.

In past decade, cephalosporins have developed significantly, and data regarding novel cephalosporins (i.e., ceftobiprole, ceftaroline, ceftolozane/tazobactam, ceftazidime/avibactam, and cefiderocol) within septic and bacteremic subjects are rising. These compounds generally offer very promising in vitro microbiological susceptibility, although the variability among gram-negative and -positive strains of different cohorts is noticed in the literature. We require further pharmacological data to measure the best dose in order to prevent sub-therapeutic drug levels in critically ill patients. These new compounds in theory are the sparing solution in the Enterobacteriales infection group for different antimicrobial classes such as aminoglycosides notably within endovascular and GNB-bacteremias, as well as colistin and carbapenem-sparing strategies, favoring good safety profile molecules. Moreover, new cephalosporins are the basis for the actual indications to open up new and exciting prospects for serious infections in the future. In future, patients will be addressed with the desirable approach to sepsis and serious infections in terms of their clinical situation, inherent features of the host, the sensitivity profile, and local epidemiology, for which evidence of the use of new cephalosporin in the treatment of severe infections will fill the remaining gaps.

Background: Rapid recognition and antibiotic treatment, preferably preceded by blood cultures (BCs), is a mainstay in sepsis therapy. The objective of this investigation was to determine if pre‐hospital BCs were feasible and drawn with an acceptably low level of contamination and to investigate whether pre‐hospital antibiotics were administered on correct indications. Methods: We performed a register‐based study in a pre‐hospital physician‐manned mobile emergency care unit (MECU) operating in a mixed urban/rural area in Denmark. All patients who received pre‐hospital antibiotics by the MECU from November 2013 to October 2018 were reviewed. Outcome measures were characterisation of microbial findings and subsequent in‐hospital confirmation of the pre‐hospital indication for antibiotics. Results: One‐hundred‐and‐nineteen patients received antibiotics pre‐hospitally. Six were excluded. One‐hundred‐and‐thirteen patients were included in the study. BCs were drawn in 107 of the 113 patients (94.7% [88.8%‐98.0%]). We found a true pathogen of sepsis in 29 (27.1% [19.0%‐36.6%]) of these 107 patients. Nine (8.4% [3.9%‐15.4%]) patients had contaminated pre‐hospital BCs. Forty‐nine of all patients (36.3% [27.4%‐45.9%]) had causative pathogens in either their BCs or other samples confirming the pre‐hospital tentative diagnosis. Eighty‐two (72.6% [63.4%‐80.5%]) patients received antibiotic therapy in‐hospitally, while 27 (23.9% [16.4%‐32.8%]) were assigned an in‐hospital diagnosis not associated with infection. Four (3.5% [1.0%‐8.8%]) patients died in hospital before a diagnosis was established. Conclusions: Pre‐hospital administration of antibiotics preceded by BCs is feasible, although with somewhat high blood culture contamination rates. Antibiotics are administered on reasonable indications. [ABSTRACT FROM AUTHOR]

Infections in patients with systemic vasculitis represent one of the main causes of mortality. Corticosteroid use, immunosuppressive therapy, age, associated organic involvement and dialysis dependence are risk factors of infection., Objectives: To determine the prevalence of severe infection and associated factors in patients diagnosed with ANCA-associated vasculitis (AAV) and Polyarteritis Nodosa (PAN)., Methods: retrospective study was conduced in a single rheumatology center (2000-2018). We included patients diagnosed with AAV (Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA) and Microscopic Polyangiitis (PAM) and Polyarteritis nodosa (PAN). Serious infectious events requiring hospitalisation or prolonged antibiotic/antiviral treatment, recurrent infection of Herpes Zoster Virus or opportunistic infections were evaluated. Sites of infection, isolated microorganisms and mortality related were analyzed., Results: 105 patients were analyzed, follow-up time median 18 m, 58.7% were women and median age was 52 years. Types of vasculitis: 41.9% PAM, 16.2% EPGA, 40% GPA, 1.9% PAN. Constitutional, pulmonary, renal and otorhinolaryngology manifestations were the most frequent., Prevalence of Infection: 34.2%, with a median of 3 months from diagnosis of vasculitis to the infectious event. Low respiratory tract (42.8%), sepsis (31.4%), and urinary tract (14.3%) were the most common sites of infections. Bacterial aetiology was the most prevalent (67.7%). Mortality at the first event was 14.3% and a 72.2% of patients were in the induction phase of treatment. Infectious events were significantly associated with age > 65 years (p = 0.030), presence of lung (p = 0.016) and renal involvement (p = 0.001), BVASv3 > 15, mortality (p = 0.0002)., Conclusions: The prevalence of infection was 34.2%. Lower airway infections, septicemia and urinary tract infections were the most prevalent. Infections were associated with renal and pulmonary involvement, age older than 65 years and score BVAS > 15. Severe infections were associated with mortality, especially in elderly patients., (Copyright © 2024 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Severe infections are common in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We aimed to describe the characteristics of patients with AAV and severe infections according to clinical phenotype. Retrospective cohort study including patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Baseline characteristics were compared between patients with and without at least one severe infection. Demographics, comorbidities, clinical characteristics, laboratory and treatment were retrieved at diagnosis and at every infectious event. One hundred and eight patients were included (57 with and 51 without infections). Patients with an infection had received more frequently methylprednisolone boluses at AAV diagnosis than patients without infections (OR 2.6, 95% CI 1.1–5.9, p = 0.01). There were a total of 108 severe infections in 57 patients (median follow-up 18 months). Thirty-two patients (56%) had an infectious complication within the first year of AAV diagnosis, 43 (75%) had pulmonary involvement during the first infection. The most frequent type of infection was pneumonia. Phenotypes were: Non-severe AAV (n = 11), severe PR3-AAV (n = 30), severe MPO-AAV (n = 9); the number of infectious events in each group was 11, 69, 18, respectively. Patients with severe MPO phenotype were older and required more frequently ICU stay compared to other phenotypes. Positive correlation was found between total of infections and pulmonary infiltrates due to vasculitis (ρ = 0.40, p = 0.003), endobronchial involvement (ρ = 0.40, p = 0.003), and alveolar hemorrhage (ρ = 0.34, p = 0.015). Severe infections, most commonly pneumonia, were frequent in this cohort, especially during the first year after diagnosis, in patients with pulmonary involvement and severe PR3 phenotype who received methylprednisolone boluses. [ABSTRACT FROM AUTHOR]

Background: Patients with severe bacterial infections often experience delay in receiving appropriate treatment. Consolidated evidence of the impact of delayed appropriate treatment is needed to guide treatment and improve outcomes.Research Question: What is the impact of delayed appropriate antibacterial therapy on clinical outcomes in patients with severe bacterial infections?Study Design and Methods: Literature searches of MEDLINE and Embase, conducted on July 24, 2018, identified studies published after 2007 reporting the impact of delayed appropriate therapy on clinical outcomes for hospitalized adult patients with bacterial infections. Where appropriate, results were pooled and analyzed with delayed therapy modeled three ways: delay vs no delay in receiving appropriate therapy; duration of delay; and inappropriate vs appropriate initial therapy. This article reports meta-analyses on the effect of delay and duration of delay.Results: The eligibility criteria were met by 145 studies, of which 37 contributed data to analyses of effect of delay. Mortality was significantly lower in patients receiving appropriate therapy without delay compared with those experiencing delay (OR, 0.57; 95% CI, 0.45-0.72). Mortality was also lower in the no-delay group compared with the delay group in subgroups of studies reporting mortality at 20 to 30 days, during ICU stay, or in patients with bacteremia (OR, 0.57 [95% CI, 0.43-0.76]; OR, 0.47 [95% CI, 0.27-0.80]; and OR, 0.54 [95% CI, 0.40-0.75], respectively). No difference was found in time to appropriate therapy between those who died and those who survived (P = .09), but heterogeneity between studies was high.Interpretation: Avoiding delayed appropriate therapy is essential to reduce mortality in patients with severe bacterial infections.Clinical Trial Registration: PROSPERO; No.: CRD42018104669; URL: www.crd.york.ac.uk/prospero/. [ABSTRACT FROM AUTHOR]

Background: In critically ill patients, the use of high tigecycline dosages (HD TGC) (200 mg/day) has been recently increasing but few pharmacokinetic/pharmacodynamic (PK/PD) data are available. We designed a prospective observational study to describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of HD TGC in a cohort of critically ill patients with severe infections. Results: This was a single centre, prospective, observational study that was conducted in the 20-bed mixed ICU of a 1500-bed teaching hospital in Rome, Italy. In all patients admitted to the ICU between 2015 and 2018, who received TGC (200 mg loading dose, then 100 mg q12) for the treatment of documented infections, serial blood samples were collected to measure steady-state TGC concentrations. Moreover, epithelial lining fluid (ELF) concentrations were determined in patients with nosocomial pneumonia. Amongst the 32 non-obese patients included, 11 had a treatment failure, whilst the other 21 subjects successfully eradicated the infection. There were no between-group differences in terms of demographic aspects and main comorbidities. In nosocomial pneumonia, for a target AUC0-24/MIC of 4.5, 75% of the patients would be successfully treated in presence of 0.5 mcg/mL MIC value and all the patients obtained the PK target with MIC ≤ 0.12 mcg/mL. In intra-abdominal infections (IAI), for a target AUC0-24/MIC of 6.96, at least 50% of the patients would be adequately treated against bacteria with MIC ≤ 0.5 mcg/mL. Finally, in skin and soft-tissue infections (SSTI), for a target AUC0-24/MIC of 17.9 only 25% of the patients obtained the PK target at MIC values of 0.5 mcg/mL and less than 10% were adequately treated against germs with MIC value ≥ 1 mcg/mL. HD TGC showed a relevant pulmonary penetration with a median and IQR ELF/plasma ratio (%) of 152.9 [73.5–386.8]. Conclusions: The use of HD TGC is associated with satisfactory plasmatic and pulmonary concentrations for the treatment of severe infections due to fully susceptible bacteria (MIC < 0.5 mcg/mL). Even higher dosages and combination strategies may be suggested in presence of difficult to treat pathogens, especially in case of SSTI and IAI. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the clinical characteristics and risk factors associated with severe pneumonia in systemic lupus erythematosus (SLE) patients from China. Method: We performed a retrospective study in 112 hospitalized SLE patients who had had pneumonia for 8 years. The primary outcome was severe pneumonia, followed by descriptive analysis, group comparison and bivariate analysis. Results: A total of 28 SLE patients were diagnosed with severe pneumonia, with a ratio of 5:23 between men and women. The mean age at diagnosis was 44.36 ± 12.389 years. The median disease duration was 72 months, and the median SLE Disease Activity Index 2000 (SLEDAI 2K) score was 8. The haematological system was the most affected, with an incidence of anaemia in 85.7% of cases and thrombocytopenia in 75% of cases, followed by lupus nephritis in 50% of cases and central nervous system involvement in 10.71% of cases. Cultured sputum specimens were positive in 17 (68%) SLE patients with severe pneumonia, of whom nine (36%) were cases of fungal infection, five (20%) were cases of bacterial infection and three (12%) were cases of mixed infection. Using multivariate logistic regression analysis, we concluded that a daily dosage of prednisone (>10 mg; odds ratio (OR) = 3.193, p = 0.005), a low percentage of CD4+ T lymphocytes (OR = 0.909, p = 0.000), a high SLEDAI 2K score (OR = 1.182, p = 0.001) and anaemia (OR = 1.182, p = 0.001) were all independent risk factors for pneumonia in SLE patients, while a low percentage of CD4+ T lymphocytes (OR = 0.908, p = 0.033), a daily dose of prednisone of >10 mg (OR = 35.67, p = 0.001) were independent risk factors for severe pneumonia in SLE patients. Conclusion: Severe pneumonia is not rare in lupus, and is associated with high mortality and poor prognosis. Monitoring CD4+ T-cell counts and giving a small dose of glucocorticoids can reduce the occurrence of severe pneumonia and improve the prognosis of patients with lupus. [ABSTRACT FROM AUTHOR]

Severe infections are a major public health problem responsible for about 40-65% of hospitalizations in intensive care units (ICU). The high mortality (30-50%) of persons diagnosed with severe infection is caused by largely unknown mechanisms of sepsis-induced immune system response. Severe infections with dynamic progress are accompanied with SIRS (systemic inflammatory reaction syndrome) and CARS (compensatory anti-inflammatory response syndrome), and require a biological treatment appropriate to the phase of immune response. The mechanisms responsible for severe infection related to immune system response particularly attract extensive interest of non-specific defense mechanisms, including signaling pathways of Toll-like receptors (mainly TLR4 and TLR2) that recognize distinct pathogen-associated molecular patterns (PAMP) and play a critical role in innate immune response. There are attempts of treatment, followed by blocking ligand binding with TLR or modulation of intracellular signaling pathways, to inhibit signal transduction. Moreover, researches regarding new and more efficient diagnostics biomarkers were mostly focused on indicators related to innate response to infection as well as connections of pro-inflammatory response with anti-inflammatory response. According to these studies, in case of ICU septic patients with high-risk of mortality, the solution for the problem will require mainly early immune and genetic diagnostics (e.g. cytokines, microRNA, cluster of differentiation-64 [CD64], triggering receptor expressed on myeloid cells-1 [TREM-1], and high mobility group box 1 protein [HMGB1]). [ABSTRACT FROM AUTHOR]

Patients with severe infections are often treated with multiple courses of antibiotics in the intensive care unit (ICU), making the ICU a true antibiotic hotspot. The increasing incidence of multidrug resistance worldwide emphasizes the need for continued efforts in developing and implementing antibiotic stewardship programs. Using a pragmatic approach for the bedside clinical team, this review will highlight different key moments for antibiotic decision making throughout the course of the antibiotic treatment in patients with severe infections. We will focus especially on the importance of adequate empirical therapy, source control in infections, assessment of immune status, and two separate antibiotic time-out moments early in the course, as well as the moment of stopping antibiotics. Additionally, the importance of a team-based approach and clinical decision support systems will be highlighted. [ABSTRACT FROM AUTHOR]

Background: Poor outcomes in severe and resistant infections, together with the economic struggles of companies active in the field of anti-infective development, call for new solutions and front runners with novel approaches. Among “non-traditional” approaches, blocking virulence could be a game changer. Objectives: This review offers a perspective on parameters that have determined the development path of CAL02, a novel anti-virulence agent, with a view to steering clear of the obstacles and limitations that impede market sustainability for new anti-infective drugs. Conclusions and implications of key findings: This case study highlights four pillars that may support the development of other non-traditional drugs and, concurrently, provide a new model that could reshape the field. Therapeutic triggers, study designs, and economic parameters are discussed.

Autorii raportează cazul unui sugar de sex masculin diagnosticat, la vârsta de 10 luni, cu sindrom hiper-IgM în contextul infecțiilor severe cauzate de Streptococcus pneumoniae, Staphylococcus aureus și Candida albicans. În ciuda terapiei de substituție cu gamaglobulină umană, sugarul a continuat să prezinte frecvente episoade de otită medie supurată cauzate de Candida și pneumococ penicilino-rezistent și abces antebraț determinat de Staphylococcus aureus. În evoluție sugarul a dezvoltat cataractă ambii ochi, hepatită cronică și fractură cominutivă femur secundară demineralizării osoase. Pacientul nu a prezentat infecții cu germeni oportuniști comparativ cu pacienții cu deficiență CD40 Ligand. Spre deosebire de majoritatea bolnavilor cu fenotip hiper-IgM, pacientul a necesitat cantități reduse de gamaglobulină umană. Ca particularitate imunologică, în evoluție valoarea serica a IgM a crescut la valori foarte mari.

Background Severe infection is life-threatening in children with hematologic malignancies and its treatment is challenging because of an increasing number of multidrug-resistant pathogens. Tigecycline has an expanded antibacterial activity spectrum; some successful cases of tigecycline treatment have been reported in the literature. Objective To examine the efficacy and safety of tigecycline in children. Setting Department of hematologic malignancies in a tertiary hospital. Method A retrospective chart review from May 1, 2012 to May 1, 2017. The patients were identified by the hospital information system and a custom-made Microsoft Excel 2007 database of patients was created to record demographic and medical data. Main outcome measure Efficacy and safety of tigecycline use in severe infection children with hematologic malignancies. Results Thirty-seven patients were enrolled and the predominant diagnosis was acute lymphoblastic leukemia. The median duration of tigecycline therapy was 9 days. Most prescriptions were empirical. Eighteen patients received a maintenance dose of 2 mg/kg q12 h, without a loading dose. Sulperazone was the most frequently prescribed concomitant drug. At the end of tigecycline therapy, improvement was observed in 48.7% of cases. After treatment, interleukin-10 levels notably decreased. The only reported adverse event was a case of tooth discoloration. Conclusion Tigecycline can be used as salvage therapy in children with hematologic malignancy and seems tolerable. Prospective controlled studies are required to definitively evaluate the efficacy and safety of tigecycline in children. [ABSTRACT FROM AUTHOR]

Sepsis is still related to high mortality and hospitalization rates in the paediatric population despite medical progress. Prompt recognition of sepsis and consequent initiation of an appropriate treatment are essential elements in securing a positive outcome in adults and children. In such scenario, various biomarkers have been studied to support the clinician in the diagnosis of severe infections, in the identification of patients at risk of progression towards sepsis as well as in the evaluation of the response to treatment. In children, the performance of C-reactive protein and procalcitonin has been largely investigated, whereas data on newer biomarkers of sepsis are scant. The aim of the present review is to summarise the available data on the use of pro-adrenomedullin in the paediatric age.

Copyright of Revista Española de Quimioterapia is the property of Sociedad Espanola de Quimioterapia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: In this era of rising antimicrobial resistance, slowly refilling antibiotic development pipelines, and an aging population, we need to ensure that randomized clinical trials (RCTs) determine the added benefit of new antibiotic agents effectively and in a valid way, especially for severely ill patients. Unfortunately, universally accepted endpoints for the evaluation of new drugs in severe infections are lacking.Methods: We review and discuss the current practices and challenges regarding endpoints in RCTs in this field and propose novel approaches.Results: Usual endpoints actually recommended for drug development suffer from important flaws. Mortality requires large sample size and only partly related to the infectious process. Clinical cure rate is highly subjective in critically ill patients where symptoms may be related to other intercurrent events. Currently, composite endpoints, hierarchical nested designs, and competing risks analysis seem to be the most promising new tools for designing and analyzing clinical trials in this area, although they require further validation.Conclusion: Regulatory authorities, pharmaceutical companies, and clinicians need to agree on the most appropriate clinical endpoints for severe infections to ensure efficient approval of new, effective antibiotic agents. [ABSTRACT FROM AUTHOR]

This multicenter observational study included 171 COVID-19 adult patients hospitalized in the ICUs of nine hospitals in Lombardy (Northern Italy) from December, 1st 2021, to February, 9th 2022. During the study period, the Delta/Omicron variant ratio of cases decreased with a delay of two weeks in ICU patients compared to that in the community; a higher proportion of COVID-19 unvaccinated patients was infected by Delta than by Omicron whereas a higher rate of COVID-19 boosted patients was Omicron-infected. A higher number of comorbidities and a higher comorbidity score in ICU critically COVID-19 inpatients was positively associated with the Omicron infection as well in vaccinated individuals. Although people infected by Omicron have a lower risk of severe disease than those infected by Delta variant, the outcome, including the risk of ICU admission and the need for mechanical ventilation due to infection by Omicron versus Delta, remains uncertain. The continuous monitoring of the circulating SARS-CoV-2 variants remains a milestone to counteract this pandemic., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 SPLF and Elsevier Masson SAS. All rights reserved.)