Spontaneous bacterial peritonitis and extraperitoneal infections in patients with cirrhosis

Infections are a frequent complication and a major cause of death among patients with cirrhosis. The important impact of infections in general and especially spontaneous bacterial peritonitis on the course of disease and prognosis of patients with cirrhosis has been recognized for many years. Nevertheless, such importance has recently increased due to the comprehension of infection as one of the most prominent risk factors for patients to develop acute-on-chronic liver failure. Furthermore, the issue of infections in cirrhosis is a focus of increasing attention because of the spreading of multidrug resistant bacteria, which is an emerging concern among physicians assisting patients with cirrhosis. In the present paper, we will review the current epidemiology of infections in patients with cirrhosis and particularly that of infections caused by resistant bacteria, demonstrating the relevance of the subject. Besides, we will discuss the current recommendations on diagnosis and treatment of different kinds of infections, including spontaneous bacterial peritonitis, and we will highlight the importance of knowing local microbiological profiles and choosing empirical antibiotic therapy wisely. Finally, we will debate the existing evidences regarding the role of volume expansion with albumin in patients with cirrhosis and extraperitoneal infections, and that of antibiotic prophylaxis of spontaneous bacterial peritonitis.     

Spontaneous bacterial and fungal peritonitis in patients with liver cirrhosis: A literature review

Spontaneous bacterial(SBP) and spontaneous fungal peritonitis(SFP) can be a life-threatening infection in patients with liver cirrhosis(LC) and ascites. One of the possible mechanisms of developing SBP is bacterial translocation. Although the number of polymorphonuclear cells in the culture of ascitic fluid is diagnostic for SBP, secondary bacterial peritonitis is necessary to exclude. The severity of underlying liver dysfunction is predictive of developing SBP; moreover, renal impairment and infections caused by multidrug-resistant(MDR) organism are associated with a fatal prognosis of SBP. SBP is treated by antimicrobials, but initial empirical treatment may not succeed because of the presence of MDR organisms, particularly in nosocomial infections. Antibiotic prophylaxis is recommended for patients with LC at a high risk of developing SBP, gastrointestinal bleeding, or a previous episode of SBP, but the increase in the risk of developing an infection caused by MDR organisms is a serious concern globally. Less is known about SFP in patients with LC, but the severity of underlying liver dysfunction may increase the hospital mortality. SFP mortality has been reported to be higher than that of SBP partially because the difficulty of early differentiation between SFP and SBP induces delayed antifungal therapy for SFP.     

Diagnosis and management of bacterial infections in decompensated cirrhosis

Bacterial infections are one of the most frequent complications in cirrhosis and result in high mortality rates.Patients with cirrhosis have altered and impaired immunity,which favours bacterial translocation.Episodes of infections are more frequent in patients with decompensated cirrhosis than those with compensated liver disease.The most common and life-threatening infection in cirrhosis is spontaneous bacterial peritonitis followed by urinary tract infections,pneumonia,endocarditis and skin and soft-tissue infections.Patients with decompensated cirrhosis have increased risk of developing sepsis,multiple organ failure and death.Risk factors associated with the development of infections are severe liver failure,variceal bleeding,low ascitic protein level and prior episodes of spontaneous bacterial peritonitis (SBP).The prognosis of these patients is closely related to a prompt and accurate diagnosis.An appropriate treatment decreases the mortality rates.Preventive strategies are the mainstay of the management of these patients.Empirical antibiotics should be started immediately following the diagnosis of SBP and the first-line antibiotic treatment is third-generation cephalosporins.However,the efficacy of currently recommended empirical antibiotic therapy is very low in nosocomial infections including SBP,compared to community-acquired episodes.This may be associated with the emergence of infections caused by Enterococcus faecium and extended-spectrum β-lactamaseproducing Enterobacteriaceae,which are resistant to the first line antimicrobial agents used for treatment.The emergence of resistant bacteria,underlines the need to restrict the use of prophylactic antibiotics to patients with the greatest risk of infections.Nosocomial infections should be treated with wide spectrum antibiotics.Further studies of early diagnosis,prevention and treatment are needed to improve the outcomes in patients with decompensated cirrhosis.     

Immunomodulating effects of antibiotics used in the prophylaxis of bacterial infections in advanced cirrhosis

The use of norfloxacin either as primary or secondary prophylaxis of bacterial infections in advanced cirrhosis has improved patient's survival. This may be explained not only due to a significant decrease in the number of infections, but also because of a direct immunomodulatory effect. Selective intestinal decontamination with norfloxacin reduces translocation of either viable bacteria or bacteria-driven products from the intestinal lumen. In addition, norfloxacin directly modulates the systemic inflammatory response. The proinflammatory cytokine profile secreted by neutrophils from these patients shows a close, significant, and inverse correlation with serum norfloxacin levels. Similar effects have been described with other quinolones in different clinical conditions. Although the underlying mechanisms are not well defined for most of the antibiotics, the pathways triggered for norfloxacin to induce such immunomodulatory effects involve the down-regulation of pro-inflammatory inducible nitric oxide synthase, cyclooxygenase-2, and NF-κB and the up-regulation of heme-oxygenase 1 and IL-10 expression. The knowledge of these immunomodulatory effects, additional to their bactericidal role, improves our comprehension of the interaction between antibiotics and the cellular host response and offer new possibilities for the development of new therapeutic strategies to manage and prevent bacterial infections in cirrhosis.     

Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites

Background/Aims: Translocation of indigenous bacterial from the gut lumen of cirrhotic animals to mesenteric lymph nodes appears to be an important step in the pathogenesis of spontaneous bacterial peritonitis. However, the sequence of events leading to translocation remains unclear. One of the most predictable risk factors for translocation is overgrowth of gut bacterial flora. The present study was designed to compare the intestinal aerobic bacterial flora of cecal stools at the time of sacrifice between cirrhotic and normal rats and to evaluate the role of intestinal aerobic bacterial overgrowth in bacterial translocation in cirrhotic rats.Methods: Thirty-five male Sprague-Dawley rats with carbon tetrachloride-induced cirrhosis and ascites and 10 normal rats were included in this study. Cirrhotic rats were sacrificed when ill and samples of ascitic fluid, mesenteric lymph nodes and cecal stool were taken for detecting quantitatively aerobic bacteria.Results: Total intestinal aerobic bacterial count in cecal stool at the time of sacrifice was significantly increased in cirrhotic rats with bacterial translocation with or without spontaneous bacterial peritonitis compared to cirrhotic rats without bacterial translocation (p<0.001 and p<0.001, respectively) and to normal rats (p<0.001 and p<0.001, respectively). Of the 42 species of bacteria translocating to the mesenteric lymph nodes, 41 (97.6%) were found in supranormal numbers in the stool at the time of sacrifice.Conclusions: Carbon tetrachloride-induced cirrhotic rats with bacterial translocation have increased total intestinal aerobic bacteria count, and intestinal bacterial overgrowth appears to play an important role in bacterial translocation in this experimental model of cirrhosis in rats.     

肠黏膜通透性改变对肝硬化自发性细菌性腹膜炎的影响

目的探讨肠黏膜通透性改变对肝硬化自发性细菌性腹膜炎（SBP）的影响。方法 采用高压液相色谱-示差法，检测45例住院肝硬化腹水患者（34例白发性腹膜炎和11例肝硬化无菌性腹水）治疗前后口服糖分子探针乳果糖、甘露醇后尿液排泄率比值（LAC／MAN）情况，评估病人肠黏膜通透性水平；采用鲎试剂三肽显色基质偶氮法检测病人治疗前后血浆内毒素（LPS）水平，另11例健康志愿者作为对照组结果治疗前肝硬化SBP尿LAC／MAN、血浆内毒素水平均显著高于无菌性腹水（SA）组和健康对照组（P均〈0．001）Pearson相关性分析：肝硬化腹水患者尿LAC／MAN改变与血浆LPS水平呈正相关（r=0．187，P〈0．001）治疗1周后肝硬化SBP患者尿LAC／MAN及血浆LPS水平平行下降。结论肝硬化SBP患者存在肠黏膜通透性异常，且肠黏膜通透性改变与内毒素血症有关．     

肝硬化并发自发性细菌性腹膜炎的临床特征及病原菌耐药分析

目的探讨肝硬化合并自发性细菌性腹膜炎(SBP)的临床特征及病原菌耐药情况。方法分析135例肝硬化合并SBP患者在抗感染治疗前后体温、腹部症状和体征、血常规、腹水白细胞及多核细胞数变化、腹水培养及药物敏感试验。结果 82.2%患者有发热,90.4%有腹部症状,88.9%有中等以上腹水7,0.4%有顽固性腹水;21.5%外周血白细胞数≥10.0×109/L,63.7%中性粒细胞0.7;45.2%腹水白细胞数0.5×109/L,57.8%多核细胞0.5;25.4%(30/118)细菌培养阳性,其中革兰氏阴性菌25例(83.3%),革兰氏阳性菌5例(16.7%),检测出的革兰氏阴性菌对大部分常用的抗菌药物耐药;治愈40例(29.63%),好转48例(35.56%),无效、恶化或自动出院47例(34.81%),其中死亡15例。结论肝硬化合并SBP的临床症状不典型,腹水培养阳性率低,以革兰阴性菌为主。除应尽早行腹水培养外,需根据临床症状、体征、血常规、腹水常规检查等综合分析,及时应用有效抗生素治疗,以提高患者的生存率。     

腹腔穿刺放液灌洗及注射抗生素对肝硬化自发性细菌性腹膜炎的治疗价值

为探讨腹腔穿刺放液,灌主注射生素对肝硬化合并自发性细菌性腹膜炎（ＳＢＰ）的治疗价值。对单纯静滴抗生素（１组）与静滴抗生素并用排放腹水、腹腔灌洗和注射抗生素（Ⅱ组）治疗ＳＢＰ的效果进行比较研究。结果显示,Ⅱ组患者的治愈好转率明显高于Ⅰ组。说明腹腔穿刺放液、灌洗及注射抗生素是 治疗肝硬化     

肝硬化细菌移位及其后果

随着人们对细菌移位（bacterial translocation，BT）后果研究的不断深入，BT的概念已从传统的有活性的肠道菌群通过肠道屏障到达肠系膜淋巴结和肠腔外其他器官或部位，延伸到细菌释放产物（如内毒素和细菌DNA）的移位。现就细菌移位过程中的多种机制，特别是肠内菌群和黏膜屏障功能的改变及免疫防御机制综述如下。     

肝硬化合并自发性细菌性腹膜炎患者腹水细菌移位及预后影响因素的初步研究

目的探讨应用PCR技术检测肝硬化患者腹水细菌移位（BT）的可行性,并通过为期半年的随访了解影响自发性细菌性腹膜炎（SBP）患者预后的主要因素。方法在细菌16S核糖体RNA（16SrRNA）基因保守区设计1对细菌通用引物,分别对14株标准细菌菌株、白色念珠菌DNA、人基因组DNA、HBVDNA、21例肝硬化合并SBP患者的腹水和血清进行PCR扩增,对腹水和血清细菌DNA阳性者进一步通过核苷酸序列测定鉴别细菌的种属。半年后对入组患者进行随访,了解临床转归,对患者的临床和实验室资料进行分析,了解影响SBP患者预后的主要因素。结果所有14株标准细菌菌株均可见预期370bp左右长度的细菌通用引物DNA条带,而白色念珠菌DNA、人基因组DNA及HBVDNA未见该条带。21例SBP患者腹水细菌DNA阳性19例（90．48％）,血清细菌DNA阳性14例（66．67％）。经基因序列鉴定,腹水和血清中的细菌均以大肠埃希氏菌为主,同一患者腹水和血清中的细菌鉴定结果均为同一菌种且序列同源性达99％以上。与SBP患者预后相关的独立预测指标为肝功能Child—Pugh评分。结论应用PCR技术检测细菌DNA具有较高的特异性和敏感性,可用于BT的临床研究。肝硬化患者腹水和血清中移位的细菌来源于肠道,单个细菌克隆参与BT和全身循环过程,且极有可能细菌从肠道直接经肠壁进入腹腔。SBP患者的预后主要取决于基础肝病的严重程度。     

Multiresistant bacterial infections in liver cirrhosis: Clinical impact and new empirical antibiotic treatment policies

Recently, important changes have been reported regarding the epidemiology of bacterial infections in liver cirrhosis. There is an emergence of multiresistant bacteria in many European countries and also worldwide, including the United States and South Korea. The classic empirical antibiotic treatment(third-generation cephalosporins, e.g., ceftriaxone, cefotaxime or amoxicillin-clavulanic acid) is still effective in infections acquired in the community, but its failure rate in hospital acquired infections and in some health-care associated infections is high enough to ban its use in these settings. The current editorial focuses on the different epidemiology of bacterial infections in cirrhosis across countries and on its therapeutic implications.     

血清及腹水脂多糖结合蛋白检测在肝硬化自发性细菌性腹膜炎诊断中的意义

目的 检测肝硬化患者血清及腹水中脂多糖结合蛋白(LBP)的水平,探讨血清及腹水LBP检测对自发性细菌性腹膜炎(SBP)的诊断价值. 方法 将肝硬化患者分为肝硬化SBP组、腹水非SBP组、肝硬化无腹水组3组,同时将腹水非SBP组分别以有无腹痛、血白细胞计数(WBC)增高、腹痛+血WBC升高为标准分为2组,探讨LBP对临床疑诊SBP的意义.并加设阳性和阴性对照组(腹腔脓液组、健康对照组).以酶联免疫吸附法测定各组血清及腹水LBP水平;肝硬化腹水患者同时完成腹水常规、腹水培养、腹水白蛋白等检查.组间数据比较采用t检验或独立样本的非参数检验,曲线下面积(AUC)比较采用Z检验. 结果 腹腔脓液组血清及脓液LBP水平较肝硬化腹水组血清及腹水LBP水平明显增高,对比组之间的差异具有统计学意义(P＜0.01).肝硬化SBP组血清LBP水平较,腹水非SBP组及无腹水组血清LBP水平明显增高,对比组之间的差异具有统计学意义(P＜0.01);肝硬化SBP组腹水LBP水平较腹水非SBP组腹水LBP水平差异无统计学意义(P＞0.05).临床疑诊的肝硬化SBP组血清及腹水LBP水平较肝硬化腹水非SBP组血清及腹水LBP水平明显增高,对比组之间的差异具有统计学意义(中位数分别为228.00μg/ml对比80.95 μg/ml及22.50 μg/ml对比11.45 μg/ml,P＜0.05).血清LBP测定较腹水LBP测定及腹水WBC具有更高的敏感性.结论 腹腔内革兰阴性菌感染可使患者血清及体液LBP水平明显升高.肝硬化SBP患者血清LBP水平明显增高.临床疑诊SBP的肝硬化患者血清及腹水LBP明显升高,血清LBP结合腹水LBP检测能提示腹腔内感染存在,对SBP有一定的诊断价值.     

肝硬化并发自发性细菌性腹膜炎临床研究进展*

目的 自发性细菌性腹膜炎(SBP)为目前肝硬化患者最常见的并发症之一,具有发病率高,疾病发展快,病死率高等特征。该病临床表现常不典型,腹腔感染的诊断主要基于腹腔积液白细胞计数。治疗则以经验性抗生素使用为主,联合调节肠道菌群、补充白蛋白等。有条件者可考虑肝移植。早期发现并积极实施干预对改善本病预后、降低病死率都有着重要的意义,但在有关SBP诊断、治疗和预防方面,仍面临巨大的挑战,需要深入研究进一步解决相关问题的策略,从而更好地指导临床实践,改善患者预后。     

肝炎肝硬化并发自发性细菌性腹膜炎治疗探讨

目的探讨肝炎肝硬化并发自发性细菌性腹膜炎的治疗。方法147例肝炎肝硬化并发自发性细菌性腹膜炎患者行综合治疗:1积极支持治疗;2舒普深抗感染,每日4克,共3周;3每次放腹水后使用罗氏芬1克,腹腔注射。同期另118例肝炎肝硬化并发自发性细菌性腹膜炎患者,接受积极支持治疗和舒普深抗感染,每日4克,共2周。结果与对照组比,抗感染3周疗程加放腹水组患者腹水消退快,总胆红素下降明显,腹腔感染控制较彻底,一年后自发性细菌性腹膜炎复发率显著降低(P<0.05)。结论肝炎肝硬化并发自发性细菌性腹膜炎的抗感染治疗疗程要长,适时放腹水可提高疗效。     

Evaluation of prophylactic antibiotic regimens on recurrence and mortality in spontaneous bacterial peritonitis

Introduction and objectivesLimited data describe current SBP epidemiology and specific secondary SBP prophylactic regimens, leading to variable prescribing practices. This work aims to compare 90-day and one-year SBP recurrence and mortality based on secondary SBP antibiotic prophylaxis regimens.Materials and methodsWe performed a retrospective cohort of patients >18 years with an SBP diagnosis from 2010 to 2015 at two academic institutions. Eligible patients had ascitic PMN counts ≥250 cells/mm³ or a positive ascitic culture. Patients were compared based on secondary SBP prophylaxis regimens (i.e., daily, intermittent, or no prophylaxis).ResultsOf 791 patients with ascitic fluid samples, 86 patients were included. Antibiotic prophylaxis included daily (n = 34), intermittent (n = 36), or no prophylaxis (n = 16). Nearly half of SBP episodes had a positive ascitic fluid culture; 50% were gram-negative pathogens, and 50% were gram-positive pathogens. Daily and intermittent regimens had similar rates of recurrence at 90-days (19.4% vs. 14.7%, p = 0.60) and one-year (33.3% vs. 26.5%, p = 0.53). Similarly, mortality did not differ among daily and intermittent regimens at 90-days (32.4% vs. 30.6%, p = 0.87) or one-year (67.6% vs. 63.9%, p = 0.74). When comparing any prophylaxis vs. no prophylaxis, there were no differences in 90-day or one-year recurrence or mortality.ConclusionsIn patients with a history of SBP, our data indicate similar outcomes with daily, intermittent, or no secondary antibiotic prophylaxis. With available data, including ours, demonstrating a changing epidemiology for SBP pathogens, further data is required to determine if traditional approaches to secondary SBP prophylaxis remain appropriate.     

Toll-like receptor 4 polymorphisms and bacterial infections in patients with cirrhosis and ascites

AIM To assess the relationship between the presence of toll-like receptor 4(TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites. METHODS We prospectively included consecutive patients with cirrhosis and ascites hospitalized during a 6-year period. Patients with human immunodeficiency virus(HIV) infection or any other immunodeficiency, patients with advanced hepatocellular carcinoma(beyond Milan's criteria) or any other condition determining poor short-term prognosis, and patients with a permanent urinary catheter were excluded. The presence of D299 G and/or T399 I TLR4 polymorphisms was determined by sequencing and related to the incidence and probability of bacterial infections, other complications of cirrhosis, hepatocellular carcinoma, and mortality during follow-up. A multivariate analysis to identify predictive variables of mortality in the whole series was performed. RESULTS We included 258 patients: 28(10.8%) were carriers of D299G and/or T399I TLR4 polymorphisms(polymorphism group) and 230 patients were not(wildtype group). The probability of developing any bacterial infection at one-year follow-up was 78% in the polymorphism group and 69% in the wild-type group(P = 0.54). The one-year probability of presenting infections caused by gram-negative bacilli(51% vs 44%, P = 0.68), infections caused by gram-positive cocci(49% vs 40%, P = 0.53), and spontaneous bacterial peritonitis(29% vs 34%, respectively, P = 0.99) did not differ between the two groups. The oneyear probability of transplant-free survival was 55% in the polymorphism group and 66% in the wild-type group(P = 0.15). Multivariate analysis confirmed that age, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy, hepatocellular carcinoma and serum creatinine were associated with a higher risk of death during follow-up. CONCLUSION Genetic polymorphisms D299 G and/or T399 I of TLR4 do not seem to play a relevant role in the predisposition of cirrhotic patients with ascites to bacterial infections.     

选择性肠道清洁预防肝硬化自发性细菌性腹膜炎的疗效

目的观察采用选择性肠道清洁（SID）对肝硬化腹水有自发性细菌性腹膜炎（SBP）易患因素的病人预防SBP发生的疗效。方法①短期SID：肝硬化腹水有易患SBP因素住院病人60例分为预防组30例（除常规治疗外，给予口服诺氟沙星400mg，2次／d，共7d）和对照组30例（仅给予常规治疗）两组；②长期SID：肝硬化腹水无SBP的易患SBP病人50例，分为预防组25例（除常规治疗外加用口服诺氟沙星400mg，2次／d，3d／周，共半年）和对照组25例（仅给予常规治疗）两组。结果①短期SID中，预防组SBP发生率（6.67％）明显低干对照组（16.67％）（P〈0.05）；②长期SID中，预防组发生SBP（8％）明显低干对照组（32％）（P〈0.05），预防组腹水总蛋白和补体C3较治疗前显著增加（P〈0.05），而对照组治疗前后无明显变化（P〉0.05）。两方案中，预防组死亡例数少于对照组，未见明显副反应发生。结论短期或长期SID对存在SBP易患因素肝硬化腹水病人SBP的发生具有良好的预防作用。     

Challenges and recommendations when selecting empirical antibiotics in patients with cirrhosis

There is abundant evidence that bacterial infections are severe complications in patients with cirrhosis,being the most frequent trigger of acute-on-chronic liver failure and causing death in one of every four patients during hospitalization.For these reasons,early diagnosis and effective treatment of infections are mandatory to improve patient outcomes.However,treating physicians are challenged in daily practice since diagnosing bacterial infections is not always straightforward.This situation ...