Juan Acevedo

Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: A prospective study†

Epidemiology, risk factors, and clinical effect of infections by multiresistant bacteria in cirrhosis are poorly known. This work was a prospective evaluation in two series of cirrhotic patients admitted with infection or developing infection during hospitalization. The first series was studied between 2005 and 2007 (507 bacterial infections in 223 patients) and the second between 2010 and 2011 (162 bacterial infections in 110 patients). In the first series, 32% of infections were community acquired (CA), 32% healthcare associated (HCA), and 36% nosocomial. Multiresistant bacteria (92 infections; 18%) were isolated in 4%, 14%, and 35% of these infections, respectively (P < 0.001). Extended‐spectrum β‐lactamase‐producing Enterobacteriaceae (ESBL‐E; n = 43) was the main multiresistant organism identified, followed by Pseudomonas aeruginosa (n = 17), methicillin‐resistant Staphylococcus aureus (n = 14), and Enterococcus faecium (n = 14). The efficacy of currently recommended empirical antibiotic therapy was very low in nosocomial infections (40%), compared to HCA and CA episodes (73% and 83%, respectively; P < 0.0001), particularly in spontaneous bacterial peritonitis, urinary tract infection, and pneumonia (26%, 29%, and 44%, respectively). Septic shock (26% versus 10%; P < 0.0001) and mortality rate (25% versus 12%; P = 0.001) were significantly higher in infections caused by multiresistant strains. Nosocomial origin of infection (hazard ratio [HR], 4.43), long‐term norfloxacin prophylaxis (HR, 2.69), recent infection by multiresistant bacteria (HR, 2.45), and recent use of β‐lactams (HR, 2.39) were independently associated with the development of multiresistant infections. Results in the second series were similar to those observed in the first series. Conclusions: Multiresistant bacteria, especially ESBL‐producing Enterobacteriaceae, are frequently isolated in nosocomial and, to a lesser extent, HCA infections in cirrhosis, rendering third‐generation cephalosporins clinically ineffective. New antibiotic strategies tailored according to the local epidemiological patterns are needed for the empirical treatment of nosocomial infections in cirrhosis. (HEPATOLOGY 2012)

Relative adrenal insufficiency in decompensated cirrhosis: Relationship to short‐term risk of severe sepsis, hepatorenal syndrome, and death

The prevalence of relative adrenal insufficiency (RAI) in critically ill cirrhosis patients with severe sepsis is over 60% and associated features include poor liver function, renal failure, refractory shock, and high mortality. RAI may also develop in noncritically ill cirrhosis patients but its relationship to the clinical course has not yet been assessed. The current study was performed in 143 noncritically ill cirrhosis patients admitted for acute decompensation. Within 24 hours after hospitalization adrenal function, plasma renin activity, plasma noradrenaline and vasopressin concentration, and serum levels of nitric oxide, interleukin‐6 and tumor necrosis factor alpha were determined. RAI was defined as a serum total cortisol increase <9 μg/dL after 250 μg of intravenous corticotropin from basal values <35 μg/dL. Patients were followed for 3 months. RAI was detected in 26% of patients (n = 37). At baseline, patients with RAI presented with lower mean arterial pressure (76 ± 12 versus 83 ± 14 mmHg, P = 0.009) and serum sodium (131 ± 7 versus 135 ± 5 mEq/L, P = 0.007) and higher blood urea nitrogen (32 ± 24 versus 24 ± 15 mg/dl, P = 0.06), plasma renin activity (7.1 ± 9.9 versus 3.4 ± 5.6 ng/mL*h, P = 0.03), and noradrenaline concentration (544 ± 334 versus 402 ± 316 pg/mL, P = 0.02). During follow‐up, patients with RAI exhibited a higher probability of infection (41% versus 21%, P = 0.008), severe sepsis (27% versus 9%, P = 0.003), type‐1 hepatorenal syndrome (HRS) (16% versus 3%, P = 0.002), and death (22% versus 7%, P = 0.01). Conclusion: RAI is frequent in noncritically ill patients with acute decompensation of cirrhosis. As compared with those with normal adrenal function, patients with RAI have greater impairment of circulatory and renal function, higher probability of severe sepsis and type‐1 HRS, and higher short‐term mortality. (Hepatology 2013;58:1757–1765)

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.

Clinical course and short‐term mortality of cirrhotic patients with infections other than spontaneous bacterial peritonitis

Clinical course and risk factors of death in non‐spontaneous bacterial peritonitis (SBP) infections are poorly known. We assessed the prevalence of acute kidney injury (AKI) and type‐1 hepatorenal syndrome (HRS), hospital, 30‐day and 90‐day mortality and risk factors of death in 441 decompensated patients.

Effects of pentoxifylline on intestinal bacterial overgrowth, bacterial translocation and spontaneous bacterial peritonitis in cirrhotic rats with ascites

BACKGROUND Prophylaxis of spontaneous bacterial peritonitis with norfloxacin has been associated to development of antibiotic resistance. We investigated whether pentoxifylline compared to norfloxacin reduces bacterial translocation and spontaneous bacterial peritonitis in rats with CCl(4)-induced cirrhosis and ascites. METHOD After development of cirrhosis and ascites, animals were randomly allocated to receive pentoxifylline (16 mg/kg/d every 8h, oral route, n=13) or placebo (n=12) for 15 days. An additional group of 8 cirrhotic rats was given norfloxacin (5mg/kg/d for 15 days). Six healthy rats served as controls. Cecal flora and the prevalence of bacterial translocation and spontaneous bacterial peritonitis were analysed. Serum and ascitic fluid levels of TNF-alpha and cecal levels of malondialdehyde were also measured. RESULTS Pentoxifylline in comparison to placebo reduced intestinal bacterial overgrowth (21% vs. 67%, p=0.04), bacterial translocation to cecal lymph nodes (23% vs. 75%, p=0.03) and prevented spontaneous bacterial peritonitis (0% vs. 33%, p=0.04) by Enterobacteriaceae. Norfloxacin administration induced similar results. Pentoxifylline (0.18 ± 0.10 nmol/mg), but not norfloxacin (0.25 ± 0.13; p=0.02), significantly reduced cecal mucosal levels of malondialdehyde compared to placebo (0.33 ± 0.16; p=0.03). CONCLUSION In cirrhotic rats with ascites: (a) pentoxifylline as well as norfloxacin reduced intestinal bacterial overgrowth and bacterial translocation and prevented spontaneous bacterial peritonitis; (b) pentoxifylline, but not norfloxacin, reduced oxidative stress in cecal mucosal.

The new epidemiology of nosocomial bacterial infections in cirrhosis: therapeutical implications

Cirrhotic patients are at increased risk of developing infection, sepsis and death. Enterobacteriaceae and nonenterococcal streptococci are the main bacteria responsible for spontaneous and urinary infections in this population. Prompt and appropriate treatment is basic in the management of cirrhotic patients with infection. Third-generation cephalosporins continue to be the gold-standard antibiotic treatment of the majority of infections acquired in the community because responsible strains are usually susceptible to β-lactams. By contrary, nosocomial infections are nowadays frequently caused by multiresistant bacteria (extended-spectrum β-lactamase-producing Enterobacteriaceae, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci among others) that are nonsusceptible to the main antibiotics. Treatment of these infections requires the use of broader spectrum antibiotics (carbapenems) or of antibiotics that are active against specific resistant bacteria (glycopeptides, linezolid, daptomycin, amikacin and colistin). Empirical antibiotic schedules must be adapted to the local epidemiological pattern of antibiotic resistance. Careful restriction of antibiotic prophylaxis to the high-risk population is also mandatory to reduce the spread of multiresistant bacteria in cirrhosis.

Changing Options for Prevention and Treatment of Infections in Cirrhosis

Opinion statementBacterial 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.

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.

Response to the clinical course and short‐term mortality of cirrhotic patients with non‐spontaneous bacterial peritonitis infections

To the Editor: We read with interest the comments made by the group of Wenzhou, China, on our manuscript.1 We completely agree on the prognostic relevance of the initiation of a timely and adequate empirical antibiotic therapy in patients with advanced cirrhosis and infection. This feature has been demonstrated in both general2 and cirrhotic populations.3-5 Accordingly, EASL guidelines on the empirical treatment of bacterial infections in cirrhosis have been recently changed and recommend nowadays adapting empirical strategies to the local epidemiological pattern of multiresistance.6,7 Although effectiveness of empiric antibiotic therapy could have had an impact on the clinical course of the infected patients included in our study, the empirical strategies used in the three series were adapted to the epidemiological changes observed in our centre at each moment. Moreover, and in order to minimize the impact of an inadequate antibiotic coverage, patients developing septic shock within 48 h after diagnosis of infection were excluded from this study. Our results probably reflect the natural history of non-SBP infections receiving an appropriate antibiotic therapy since 96% of them were solved. The second point raised in the letter is the potential impact of albumin administration on the outcome of patients with nonSBP infections. As stated in the manuscript, albumin administration was not recorded in this manuscript. However, at the time of hospitalization of the patients included in this study, local protocols limited the use of albumin to patients with SBP, type1 HRS and large volume paracentesis. We agree that albumin administration could be beneficial in selected patients with nonSBP infections; feature not demonstrated in previous RCT.8,9 In that sense, a new RCT is currently exploring the impact of prophylactic albumin administration on the clinical course of patients with nonSBP and poor shortterm prognosis (ClinicalTrials.gov number: NCT02034279). The target population included in this RCT was selected on the basis on the results of this study. Finally, only patients with hepatocellular carcinoma (HCC) within Milan criteria were included in this study. The exclusion of patients with advanced HCC prevented any impact of HCC on shortterm prognosis. In fact, hospital (8% vs 11.5%), 30d (13% vs 11.5%) and 90d (19% vs 18%) mortality rates did not differ between patients with and without HCC. Patients with HCC of different aetiologies (56 HCV, nine HCV plus alcohol, eight alcohol, eight HBV and four other) showed similar clinical outcome. FUNDING INFORMATION

Insuficiencia suprarrenal relativa en la insuficiencia hepática aguda y crónica

Cortisol is a pluripotent hormone that is vital in the host adaptation to stress. It is essential to maintain the normal vascular tone, endothelial integrity and vascular permeability. Consequently, the failure of an appropriate adrenal response in the setting of critical illness, alteration known as relative adrenal insufficiency, may have important clinical consequences. The diagnosis of this entity is not possible on clinical grounds and relies on the measurement of plasma cortisol levels prior and after adrenal stimulation with synthetic corticotrophin. Several studies performed in the general population have shown that relative adrenal insufficiency contributes to vascular hyporesponsiveness in septic shock and increases mortality. However, contradictory data exist regarding the effects of hydrocortisone administration in these patients. Moreover, recent studies indicate that relative adrenal insufficiency is very frequent in patients with advanced cirrhosis and septic shock and in fulminant hepatic failure. This chapter summarizes the main aspects of the physiopathology, diagnosis and treatment of this entity in patients with acute or chronic liver disease.