Current concepts in combination antibiotic therapy for critically ill patients

Widespread emergence of multidrug resistant (MDR) bacterial pathogens is a problem of global dimension. MDR infections are difficult to treat and frequently associated with high mortality. More than one antibiotic is commonly used to treat such infections, but scientific evidence does not favor use of combination therapy in most cases. However, there are certain subgroups where combination therapy may be beneficial, e.g. sepsis due to carbapenem-resistant Enterobacteriaceae (CRE), bacteremic pneumococcal pneumonia, and patients with multiple organ failure. Well-designed prospective studies are needed to clearly define the role of combination therapy in these subgroups.     

Blockade of the T cell immunoglobulin and mucin domain protein 3 pathway exacerbates sepsis-induced immune deviation and immunosuppression

Sepsis is a life-threatening condition, but the pathophysiological basis and biomarkers for the monitoring of sepsis and as targets for therapy remain to be determined. We have shown previously that T cell immunoglobulin and mucin domain protein 3 (Tim-3), a negative immune regulator, is involved in the physiopathology of sepsis, but the underlying mechanisms remain unclear. In the present study, we showed that Tim-3 signalling modulated the response patterns of both macrophages and T helper cells in sepsis. Blockade of the Tim-3 pathway exacerbated sepsis-induced proinflammatory macrophage responses and lymphocyte apoptosis during the early phase of sepsis, and enhanced the shift to anti-inflammatory responses for both macrophages and T helper cells during the late phase of sepsis. Tim-3 signalling was found to regulate CD80 and CD86 expression on macrophages both in vivo and in vitro. Co-culture of T cells with Tim-3 knock-down macrophages led to a biased T helper type 2 (Th2) response, partially explaining how Tim-3 signalling shapes inflammation patterns in vivo. Further studies on this pathway might shed new light on the pathogenesis of sepsis and suggest new approaches for intervention.     

Association of late-onset neonatal sepsis with late neurodevelopment in the first two years of life of preterm infants with very low birth weight

Objectiveto establish the influence of late-onset sepsis on neurodevelopment of preterm infants with very low birth weight (VLBW), according to the etiologic agent.Methodthis was a cohort of newborns with birth weight < 1,500 g and gestational age less than 32 weeks, admitted to the institutional intensive care unit (ICU) with up to 48 hours of life, and followed-up at the outpatient follow-up clinic for preterm infants with VLBW until 2 years of corrected age. Exclusion criteria: death within the first 72 hours of life, congenital malformations and genetic syndromes, children with congenital infection by the human immunodeficiency virus (HIV), congenital infection (STORCH), presence of early-onset sepsis and cases with more than one pathogen growth in blood cultures. Septic and non-septic infants were compared regarding neonatal outcomes and mortality. Neurodevelopment was assessed using the Bayley Scale (BSDI-II) at 18 to 24 months of corrected age.Results411 preterm infants with VLBW were eligible; the mean gestational age was 29 ± 2.2 weeks and mean birth weight was 1,041 ± 281grams. Late-onset sepsis occurred in 94 preterm infants with VLBW (22.8%). VLBW infants with Gram-positive infection showed motor deficit when compared to the non-septic group, 68.8% vs. 29.3%, respectively (OR 6; 1.6-21.8, p = 0.006); the cognitive development was similar between the groups. The overall mortality rate from infection was 26.7%; considering the pathogens, the rates were 18.7% for coagulase-negative Staphylococcus, 21.8% for Gram-positive bacteria, and 50% for Gram-negative bacteria and fungi.Conclusionneonatal sepsis has a significant influence on late neurodevelopment at 2 years of corrected age in preterm infants with VLBW, and Gram-positive infections are associated with motor deficit.     

脓毒血症患者乳酸清除率、红细胞分布宽度 和血乳酸水平及与预后的关系

目的 探讨脓毒血症患者乳酸清除率（LCR）、红细胞分布宽度（RDW）和血乳酸（Lac）水平 及与临床预后的关系。方法 选取2016 年5 月—2018 年9 月保定市第一中心医院收治的脓毒血症患者92 例 作为观察组,同期该院92 例健康体检者作为对照组。将观察组患者按照病情严重程度分为脓毒症亚组46 例、 严重脓毒症亚组29 例和脓毒性休克亚组17 例。检测两组治疗前血清RDW、Lac 水平。检测观察组治疗后 血清RDW、Lac,并计算LCR。比较两组治疗前RDW、Lac 水平,比较观察组中各亚组患者治疗前后血清 LCR、RDW 及Lac 水平。采用Pearson 法分析LCR、RDW、Lac 与脓毒血症患者病情严重程度的相关性, 生存曲线分析血清RDW、Lac 与脓毒血症患者预后的关系。结果 观察组患者治疗前RDW、Lac 水平高于 对照组（P <0.05）。严重脓毒症亚组、脓毒性休克亚组患者治疗前后血清RDW、Lac 水平高于脓毒症亚组 （P <0.05）;而LCR 低于脓毒症亚组（P <0.05）。各亚组患者治疗后血清RDW、Lac 水平低于同组治疗前 （P <0.05）。Pearson 相关性分析显示,RDW、Lac 与脓毒血症患者病情严重程度呈正相关（r =0.776 和0.817, P <0.05）;而LCR 与脓毒血症患者病情严重程度呈负相关（r =-0.851,P <0.05）。低Lac 患者中位生存时间 长于高Lac 患者（36 d VS 28 d）（P <0.05）。低RDW 患者中位生存时间长于高RDW 患者（38 d VS 30 d） （P <0.05）。结论 LCR、RDW、Lac 水平能有效反映脓毒血症患者的病情严重程度,RDW 和Lac 水平能有 效评估脓毒血症患者预后。     

Toll-like receptor signaling in neonatal sepsis and inflammation: a matter of orchestration and conditioning

Altered neonatal Toll-like receptor (TLR) function is hypothesized to contribute to the heightened susceptibility to infection and perpetuated inflammation in term and preterm neonates, clinically evident in neonatal sepsis and increased rates of inflammatory disorders. Current data indicate that basal TLR expression in term neonates equals adult expression patterns, while expression in preterm infants seems to increase, depending on gestational age. Regarding TLR signaling, some studies suggest TLR incompetence in neonates associated with impaired pro-inflammatory responses, others describe neonatal TLR function well developed and allude to its hyper-inflammation tendency. We discuss the competing positions and considerable limitations of research approaches and conclude that neonatal innate immunity is not generally less able to respond to TLR stimulation. Moreover, we describe pre-conditioning factors other than immaturity having a comparable impact. In the long term, better understanding of the complex interplay of pre- and postnatal conditions and maturation-dependent neonatal TLR function may provide new therapeutic approaches.     

The Role of Complement,C5a and Its Receptors in Sepsis and Multiorgan Dysfunction Syndrome

Sepsis continues to be a major clinical problem that is difficult to treat, as the pathophysiology of the disease is still unclear. Despite promising experimental strategies, therapeutic interventions have been largely unsuccessful. There is now increasing evidence that the disturbance of innate immunity during sepsis and multiorgan dysfunction syndrome (MODS) may be linked to uncontrolled activation of the complement system. Especially, the powerful anaphylatoxin C5a seems to play a key role in the development of immune paralysis. In this review, we describe our present understanding of the role of complement in the inflammatory response during sepsis and MODS.