Bacterial infections other than spontaneous bacterial peritonitis in cirrhosis

Cirrhotic patients are immunocompromised with a high risk of infection.Proinflammatory cytokines and hemodynamic circulation derangement further facilitate the development of serious consequences of infections.Other than spontaneous bacterial peritonitis,bacteremia and bacterial infections of other organ systems are frequently observed.Gram-negative enteric bacteria are the most common causative organism.Other bacterial infections,such as enterococci,Vibrio spp.,Aeromonas spp.,Clostridium spp.,Listeria monocytogenes,Plesiomonas shigelloides and Mycobacterium tuberculosis are more prevalent and more virulent.Generally,intravenous third generation cephalosporins are recommended as empirical antibiotic therapy.Increased incidences of gram-positive and drug-resistant organisms have been reported,particularly in hospitalacquired infections and in patients receiving quinolones prophylaxis.This review focuses upon epidemiology,microbiology,clinical features and treatment of infections in cirrhosis other than spontaneous bacterial peritonitis,including pathogen-specific and liver diseasespecific issues.     

Unresolved issues in the prophylaxis of bacterial infections in patients with cirrhosis

Bacterial infections are highly prevalent and a frequent cause of hospitalization and short-term mortality in patients with cirrhosis. Due to their negative impact on survival, antibiotic prophylaxis for bacterial infections in high-risk subgroups of patients with cirrhosis has been the standard of care for decades. Patients with prophylaxis indications include those at risk for a first episode of spontaneous bacterial peritonitis(SBP) due to a low ascitic fluid protein count and impaired liver and kidney function, patients with a prior episode of SBP and those with an episode of gastrointestinal bleeding. Only prophylaxis due to gastrointestinal bleeding has a known and short-time duration. All other indications imply longlasting exposure to antibiotics-once the threshold requirement for initiating prophylaxis is met-without standardized criteria for re-assessing antibiotic interruption. Despite the fact that the benefit of antibiotic prophylaxis in reducing bacterial infections episodes and mortality has been thoroughly reported, the extended use of antibiotics in patients with cirrhosis has also had negative consequences, including the emergence of multi-drug resistant bacteria.Currently, it is not clear whether restricting the use of broad and fixed antibiotic regimens, tailoring the choice of antibiotics to local bacterial epidemiology or selecting non-antibiotic strategies will be the preferred antibiotic prophylaxis strategy for patients with cirrhosis in the future.     

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.     

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.     

Adrenocortical dysfunction in liver disease: a systematic review

In patients with cirrhosis, adrenal insufficiency (AI) is reported during sepsis and septic shock and is associated with increased mortality. Consequently, the term "hepato-adrenal syndrome" was proposed. Some studies have shown that AI is frequent in stable cirrhosis as well as in cirrhosis associated with decompensation other than sepsis, such as bleeding and ascites. Moreover, other studies showed a high prevalence in liver transplant recipients immediately after, or some time after, liver transplantation. The effect of corticosteroid therapy in critically ill patients with liver disease has been evaluated in some studies, but the results remain controversial. The 250-μg adreno-cortico-tropic-hormone stimulation test to diagnose AI in critically ill adult patients is recommended by an international task force. However, in liver disease, there is no consensus on the appropriate tests and normal values to assess adrenal function; thus, standardization of normal ranges and methodology is needed. Serum total cortisol assays overestimate AI in patients with cirrhosis, so that direct free cortisol measurement or its surrogates may be useful measurements to define AI, but further studies are needed to clarify this. In addition, the mechanisms by which liver disease leads to adrenal dysfunction are not sufficiently documented. This review evaluates published data regarding adrenal function in patients with liver disease, with a particular focus on the potential limitations of these studies as well as suggestions for future studies.     

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.     

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.     

Bacterial infections in cirrhosis.

Hospitalized patients with cirrhosis are at increased risk of developing bacterial infections, the most common being spontaneous bacterial peritonitis (SBP) and urinary tract infections. Independent predictors of the development of bacterial infections in hospitalized cirrhotic patients are poor liver synthetic function and admission for gastrointestinal hemorrhage. Short term (seven-day) prophylaxis with norfloxacin reduces the rate of infections and improves survival and should therefore be administered to all patients with cirrhosis and variceal hemorrhage. Cirrhotic patients who develop abdominal pain, tenderness, fever, renal failure or hepatic encephalopathy should undergo diagnostic paracentesis, and those who meet the criterion for SBP (eg, an ascites neutrophil count greater than 250/mm3) should receive antibiotics, preferably a third-generation cephalosporin. In addition to antibiotic therapy, albumin infusions have been shown to reduce the risk of renal failure and mortality in patients with SBP, particularly in those with renal dysfunction and hyperbilirubinemia at the time of diagnosis. Patients who recover from an episode of SBP should be given long term prophylaxis with norfloxacin and should be assessed for liver transplantation.     

Editorial: Treatment of patients with HCV-related cirrhosis with peginterferon and ribavirin: Swinging the pendulum toward treatment

Patients with hepatitis C virus-related cirrhosis are at increased risk for hepatic decompensation and hepatocellular carcinoma (HCC). They also responded less well to standard therapy compared with those without cirrhosis. Several recent studies have demonstrated that patients with cirrhosis can be safely treated and those who achieve a sustained virological response have better clinical outcomes compared with nonresponders. These results support treatment for patients with compensated cirrhosis. In addition, cirrhotic patients should be monitored after a sustained virological response is obtained, because some patients remain at risk for complications of liver disease, particularly HCC. Newer, more effective therapy is needed for patients with cirrhosis.     

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 ...     

Multi-resistant bacteria in spontaneous bacterial peritonitis: A new step in management?

Spontaneous bacterial peritonitis(SBP) is the most typical infection observed in cirrhosis patients. SBP is responsible for an in-hospital mortality rate of approximately 32%. Recently, pattern changes in the bacterial flora of cirrhosis patients have been observed, and an increase in the prevalence of infections caused by multi-resistant bacteria has been noted. The wide-scale use of quinolones in the prophylaxis of SBP has promoted flora modifications and resulted in the development of bacterial resistance. The efficacy of traditionally recommended therapy has been low in nosocomial infections(up to 40%), and multi-resistance has been observed in up to 22% of isolated germs in nosocomial SBP. For this reason, the use of a broad empirical spectrum antibiotic has been suggested in these situations. The distinction between community-acquired infectious episodes, healthcare-associated infections, or nosocomial infections, and the identification of risk factors for multi-resistant germs can aid in the decision-making process regarding the empirical choice of antibiotic therapy. Broad-spectrum antimicrobial agents, such as carbapenems with or without glycopeptides or piperacillin-tazobactam, should be considered for the initial treatment not only of nosocomial infections but also of healthcare-associated infections when the risk factors or severity signs for multi-resistant bacteria are apparent. The use of cephalosporins should be restricted to community-acquired infections.     

Approach to the patient with chronic hepatitis B and decompensated cirrhosis

Patients with chronic hepatitis B virus (HBV) can develop progressive fibrosis, cirrhosis and hepatocellular carcinoma. Patients with chronic HBV and cirrhosis are at risk of developing hepatic decompensation and have high mortality without antiviral therapy and/or liver transplantation. Treatment of chronic HBV with antiviral therapy is indicated in all patients with cirrhosis whatever the HBe‐antigen status and serum alanine aminotransferase (ALT), so that hepatic decompensation can be prevented. Initiating antiviral therapy in patients with decompensated cirrhosis can improve liver function, Child‐Turcotte‐Pugh (CTP) and model for end‐stage liver disease (MELD) scores, as well as the need for liver transplantation and mortality. Patients with chronic HBV and cirrhosis who do not respond to antiviral therapy with normalization of ALT may have a co‐existent liver disorder. One of the most common co‐existent liver disorders present in patients with chronic HBV is non‐alcoholic fatty liver disease (NAFLD). Patients with chronic HBV, NAFLD and cirrhosis may be at risk of developing decompensated cirrhosis and require a liver transplant. If patients with chronic HBV require liver transplantation, infection of the liver graft with HBV can be prevented with antiviral therapy.     

Prevention of infectious complications after transjugular intrahepatic portosystemic shunt in cirrhotic patients with a single dose of ceftriaxone.

BACKGROUND/AIMS: Patients with cirrhosis of the liver are prone to bacterial infections. Therapeutic interventions such as endoscopic sclerotherapy increase the risk of bacterial infections in these patients. Following insertion of a transjugular intrahepatic portosystemic shunt (TIPS), the incidence of severe bacterial infections was recently shown to be 20% after elective procedures. This finding suggests antibiotic prophylaxis with the TIPS procedure. Antibiotic prophylaxis using cefotiam or cefotaxime/ampicillin did not significantly reduce infectious complications. The aim of the present study was therefore to investigate the efficacy of two different doses of a long-acting cephalosporin in prevention of bacterial infection after TIPS. METHODOLOGY: Eighty-two patients with cirrhosis (age: 52 +/- 2 years) who underwent elective TIPS were randomized to receive a single i.v. dose of either 1 g or 2 g Ceftriaxone 1 hour before the intervention. Patients with evidence of or suspected infections and patients on antibiotic therapy within 7 days prior to TIPS were excluded. Body temperature was monitored t.i.d. for 1 week and white blood count (WBC) and C-reactive protein (CRP) were determined before TIPS and 1 day and 1 week after TIPS. RESULTS: Only 2 of 82 patients (2.6%) showed signs of infection following TIPS insertion: One of 40 patients receiving 1 g Ceftriaxone and 1 of 42 patients receiving 2 g Ceftriaxone prior to TIPS developed temperature > 38.5 degrees C. In the latter patient this was due to pneumonia. This patient received antibiotic treatment with imipenem for 10 days. Temperature in the other patient normalized within 12 hours and he did not require antibiotic treatment. No significant differences in temperature, WBC and CRP between the different doses of Ceftriaxone were observed. CONCLUSIONS: Prophylactic treatment with Ceftriaxone reduces the reported incidence of bacterial infections after TIPS in patients with cirrhosis of the liver. Prophylaxis with 1 g Ceftriaxone seems as efficacious as 2 g.     

Current and future pharmacological therapies for managing cirrhosis and its complications

Due to the restrictions of liver transplantation,complication-guided pharmacological therapy has become the mainstay of long-term management of cirrhosis.This article aims to provide a complete overview of pharmacotherapy options that may be commenced in the outpatient setting which are available for managing cirrhosis and its complications,together with discussion of current controversies and potential future directions.PubMed/Medline/Cochrane Library were electronically searched up to December 2018 to identify studies evaluating safety,efficacy and therapeutic mechanisms of pharmacological agents in cirrhotic adults and animal models of cirrhosis.Non-selective betablockers effectively reduce variceal re-bleeding risk in cirrhotic patients with moderate/large varices,but appear ineffective for primary prevention of variceal development and may compromise renal function and haemodynamic stability in advanced decompensation.Recent observational studies suggest protective,haemodynamically-independent effects of beta-blockers relating to reduced bacterial translocation.The gut-selective antibiotic rifaximin is effective for secondary prophylaxis of hepatic encephalopathy;recent small trials also indicate its potential superiority to norfloxacin for secondary prevention of spontaneous bacterial peritonitis.Diuretics remain the mainstay of uncomplicated ascites treatment,and early trials suggest alpha-adrenergic receptor agonists may improve diuretic response in refractory ascites.Vaptans have not demonstrated clinical effectiveness in treating refractory ascites and may cause detrimental complications.Despite initial hepatotoxicity concerns,safety of statin administration has been demonstrated in compensated cirrhosis.Furthermore,statins are suggested to have protective effects upon fibrosis progression,decompensation and mortality.Evidence as to whether proton pump inhibitors cause gut-liver-brain axis dysfunction is conflicting.Emerging evidence indicates that anticoagulation therapy reduces incidence and increases recanalisation rates of non-malignant portal vein thrombosis,and may impede hepatic fibrogenesis and decompensation.Pharmacotherapy for cirrhosis should be implemented in accordance with up-to-date guidelines and in conjunction with aetiology management,nutritional optimisation and patient education.     

New antibiotic strategies in patients with cirrhosis and bacterial infection

Early diagnosis and adequate empirical antibiotic treatment of bacterial infections in advanced cirrhosis is essential to improve outcomes given the high risk of developing severe sepsis, multiple organ failure and death. β-lactams and quinolones are nowadays frequently ineffective in nosocomial and healthcare associated infections, due to the increasing prevalence of multidrug resistant (MDR) bacteria reported across different geographical areas. Recent antibiotic exposure also increases the risk of developing MDR bacterial infections. Initial antibiotic strategies should therefore be tailored according to the presence or absence of risk factors of MDR bacteria and to the severity of infection and should consider the local epidemiology. Empirical treatment in the population at high risk of MDR bacterial infections requires the use of broad-spectrum antibiotics (carbapenems or tigecycline) and of drugs active against specific resistant bacteria (glycopeptides, linezolid, daptomycin, amikacin, colistin). Early de-escalation policies are recommended to prevent the spread of MDR bacteria in cirrhosis.     

Risk factors and outcome of bacterial infections in cirrhosis

Viable and non-viable pathological bacterial translocation promote a self-perpetuating circle of dysfunctional immune activation and systemic inflammation facilitating infections and organ failure in advanced cirrhosis.Bacterial infections and sepsis are now recognized as a distinct stage in the natural progression of chronic liver disease as they accelerate organ failure and contribute to the high mortality observed in decompensated cirrhosis.The increasing knowledge of structural,immunological and hemodynamic pathophysiology in advanced cirrhosis has not yet translated into significantly improved outcomes of bacterial infections over the last decades.Therefore,early identification of patients at the highest risk for developing infections and infectionrelated complications is required to tailor the currently available measures of surveillance,prophylaxis and therapy to the patients in need in order to improve the detrimental outcome of bacterial infections in cirrhosis.     

Impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes of liver disease

Chronic infections with the hepatitis B and C viruses have significant worldwide health and economic impacts. Previous treatments for hepatitis C such as interferon and ribavirin therapy were ineffective and poorly tolerated by patients. The introduction of directly acting curative antiviral therapy for hepatitis C and the wider use of nucleos(t)ide analogues for suppression of chronic Hepatitis B infection have resulted in many positive developments. Decreasing the prevalence of hepatitis B and C have concurrently reduced transmission rates and hence, the number of new infections. Antiviral treatments have decreased the rates of liver decompensation and as a result, lowered hospitalisation and mortality rates for both chronic hepatitis B and C infection. The quality of life of chronically infected patients has also been improved significantly by modern treatment. Antiviral therapy has stopped the progression of liver disease to cirrhosis in certain patient cohorts and prevented ongoing hepatocellular damage in patients with existing cirrhosis. Longer term benefits of antiviral therapy include a reduced risk of developing hepatocellular carcinoma and decreased number of patients requiring liver transplantation. This review article assesses the literature and summarises the impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes from liver disease.     

Is vaccination against hepatitis A virus required in patients with cirrhosis of the liver?

Hepatitis A virus (HAV) superinfection can cause decompensation in patients with chronic liver disease. The risk of HAV superinfection depends on the endemicity of HAV in that particular population. Recommendations of vaccination against HAV in patients with cirrhosis of the liver in India are lacking. Our aim was to assess the seroprevalence of anti-HAV antibodies in our population of patients with cirrhosis of the liver. In a retrospective analysis, the serum of 55 patients with cirrhosis of the liver was tested for total anti-HAV antibodies by ELISA. In the 35 patients who presented with acute decompensation, the serum was also analysed for IgM anti-HAV antibodies. Fifty-four of the 55 cirrhotics (99%) were positive for total anti-HAV antibodies. All 35 patients with decompensated liver disease were also positive for total anti-HAV antibodies, and none of them tested positive for IgM anti-HAV antibodies. Most of the patients with cirrhosis of the liver in the population studied were already exposed to HAV. Routine vaccination against HAV cannot be recommended in these patients.     

Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office

Chronic hepatitis C virus (HCV) infection affects approximately 1.3 % of the United States population and 4 % of veterans who use Department of Veterans Affairs medical services. Chronic HCV is the primary cause of cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease requiring liver transplantation in the United States. Management of chronic HCV is aimed at halting disease progression, preventing cirrhosis decompensation, reducing the risk of HCC, and treating extrahepatic complications of the infection. As part of a comprehensive HCV management strategy, peginterferon alfa and ribavirin, along with the addition of a hepatitis C protease inhibitor therapy for many genotype 1-infected patients, are the current standard of care. Antiviral therapy should be provided to those individuals who are clinically stable, have moderate liver disease or compensated cirrhosis, and are motivated to pursue therapy. Many patients have comorbid medical and psychiatric conditions, which may affect their adherence to antiviral therapy or worsen while on antiviral therapy. To optimally manage hepatitis C and associated comorbidities, patients benefit from multidisciplinary teams that can provide HCV-specific care and treatment. Sustained virologic response is associated with "cure" of chronic HCV, and results in improved liver disease outcomes and prolonged survival.     

Immune dysfunction in cirrhosis

Innate and adaptive immune dysfunction,also referred to as cirrhosis-associated immune dysfunction syndrome,is a major component of cirrhosis,and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function.During the evolution of the disease,acute decompensation events associated with organ failure(s),so-called acute-on chronic liver failure,and chronic decompensation with progression of liver fibrosis and also development of disease specific complications,comprise distinct clinical entities with different immunopathology mechanisms.Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations.Acute and chronic exposure to bacteria and/or their products,however,can result in variable clinical consequences.The immune status of patients is not constant during the illness;consequently,alterations of the balance between pro-and anti-in-flammatory processes result in very different dynamic courses.In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis.We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms.Moreover,we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease.Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications,delaying progression and reducing mortality.