Infections In Cirrhosis Research Articles

Impact of rifaximin in the prevention of bacterial infections in cirrhosis

Impact of rifaximin in the prevention of bacterial infections in 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 pro-inflammatory 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.

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.

Use of proton pump inhibitors decrease cellular oxidative burst in patients with decompensated cirrhosis.

Proton pump inhibitors (PPIs) are commonly used antisecretory drugs and have been linked to an increased risk of bacterial infections in cirrhosis. We investigated whether the treatment with PPIs in cirrhosis affects the oxidative burst activity of granulocytes and monocytes and its possible interference with serum norfloxacin (Nflx) levels in these patients. 70 patients with cirrhosis and ascitic fluid and 24 healthy controls were included in the study and distributed into groups according to the regular use of PPIs and/or norfloxacin. The blood granulocyte and monocyte's phagocytic activity and oxidative burst were evaluated by flow cytometry. Blood levels of norfloxacin were measured by HPLC and bacterial translocation was evaluated by detection of bacterial DNA in blood. Use of PPIs was associated with a decreased granulocyte and monocyte oxidative burst, but not of phagocytic activity, as compared with patients not receiving PPIs. PPIs use did not affect serum norfloxacin levels in patients. A not significant trend to an increased bacterial DNA translocation was observed in patients receiving PPIs, including patients simultaneously receiving norfloxacin. PPIs significantly decrease cellular oxidative burst in cirrhosis. This fact may provide a pathogenic explanation to the reported high rates of bacterial infections in this setting, and strongly suggests that PPIs should only be used in patients with cirrhosis when clinically indicated.

Risks and Benefits of Large Volume Paracentesis in Spontaneous Bacterial Peritonitis With Tense Ascites: Where is the Clinical Evidence?

Introduction: Spontaneous bacterial peritonitis (SBP) is the most common bacterial infection in cirrhosis with high mortality. Antibiotics are the mainstay of treatment. Moreover, albumin infusion in SBP improves survival by 60% and decreases the risk of acute renal impairment. Large volume paracentesis (LVP) is the standard treatment for tense ascites. LVP is historically avoided in patients with SBP due to the potential risk of circulatory dysfunction. These are based on presumed physiologic mechanisms and have not been adequately studied with robust clinical outcomes. We decided to determine whether or not LVP can be safely used in SBP patients, especially in the era where albumin infusion, regardless of performing LVP or not, is part of SBP management. Potential benefits of LVP in SBP include: improved patients’ abdominal discomfort, decreased ascites microbial load, decreased intra-abdominal pro-inflammatory cytokines, and bacterial vasoactive peptides. Methods: We conducted a systematic review of randomized controlled clinical trials (RCTs). We searched Medline, EMBASE, Cochrane CENTRAL, and Clinicaltrials.gov databases using controlled vocabularies (MeSH, EMTREE), and key word searching for large volume/therapeutic paracentesis, spontaneous bacterial peritonitis, and refractory/tense ascites. We also screened all SBP trials as well as all LVP trials. We also performed hand searching and cross referencing of clinical guidelines and major reviews. Results: Our comprehensive search retrieved 189 trials in Medline, 147 in Cochrane CENTRAL, 91 in EMBASE, and 28 in Clinicaltrials.gov in English. After removing the duplicates there was only randomized controlled clinical trial that studied LVP in SBP patients. All other LVP trials had excluded SBP patients from their studies. Similarly, all SBP trials did not include LVP in their management. The AASLD clinical guidelines did not provide recommendations regarding whether or not LVP can be considered in SBP. The only available RCT of LVP in SBP randomized 42 SBP patients to receive LVP (group 1) vs. no LVP (group 2). Twelve months survival was not statistically significantly different between 2 groups (11.1% vs. 14.3%; p>0.05), however symptoms resolved faster with LVP (p=NS) but with slightly higher rate of renal impairment (p=NS ). Conclusion: There is an extreme paucity of evidence with regard to role and safety of LVP in tense ascites in SBP. The current clinical guidelines do not provide recommendations on whether or not LVP can be considered in SBP. The only retrieved small RCT showed no worse outcomes with LVP, whereas LVP may cause faster symptom relief. Further investigations are warranted to delineate clinical risks and benefits of LVP in SBP.

Healthcare-associated and nosocomial bacterial infections in cirrhosis: predictors and impact on outcome.

Population-based data on the occurrence of healthcare-associated (HCA) and hospital-acquired (HA) bacterial infections in cirrhosis, their predictors, and their impact on outcome are limited. All patients with incident cirrhosis in 2001-2010 residing in an area of 600,000 inhabitants were retrospectively identified. All serious bacterial infections (resulting in or occurring during an inpatient hospital episode) during this period were registered. Acquisition type, site of infection, occurrence of infection-related acute-on-chronic liver failure (ACLF), acute kidney injury (AKI) and bacterial resistance were analysed. Patients were followed longitudinally until death, transplant or end of 2011. A total of 398 serious infections occurred in 241/633 (38%) patients. Forty-seven per cent were HCA and 21% HA. Proton pump inhibitor (PPI) use was more common in HA (80%) vs. HCA (64%) vs. community-acquired (44%) infections (P < 0.001). In regression analysis, decompensated status, use of antibiotics and PPIs at infection diagnosis were independent predictors of HCA/HA infections (P < 0.05). After adjustment for confounders, HCA/HA infections were significantly related to infection-related ACLF (P < 0.05), but not severe sepsis, AKI or infection-related mortality (P > 0.05). Antibiotic-resistant infections were more frequent among HA (17%) than HCA (6%) or community-acquired (8%) infections (P < 0.05). Antibiotic-resistant HCA/HA infections were independently related to severe sepsis (P < 0.05). In a population-based cirrhotic cohort, two-thirds of serious bacterial infections were HCA or HA. Decompensated liver disease, antibiotics and PPIs were predictors of serious HCA/HA infections, which were associated with the development of ACLF. Antibiotic resistance was frequent, especially in HA infections, and contributed to risk of severe sepsis.

The chronic use of beta-blockers and proton pump inhibitors may affect the rate of bacterial infections in cirrhosis.

Bacterial infections are among the most common and life-threatening complications in cirrhosis. Qualitative and quantitative modifications of the gut microbiota, dysfunction of the intestinal barrier and multiple immune defects are factors that contribute to a pathological 'bacterial translocation' (BT), leading to a higher susceptibility to infections in cirrhotic patients. Long-term therapies, commonly adopted in cirrhotic patients, may influence BT and modify the risk of infection in these patients. To investigate the influence of chronic therapies on the prevalence and microbiological characteristics of infections in cirrhosis. Consecutive cirrhotic patients hospitalised from 2008 to 2013 were enrolled. All previous treatments were carefully recorded. Infections were actively sought out, patients were actively monitored for infection, and possible risk factors were evaluated. Four hundred cirrhotic patients were included. The most frequent therapies were proton pump inhibitors (PPIs) (67%), non-absorbable-disaccharides (44%), beta-blockers (BBs) (39%) and non-absorbable-antibiotics (10%). Child-Pugh C (P<0.001; OR 5; 95%CI: 2.6-9.9) and PPI therapy (P=0.008; OR 2; 95% CI: 1.2-3.2) were found to be independent predictors of infection, and the use of BBs was a protective factor (P=0.001; OR 0.46; 95%CI: 0.3-0.7). Cirrhotic patients with bacterial infection showed lower morbidity and mortality when taking BBs. Proton pump inhibitors increase the risk of infection in cirrhosis and should not be prescribed in these patients without specific indications. In contrast, the use of BBs is associated with a lower rate of infection and attenuates the consequences of infections in cirrhotic patients.

Bacterial infections in cirrhosis.

Bacterial infections occur in 25-35% of cirrhotics admitted to hospital. Health-care associated and hospital acquired (nosocomial) infections are the most common epidemiology, with community acquired infections less common (15-30%). Spontaneous bacterial peritonitis and urinary infections are the most common sites, with spontaneous bacteremia, pneumonia, cellulitis and other sites being less common. The risk of infection is increased among subjects with more severe liver disease and an infection in the past 6months. Bacteria are isolated from approximately half of patients with a clinical diagnosis of infection. Gram-negative enterobacteriaceae are the most common organisms among community acquired infections; Gram-positive cocci are the most common organisms isolated among subjects with nosocomial infections. Up to 30% of hospital associated infections are with multidrug resistant bacteria. Consequently, empiric antibiotic therapy that is recommended for community acquired infections is often inadequate for nosocomial infections. Infections worsen liver function. In-hospital and 1-year mortality of cirrhotics with infections is significantly higher than among cirrhotics without infection. In-hospital complications of infections, such as severe sepsis and septic shock, and mortality, are increased among subjects with multidrug-resistant infections as compared with cirrhotics with susceptible bacteria. Short-term antibiotic prophylaxis of cirrhotics with upper gastrointestinal bleeding and long-term antibiotic prophylaxis of selected cirrhotics with spontaneous bacterial peritonitis reduces infections and improves survival. Albumin administration to cirrhotics with SBP and evidence of advanced liver disease improves survival. The benefit of albumin administration to cirrhotics with infections other than SBP is under investigation.

Changing Options for Prevention and Treatment of Infections in Cirrhosis

Bacterial infections are more frequent and severe in cirrhosis. Most prevalent infections are spontaneous bacterial peritonitis (SBP) and urinary infections followed by pneumonia, cellulitis and bacteremia. Cirrhosis increases the risk of sepsis, severe sepsis and death. Early diagnosis and adequate treatment of infections is essential in the management of cirrhotic patients. Recent data show that currently recommended empirical antibiotic therapy, mainly based on the use of β-lactams, is effective in community-acquired infections, but frequently fails in nosocomial and healthcare-associated infections. A marked increase in the prevalence of multidrug resistant (MDR) bacteria in the healthcare environment explains this finding. Patients developing nosocomial infections or with extended lengths of hospitalization are at higher risk for second infections that are associated with poor prognosis. Antibiotic strategies should therefore be selected according to the type, severity and site of acquisition of infection, and be adapted to the local epidemiological pattern of antibiotic resistance. Treatment of MDR bacteria requires the use of broader spectrum antibiotics (carbapenems) or those active against specific resistant bacteria (glycopeptides, linezolid, daptomycin, amikacin, colistin). Restriction of antibiotic prophylaxis to the high-risk populations, prevention of antibiotic overuse, and early de-escalation policies are also mandatory to prevent the spread of MDR bacteria in cirrhosis.

Urinary neutrophil gelatinase-associated lipocalin predicts kidney outcome and death in patients with cirrhosis and bacterial infections

Infections in cirrhosis are frequently complicated by kidney dysfunction that entails a poor prognosis. Urinary biomarkers may be of potential clinical usefulness in this setting. We aimed at assessing the value of urinary neutrophil gelatinase-associated lipocalin (uNGAL), a biomarker overexpressed in kidney tubules during kidney injury, in predicting clinical outcomes in cirrhosis with infections. One-hundred and thirty-two consecutive patients hospitalized with infections were evaluated prospectively. Acute kidney injury (AKI) was defined according to AKIN criteria. uNGAL was measured at infection diagnosis and at days 3 and 7 (ELISA, Bioporto, DK). Patients with AKI (n=65) had significantly higher levels of uNGAL compared to patients without AKI (203 ± 390 vs. 79 ± 126 μg/g creatinine, p<0.001). Moreover, uNGAL levels were significantly higher in patients who developed persistent AKI (n=40), compared to those with transient AKI (n=25) (281 ± 477 vs. 85 ± 79 μg/g creatinine, p<0.001). Among patients with persistent AKI, uNGAL was able to discriminate type-1 HRS from other causes of AKI (59 ± 46 vs. 429 ± 572 μg/g creatinine, respectively; p<0.001). Moreover, the time course of uNGAL was markedly different between the two groups. Interestingly, baseline uNGAL levels also predicted the development of a second infection during hospitalization. Overall, 3-month mortality was 34%. Independent predictive factors of 3-month mortality were MELD score, serum sodium, and uNGAL levels at diagnosis, but not presence or stage of AKI. In patients with cirrhosis and infections, measurement of urinary NGAL at infection diagnosis is useful in predicting important clinical outcomes, specifically persistency and type of AKI, development of a second infection, and 3-month mortality.

Type-1 hepatorenal syndrome associated with infections in cirrhosis: Natural history, outcome of kidney function, and survival

Type-1 hepatorenal syndrome (HRS) is a common complication of bacterial infections in cirrhosis, but its natural history remains undefined. To assess the outcome of kidney function and survival of patients with type-1 HRS associated with infections, 70 patients diagnosed during a 6-year period were evaluated prospectively. Main outcomes were no reversibility of type-1 HRS during treatment of the infection and 3-month survival. Forty-seven (67%) of the 70 patients had no reversibility of type-1 HRS during treatment of the infection. [Correction to previous sentence added March 10, 2014, after first online publication: "Twenty-three (33%)" was changed to "Forty-seven (67%)."] The main predictive factor of no reversibility of type-1 HRS was absence of infection resolution (no reversibility: 96% versus 48% in patients without and with resolution of the infection; P < 0.001). Independent predictive factors of no reversibility of type-1 HRS were age, high baseline serum bilirubin, nosocomial infection, and reduction in serum creatinine <0.3 mg/dL at day 3 of antibiotic treatment. No reversibility was also associated with severity of circulatory dysfunction, as indicated by more marked activity of the vasoconstrictor systems. In the whole series, 3-month probability of survival was only 21%. Factors associated with poor prognosis were baseline serum bilirubin, no reversibility of type-1 HRS, lack of resolution of the infection, and development of septic shock after diagnosis of type-1 HRS. Type-1 HRS associated with infections is not reversible in two-thirds of patients with treatment of infection only. No reversibility of type-1 HRS is associated with lack of resolution of the infection, age, high bilirubin, and no early improvement of kidney function and implies a poor prognosis. These results may help advance the management of patients with type-1 HRS associated with infections.

Bacterial infections in cirrhosis: A position statement based on the EASL Special Conference 2013

Bacterial infections are very common and represent one of the most important reasons of progression of liver failure, development of liver-related complications, and mortality in patients with cirrhosis. In fact, bacterial infections may be a triggering factor for the occurrence of gastrointestinal bleeding, hypervolemic hyponatremia, hepatic encephalopathy, kidney failure, and development of acute-on-chronic liver failure. Moreover, infections are a very common cause of repeated hospitalizations, impaired health-related quality of life, and increased healthcare costs in cirrhosis. Bacterial infections develop as a consequence of immune dysfunction that occurs progressively during the course of cirrhosis. In a significant proportion of patients, infections are caused by gram-negative bacteria from intestinal origin, yet gram-positive bacteria are a frequent cause of infection, particularly in hospitalized patients. In recent years, infections caused by multidrug-resistant bacteria are becoming an important clinical problem in many countries. The reduction of the negative clinical impact of infections in patients with cirrhosis may be achieved by a combination of prophylactic measures, such as administration of antibiotics, to reduce the occurrence of infections in high-risk groups together with early identification and management of infection once it has developed. Investigation on the mechanisms of altered gut microflora, translocation of bacteria, and immune dysfunction may help develop more effective and safe methods of prevention compared to those that are currently available. Moreover, research on biomarkers of early infection may be useful in early diagnosis and treatment of infections. The current manuscript reports an in-depth review and a position statement on bacterial infections in cirrhosis.

Bacterial Infections in Cirrhosis: Prevention and Treatment

Bacterial infection is a frequent complication in patients with advanced cirrhosis. Incidence ranges between 25 and 30 %. Most common infections are spontaneous bacterial peritonitis and urinary infections followed by pneumonia, skin/soft tissue infections and bacteremia. Cirrhosis increases the risk to develop sepsis, severe sepsis and death. Therefore, early diagnosis and adequate treatment of infection is essential in the management of these patients. Recent data show that currently recommended empirical antibiotic strategies (β-lactams) fail frequently in nosocomial and healthcare associated infections in cirrhosis, a feature that is related to the higher prevalence of multidrug resistant bacteria in infections acquired in the healthcare environment. Empirical antibiotic treatment should therefore be selected according not only to the type and severity of infection but also to the site of acquisition of infection. Antibiotic guidelines should be tailored according to the local epidemiological pattern of multiresistance.

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 infection-related 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.

Spontaneous Bacterial Infections in Cirrhosis- Peritonitis and Beyond

Spontaneous Bacterial Infections in Cirrhosis- Peritonitis and Beyond

Spontaneous Bacterial Infections in Cirrhosis- Peritonitis and Beyond

Spontaneous Bacterial Infections in Cirrhosis- Peritonitis and Beyond

Infections in Cirrhotics: Types, Microbiological Spectrum and Risk Factors—5-Year Cohort Study

Cirrhosis is an immunocompromised state that leads to various infections, with an estimated 30% mortality. Pakistan already has a high morbidity and mortality related to complications of cirrhosis. Where the data on infection among cirrhotics is scanty, this study aimed to determine the frequency, microbiological spectrum and various risk factors of infections in cirrhosis of liver. This is a prospective cohort study conducted at a tertiary care hospital. The microbiological spectrum and frequency of infections was determined in cirrhotics. Various risk factors for infection among cirrhotics were evaluated like upper gastrointestinal bleed, use of proton pump inhibitors, malnutrition and severity of cirrhosis. Out of eleven hundred and forty-one patients with cirrhosis of liver, four hundred and ninety (42.94%) patients had infections. All kinds of infections like peritoneal, respiratory, urinary tract and skin were present in cirrhosis of liver where ascitic fluid infections (AFI) were the commonest i.e. 44.89%. The risk factors for bacterial infections among patients with cirrhosis of liver were upper gastrointestinal bleeding (odd ratio = 4.57, p = 0.0001), use of proton pump inhibitors (odd ratio = 2.57, p = 0.0001), degree of malnutrition (odd ratio = 10.34, p = 0.0001) and severity of cirrhosis (odd ratio = 12.99, p = 0.000). All types of infections occurred with varying frequency in cirrhosis of liver. Upper gastrointestinal bleeding, severity of cirrhosis, use of high dose proton pump inhibitors and severe malnutrition are important risk factors for infections among cirrhotics.

New determinants of prognosis in bacterial infections in cirrhosis.

Despite major advances in the knowledge and management of liver diseases achieved in recent decades, decompensation of cirrhosis still carries a high burden of morbidity and mortality. Bacterial infections are one of the main causes of decompensation. It is very important for clinical management to be aware of the population with the highest risk of poor outcome. This review deals with the new determinants of prognosis in patients with cirrhosis and bacterial infections reported recently. Emergence of multiresistant bacteria has led to an increasing failure rate of the standard empirical antibiotic therapy recommended by international guidelines. Moreover, it has been recently reported that endothelial dysfunction is associated with the degree of liver dysfunction and, in infected patients, with the degree of sepsis. It has also been reported that relative adrenal insufficiency is frequent in the non-critically ill cirrhotic population and it is associated with a higher risk of developing infection, severe sepsis, hepatorenal syndrome and death. We advise a change in the standard empirical antibiotic therapy in patients with high risk for multiresistant infections and also to take into account endothelial and adrenal dysfunction in prognostic models in hospitalized patients with decompensated cirrhosis.

Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis.

Liver disease is associated with qualitative and quantitative changes in the intestinal microbiota. In cirrhotic patients the alteration in gut microbiota is characterized by an overgrowth of potentially pathogenic bacteria (i.e., gram negative species) and a decrease in autochthonous familiae. Here we summarize the available literature on the risk of gut dysbiosis in liver cirrhosis and its clinical consequences. We therefore described the features of the complex interaction between gut microbiota and cirrhotic host, the so called "gut-liver axis", with a particular attention to the acquired risk of bacterial translocation, systemic inflammation and the relationship with systemic infections in the cirrhotic patient. Such knowledge might help to develop novel and innovative strategies for the prevention and therapy of gut dysbiosis and its complication in liver cirrhosis.

A case of pneumonia and sepsis in cirrhosis as paradigm of the problems in the management of bacterial infections in cirrhosis and of the limitations of current knowledge

Bacterial infections are a major problem in the management of liver cirrhosis. They represent the first precipitating cause of death since patients with cirrhosis carry an increased risk of sepsis, sepsis-induced organ failure and death. Although the clinical presentation is often misleading, the presence of bacterial infection should always be actively searched and ruled out with certainty whenever a cirrhotic patient is admitted to the hospital with an acute clinical deterioration. Major changes in the epidemiology of bacterial infections have also occurred in the last decade making the choice of empirical antibiotic therapy a challenge. We report a paradigmatic case of a 54-year old man with hepatitis C-related cirrhosis admitted to the hospital for worsening of his ascites and onset of hepatic encephalopathy, an excellent example for the difficulties of management of sepsis in cirrhosis and the limits of current knowledge.