**Table 4.** *Empirical antibiotic treatment of infection in cirrhosis (adapted from Allaire et al.) [149].*

#### *Acute on Chronic Liver Failure: Role of the Bacterial Infections DOI: http://dx.doi.org/10.5772/intechopen.93440*

*Liver Pathology*

based on the administration of third-generation cephalosporins. The resistance to classical empirical antibiotic regimens is associated with a higher mortality rate, an increased duration of in-hospital stays and higher healthcare related costs when compared to infections caused by susceptible strains [89, 91, 98, 99, 116, 133, 134]. To date, it is recommended to treated nosocomial and HCA infections with empirical MDR covering strategies, whether a classical empirical approach is recommended for CA infections (**Table 4**). Empirical MDR covering strategies are usually more effective than empiric classical schemes in nosocomial infections (81.7% vs. 68%, respectively, p = 0.01) with a positive impact on short-term survival. A trend towards statistical significance is also observed in severe sepsis/shock (81.3% vs. 60.9%, p = 0.06). Inadequacy of first line antibiotic strategies increased 28-day mortality in both AD (33.3% vs. 7.7%, p < 0.001) and ACLF patients (50% vs. 25.8%, p = 0.002). Thus, broad schemes covering all potential pathogens should be empirically used in the nosocomial setting and in severe sepsis/shock, followed by rapid de-escalation strategies to avoid a further spread of antibiotic resistance [88, 106, 114, 135]. In a recent retrospective study from Germany [136] the authors evaluated the efficacy of different first line empirical antibiotic therapies in ACLF patients with SBP. From this study emerged that meropenem-daptomycin (99.5%), meropenem-linezolid, (98.5%) and meropenem-vancomycin (96.8%) combination scheme had the highest antimicrobial susceptibility rates and piperacillin/tazobactam had the highest antimicrobial susceptibility rates among the monotherapies/fixed combinations considering all of the Gram-negative and Gram-positive bacteria. On the contrary, classical empiric therapy based on cefotaxime or ceftriaxone showed a sensibility as low as 60%. Susceptibility of bacteria to these combination regimens positively impacted on inpatient mortality and complications. However, some pharmacologic and pharmacokinetic properties of these antibiotics should be considered when empirical MDR covering therapy has to be started. Linezolid achieves rapid penetration in peritoneum and rapidly reaches high concentration in tissue [137]. However, in patients with concomitant sepsis, it might not be the best option because the effect is more towards the bacteriostatic side, and thus might be too weak to ideally treat the bacteremia component [137]. Contrarily to linezolid, vancomycin has a lower tissue concentration and weak penetrability [138]. It is therefore should be preferred for sepsis [138]. Daptomycin has a very low concentration in the peritoneal cavity (only 6% of that in serum) [139]. Thus, daptomycin should be the first-choice antibiotic to treat bacteremia and sepsis being safer than vancomycin. As to gram-negative infection, thanks to their moderate volume of distribution and excellent penetrability both piperacillin/tazobactam and meropenem could be used for infection of peritoneum as well as bacteremia/sepsis [140, 141]. As in other settings, there is a cogent need to evaluate new strategies for preventing the spread of antibiotic resistance in cirrhotic population. Many studies are investigating epidemiological surveillance through regular assessment of potential carriers of MDRs through rectal and nasal swabs during hospitalization [142, 143], rapid microbiological tests [144, 145] and antibiotic stewardship programs [112, 146, 147]. As previously stated, fungal infection is an emerging problem in cirrhotic patients, particularly in those with ACLF hospitalized in ICU. An early diagnosis of fungal infection and antifungal treatment is prognostically crucial and it has been associated with improved outcome [148]. Triazoles (fluconazole, itraconazole, voriconazole, and posaconazole) are the most frequently employed antifungal agents. However, due to reported emergence of azole resistant non-albicans spp., the first line treatment recommended in critically ill patients shifted toward a new antifungal class: the echinocandins (caspofungin, anidulafungin, and micafungin). Echinocandins are indeed, the recommended first-line treatment for patients with cirrhosis and nosocomial spontaneous fungal peritonitis. The usual intravenous

**114**

dosing regimens for invasive candidiasis are as follows: caspofungin: loading dose 70 mg, then 50 mg daily. No dose adjustement are recommended in case of moderate and severe liver disease except for caspofungin (loading dose 70 mg, then 35 mg daily) [148, 150]. De-escalation from echinocandins to fluconazole is advised in those cirrhotic patients when their condition becomes stable.

#### **4. Conclusions**

Acute-on-chronic liver failure (ACLF) is a clinical independent entity capturing the interest of hepatologists from the East and the West in the past 2 decades. Although universal definition does not exist, there is a substantial agreement that this syndrome should refer to liver failure, usually after an acute event, in a patient with chronic liver disease and characterized by an elevated short-term mortality. It should be distinguished from an ordinary decompensation of chronic liver disease and from acute liver failure of a normal liver. Although the pathophysiological mechanisms leading to this syndrome are only partly understood, systemic inflammation seems to play a crucial role. Exaggerated inflammatory response, the socalled "cytokine storm" is the main driving event leading to multiorgan failure. In most cases, bacterial infection is the initiating event of ACLF and early identification and treatment is mandatory to stop SIRS-sepsis cascade and to prevent multiorgan failure. An emerging clinical problem is represented by infection sustained by of MDR bacteria. This new epidemiologic reality has completely changed antibiotic strategies for empirical approach in decompensated cirrhosis. Control and prevention of MDR infection widespread, in particular in the nosocomial setting, as well as to make available new treatment opportunities, beside OLT, to manage liver failure are the challenge of the near future.

#### **Conflict of interest**

None to be declared.

#### **Author details**

Mauro Borzio1 \* and Elena Dionigi2

1 Department of Gastroenterology, ASST Melegnano-Martesana, Milano, Italy

2 Department of Medicine, ASST Melegnano-Martesana, Milano, Italy

\*Address all correspondence to: mauro.borzio@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**117**

*Acute on Chronic Liver Failure: Role of the Bacterial Infections*

from a large worldwide study. Liver International. 2014;**34**:1496-1503

[8] Gustot T, Jalan R. Acute-onchronic liver failure in patients with alcohol-related liver disease. Journal of

Hepatology. 2019;**70**:319-327

[9] Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, et al. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study. Gastroenterology. 2015;**148**:1340-1352

[10] Qin G, Shao JG, Zhu YC, Xu AD, Yao JH, Wang XL, et al. Populationrepresentative incidence of acute-onchronic liver failure. A prospective cross-sectional study. Journal of Clinical Gastroenterology. 2016;**50**:670-675

[11] Anand L, Choudhury A, Bihari C, Sharma BC, Kumar M, Maiwall R, et al. APASL ACLF (APASL ACLF research consortium) Working party. Flare of autoimmune hepatitis causing acute on chronic liver failure (ACLF): Diagnosis and response to corticosteroid therapy.

[12] Axley P, Ahmed Z, Arora S, Haas A, Kuo YF, Kamath PS, et al. NASH is the most rapidly growing etiology for acute-on-chronic liver failure-related hospitalization and disease burden in the United States: A populationbased study. Liver Transplantation.

[13] Jalan R, Yurdaydin C, Bajaj JS, Acharya SK, Arroyo V, Lin HC, et al. Toward an improved definition of acute-on-chronic liver failure. Gastroenterology. 2014;**147**:4-10

[14] Choudhury A, Jindal A, Maiwal R, Sarin SK, Sharma LK, Pamecha V, et al. Liver failure determines the outcome in patient of acute-on-chronic liver failure (ACLF)-comparison of APASL-ACLF

Hepatology. 2019;**70**:587-596

2019;**25**:695-705

*DOI: http://dx.doi.org/10.5772/intechopen.93440*

[2] Jalan R, Pavesi M, Saliba F, Amorós A, Fernandez J, Holland-Fischer P, et al.

Decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-on-chronic liver failure. Journal of Hepatology.

Garcia-Tsao G, Biggins SW, Wong F, Fallon MB, et al. NACSELD acute-onchronic liver failure (NACSELD-ACLF) score predicts 30-day survival in hospitalized patients with cirrhosis. Hepatology. 2018;**67**:2367-2374

[4] Sarin SK, Chandan K, Zaigham A, Amarapurkar B, Bihari C, Chan AC, et al. Acute-on-chronic liver failure: Consensus recommendations of the Asian Pacific association for the study of the liver (APASL). Hepatology International. 2014;**8**:453-471

[5] Sarin SK, Choudhury A, Sharma MK, Maiwall MK, Mahtab M, Saigal RS, et al. Acute-on-chronic liver failure: Consensus recommendations of the Asian Pacific association for the study of the liver (APASL): An update. Hepatology International.

[6] Moreau R, Jalan R, Ginès P, Pavesi M, Angeli P, Cordoba J, et al. Acute-onchronic liver failure is a distinct syndrome developing in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;**144**:1426-1437

[7] Gustot T, Felleiter P, Pickkers P, Sakr Y, Rello J, Velissaris D, et al. Impact

of infection on the prognosis of critically ill cirrhotic patients: Results

[1] Bajaj JS, Moreau R, Kamath PS, Vargas HE, Arroyo V, Reddy KR, et al. Acute-on-chronic liver failure: Getting ready for prime time? Hepatology.

2018;**68**:1621-1632

**References**

2015;**62**:831-840

2019;**13**:353-390

The CLIF consortium acute

[3] O'Leary JG, Reddy KR,

*Acute on Chronic Liver Failure: Role of the Bacterial Infections DOI: http://dx.doi.org/10.5772/intechopen.93440*

#### **References**

*Liver Pathology*

**4. Conclusions**

**116**

**Author details**

**Conflict of interest**

None to be declared.

\* and Elena Dionigi2

provided the original work is properly cited.

failure are the challenge of the near future.

1 Department of Gastroenterology, ASST Melegnano-Martesana, Milano, Italy

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

dosing regimens for invasive candidiasis are as follows: caspofungin: loading dose 70 mg, then 50 mg daily. No dose adjustement are recommended in case of moderate and severe liver disease except for caspofungin (loading dose 70 mg, then 35 mg daily) [148, 150]. De-escalation from echinocandins to fluconazole is advised in

Acute-on-chronic liver failure (ACLF) is a clinical independent entity capturing the interest of hepatologists from the East and the West in the past 2 decades. Although universal definition does not exist, there is a substantial agreement that this syndrome should refer to liver failure, usually after an acute event, in a patient with chronic liver disease and characterized by an elevated short-term mortality. It should be distinguished from an ordinary decompensation of chronic liver disease and from acute liver failure of a normal liver. Although the pathophysiological mechanisms leading to this syndrome are only partly understood, systemic inflammation seems to play a crucial role. Exaggerated inflammatory response, the socalled "cytokine storm" is the main driving event leading to multiorgan failure. In most cases, bacterial infection is the initiating event of ACLF and early identification and treatment is mandatory to stop SIRS-sepsis cascade and to prevent multiorgan failure. An emerging clinical problem is represented by infection sustained by of MDR bacteria. This new epidemiologic reality has completely changed antibiotic strategies for empirical approach in decompensated cirrhosis. Control and prevention of MDR infection widespread, in particular in the nosocomial setting, as well as to make available new treatment opportunities, beside OLT, to manage liver

those cirrhotic patients when their condition becomes stable.

2 Department of Medicine, ASST Melegnano-Martesana, Milano, Italy

\*Address all correspondence to: mauro.borzio@gmail.com

Mauro Borzio1

[1] Bajaj JS, Moreau R, Kamath PS, Vargas HE, Arroyo V, Reddy KR, et al. Acute-on-chronic liver failure: Getting ready for prime time? Hepatology. 2018;**68**:1621-1632

[2] Jalan R, Pavesi M, Saliba F, Amorós A, Fernandez J, Holland-Fischer P, et al. The CLIF consortium acute Decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-on-chronic liver failure. Journal of Hepatology. 2015;**62**:831-840

[3] O'Leary JG, Reddy KR, Garcia-Tsao G, Biggins SW, Wong F, Fallon MB, et al. NACSELD acute-onchronic liver failure (NACSELD-ACLF) score predicts 30-day survival in hospitalized patients with cirrhosis. Hepatology. 2018;**67**:2367-2374

[4] Sarin SK, Chandan K, Zaigham A, Amarapurkar B, Bihari C, Chan AC, et al. Acute-on-chronic liver failure: Consensus recommendations of the Asian Pacific association for the study of the liver (APASL). Hepatology International. 2014;**8**:453-471

[5] Sarin SK, Choudhury A, Sharma MK, Maiwall MK, Mahtab M, Saigal RS, et al. Acute-on-chronic liver failure: Consensus recommendations of the Asian Pacific association for the study of the liver (APASL): An update. Hepatology International. 2019;**13**:353-390

[6] Moreau R, Jalan R, Ginès P, Pavesi M, Angeli P, Cordoba J, et al. Acute-onchronic liver failure is a distinct syndrome developing in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;**144**:1426-1437

[7] Gustot T, Felleiter P, Pickkers P, Sakr Y, Rello J, Velissaris D, et al. Impact of infection on the prognosis of critically ill cirrhotic patients: Results

from a large worldwide study. Liver International. 2014;**34**:1496-1503

[8] Gustot T, Jalan R. Acute-onchronic liver failure in patients with alcohol-related liver disease. Journal of Hepatology. 2019;**70**:319-327

[9] Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, et al. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study. Gastroenterology. 2015;**148**:1340-1352

[10] Qin G, Shao JG, Zhu YC, Xu AD, Yao JH, Wang XL, et al. Populationrepresentative incidence of acute-onchronic liver failure. A prospective cross-sectional study. Journal of Clinical Gastroenterology. 2016;**50**:670-675

[11] Anand L, Choudhury A, Bihari C, Sharma BC, Kumar M, Maiwall R, et al. APASL ACLF (APASL ACLF research consortium) Working party. Flare of autoimmune hepatitis causing acute on chronic liver failure (ACLF): Diagnosis and response to corticosteroid therapy. Hepatology. 2019;**70**:587-596

[12] Axley P, Ahmed Z, Arora S, Haas A, Kuo YF, Kamath PS, et al. NASH is the most rapidly growing etiology for acute-on-chronic liver failure-related hospitalization and disease burden in the United States: A populationbased study. Liver Transplantation. 2019;**25**:695-705

[13] Jalan R, Yurdaydin C, Bajaj JS, Acharya SK, Arroyo V, Lin HC, et al. Toward an improved definition of acute-on-chronic liver failure. Gastroenterology. 2014;**147**:4-10

[14] Choudhury A, Jindal A, Maiwal R, Sarin SK, Sharma LK, Pamecha V, et al. Liver failure determines the outcome in patient of acute-on-chronic liver failure (ACLF)-comparison of APASL-ACLF

research consortium (AARC) and CLIF-SOFA model. Hepatology International. 2017;**11**:461-471

[15] Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nature Immunology. 2015;**16**:343-353

[16] Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. Journal of Hepatology. 2015;**63**:1272-1284

[17] Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Gines P, Moreira V, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology. 2005;**42**:439-447

[18] Nazar A, Guevara M, Sitges M, Terra C, Solá E, Guigou C, et al. Left ventricular function assessed by echocardiography in cirrhosis: Relationship to systemic hemodynamics and renal dysfunction. Journal of Hepatology. 2013;**58**:51-57

[19] Moller S, Hove JD, Dixen U, Bendtsen F. New insights into cirrhotic cardiomyopathy. International Journal of Cardiology. 2013;**167**:1101-1108

[20] Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised consensus recommendations of the International Club of Ascites. Gut. 2015;**64**:531-537

[21] Angeli P, Rodriguez E, Piano S, Ariza X, Morando F, Sola E, et al. Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis. Gut. 2015;**64**:1616-1622

[22] Maiwall R, Kumar S, Chandel SS, Kumar G, Rastogi A, Bihari C, et al.

AKI in patients with acute on chronic liver failure is different from acute decompensation of cirrhosis. Hepatology International. 2015;**9**: 627-639

[23] Cordoba J, Ventura-Cots M, Simon-Talero M, Amoros A, Pavesi M, Vilstrup H, et al. Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acuteon-chronic liver failure (ACLF). Journal of Hepatology. 2014;**60**:275-281

[24] Bajaj JS, O'Leary JG, Tandon P, Wong F, Garcia-Tsao G, Kamath PS, et al. Hepatic encephalopathy is associated with mortality in patients with cirrhosis independent of other extrahepatic organ failures. Clinical Gastroenterology and Hepatology. 2017;**15**:565-574

[25] Fernandez J, Escorsell A, Zabalza M, Felipe V, Navasa M, Mas A, et al. Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival. Hepatology. 2006;**44**:1288-1295

[26] Piano S, Favaretto E, Tonon M, Antonelli G, Brocca A, Sticca A, et al. Including relative adrenal insufficiency in definition and classification of acute on chronic liver failure. Clinical Gastroenterology and Hepatology. 2020;**18**:1188-1196

[27] Drolz A, Horvatits T, Rutter K, Landahl F, Roald K, Meersseman P, et al. Lactate improves prediction of shortterm mortality in critically ill patients with cirrhosis: A multinational study. Hepatology. 2019;**69**:258-269

[28] Jalan R, Saliba F, Pavesi M, Amoros A, Moreau R, Ginès P, et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. Journal of Hepatology. 2014;**61**:1038-1047

**119**

2020;**26**:187-195

*Acute on Chronic Liver Failure: Role of the Bacterial Infections*

[36] Gustot T, Fernandez J, Garcia E, Morando F, Caraceni P, Alessandria C, et al. Clinical course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology. 2015;**62**:243-252

[37] Artru F, Louvet A, Ruiz I,

Hepatology. 2017;**67**:708-715

2013;**19**:879-886

[38] Finkenstedt A, Nachbaur K, Zoller H, Joannidis M, Pratschke J, Graziadei IW, et al. Acute-on-chronic liver failure: Excellent outcomes after liver transplantation but high mortality on the wait list. Liver Transplantation.

[39] Jalan R, Gines P, Olson JC,

Mookerjee RP, Moreau R, Garcia-Tsao G, et al. Acute-on chronic liver failure. Journal of Hepatology. 2012;**57**:1336-1348

[40] Bahirwani R, Shaked O, Bewtra M, Forde K, Reddy KR. Acute-on-chronic liver failure before liver transplantation: Impact on post-transplant outcomes. Transplantation. 2011;**92**:952-957

[41] Sundaram V, Kogachi S, Wong RJ, Karvellas CJ, Fortune BE, Mahmud N, et al. Effect of the clinical course of acute-on-chronic liver failure prior to liver transplantation on post-transplant

survival. Journal of Hepatology.

[42] Choudhury AK, Sharma M, Mehtab M, Sarin SK, for APASL ACLF Working party, et al. The decision for liver transplant in acute-on-chronic liver failure (ACLF)—First week is the crucial period-analysis of the APASL ACLF research consortium (AARC) prospective data of 1021 patients. Journal of Hepatology. 2016;**64**:S1-S51

[43] Pamecha V, Kumar S,

Bharathy KG. Liver transplantation

2020;**72**:481-488

et al. Liver transplantation in the most severely ill cirrhotic patients: A multicenter study in acute-onchronic liver failure grade 3. Journal of

Levesque E, Labreuche J, Ursic-Bedoya J,

*DOI: http://dx.doi.org/10.5772/intechopen.93440*

[29] Lee M, Lee JH, Oh S, Jang Y, Lee W, Lee HJ, et al. CLIF-SOFA scoring system accurately predicts short-term mortality in acutely decompensated patients with alcoholic cirrhosis: A retrospective analysis. Liver International.

Reulbach U, Hahn EG, Strauss R. Shortterm prognosis in critically ill patients with cirrhosis assessed by prognostic

2015;**35**:46-57

2001;**34**:255-261

[30] Wehler M, Kokoska J,

scoring systems. Hepatology.

[31] Das V, Boelle PY, Galbois A, Guidet B, Maury E, Carbonell N, et al. Cirrhotic patients in the medical intensive care unit: Early prognosis and long-term survival. Critical Care

Medicine. 2010;**38**:2108-2116

Hepatology. 2012;**56**:95-102

[34] Maipang K, Potranun P, Chainuvati S, Nimanong S,

Chotiyaputta W, Tanwandee T, et al. Validation of the prognostic models in acute on-chronic liver failure

[35] Rosenblatt R, Shen N, Tafesh Z, Cohen-Mekelburg S, Crawford CV, Kumar S, et al. The north American consortium for the study of endstage liver disease-acute-on-chronic liver failure score accurately predicts survival: An external validation using a national cohort. Liver Transplantation.

precipitated by hepatic and extrahepatic insults. PLoS One. 2019;**14**(7):e0219516

2019;**18**:48-57

[33] Perdigoto DN, Figueiredo P,

Luís TL. The role of the CLIF-C OF and the 2016 MELD in prognosis of cirrhosis with and without acute-on-chronic liver failure. Annals of Hepatology.

[32] Levesque E, Hoti E, Azoulay D, Ichaï P, Habouchi H, Castaing D, et al. Prospective evaluation of the prognostic scores for cirrhotic patients admitted to an intensive care unit. Journal of

#### *Acute on Chronic Liver Failure: Role of the Bacterial Infections DOI: http://dx.doi.org/10.5772/intechopen.93440*

[29] Lee M, Lee JH, Oh S, Jang Y, Lee W, Lee HJ, et al. CLIF-SOFA scoring system accurately predicts short-term mortality in acutely decompensated patients with alcoholic cirrhosis: A retrospective analysis. Liver International. 2015;**35**:46-57

*Liver Pathology*

2017;**11**:461-471

2015;**16**:343-353

2015;**63**:1272-1284

research consortium (AARC) and CLIF-SOFA model. Hepatology International. AKI in patients with acute on chronic liver failure is different from acute decompensation of cirrhosis. Hepatology International. 2015;**9**:

[23] Cordoba J, Ventura-Cots M, Simon-Talero M, Amoros A, Pavesi M, Vilstrup H, et al. Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic

of Hepatology. 2014;**60**:275-281

Hepatology. 2017;**15**:565-574

[25] Fernandez J, Escorsell A,

on survival. Hepatology. 2006;**44**:1288-1295

2020;**18**:1188-1196

2014;**61**:1038-1047

Zabalza M, Felipe V, Navasa M, Mas A, et al. Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone

[26] Piano S, Favaretto E, Tonon M, Antonelli G, Brocca A, Sticca A, et al. Including relative adrenal insufficiency in definition and classification of acute on chronic liver failure. Clinical Gastroenterology and Hepatology.

[27] Drolz A, Horvatits T, Rutter K, Landahl F, Roald K, Meersseman P, et al. Lactate improves prediction of shortterm mortality in critically ill patients with cirrhosis: A multinational study.

Hepatology. 2019;**69**:258-269

[28] Jalan R, Saliba F, Pavesi M, Amoros A, Moreau R, Ginès P, et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. Journal of Hepatology.

[24] Bajaj JS, O'Leary JG, Tandon P, Wong F, Garcia-Tsao G, Kamath PS, et al. Hepatic encephalopathy is associated with mortality in patients with cirrhosis independent of other extrahepatic organ failures. Clinical Gastroenterology and

encephalopathy with and without acuteon-chronic liver failure (ACLF). Journal

627-639

[15] Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nature Immunology.

[16] Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. Journal of Hepatology.

[17] Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Gines P, Moreira V,

[18] Nazar A, Guevara M, Sitges M, Terra C, Solá E, Guigou C, et al. Left ventricular function assessed by echocardiography in cirrhosis:

Relationship to systemic hemodynamics and renal dysfunction. Journal of

et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology. 2005;**42**:439-447

Hepatology. 2013;**58**:51-57

[19] Moller S, Hove JD, Dixen U, Bendtsen F. New insights into cirrhotic cardiomyopathy. International Journal of Cardiology. 2013;**167**:1101-1108

[20] Angeli P, Gines P, Wong F,

2015;**64**:531-537

2015;**64**:1616-1622

Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised consensus recommendations of the International Club of Ascites. Gut.

[21] Angeli P, Rodriguez E, Piano S, Ariza X, Morando F, Sola E, et al. Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis. Gut.

[22] Maiwall R, Kumar S, Chandel SS, Kumar G, Rastogi A, Bihari C, et al.

**118**

[30] Wehler M, Kokoska J, Reulbach U, Hahn EG, Strauss R. Shortterm prognosis in critically ill patients with cirrhosis assessed by prognostic scoring systems. Hepatology. 2001;**34**:255-261

[31] Das V, Boelle PY, Galbois A, Guidet B, Maury E, Carbonell N, et al. Cirrhotic patients in the medical intensive care unit: Early prognosis and long-term survival. Critical Care Medicine. 2010;**38**:2108-2116

[32] Levesque E, Hoti E, Azoulay D, Ichaï P, Habouchi H, Castaing D, et al. Prospective evaluation of the prognostic scores for cirrhotic patients admitted to an intensive care unit. Journal of Hepatology. 2012;**56**:95-102

[33] Perdigoto DN, Figueiredo P, Luís TL. The role of the CLIF-C OF and the 2016 MELD in prognosis of cirrhosis with and without acute-on-chronic liver failure. Annals of Hepatology. 2019;**18**:48-57

[34] Maipang K, Potranun P, Chainuvati S, Nimanong S, Chotiyaputta W, Tanwandee T, et al. Validation of the prognostic models in acute on-chronic liver failure precipitated by hepatic and extrahepatic insults. PLoS One. 2019;**14**(7):e0219516

[35] Rosenblatt R, Shen N, Tafesh Z, Cohen-Mekelburg S, Crawford CV, Kumar S, et al. The north American consortium for the study of endstage liver disease-acute-on-chronic liver failure score accurately predicts survival: An external validation using a national cohort. Liver Transplantation. 2020;**26**:187-195

[36] Gustot T, Fernandez J, Garcia E, Morando F, Caraceni P, Alessandria C, et al. Clinical course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology. 2015;**62**:243-252

[37] Artru F, Louvet A, Ruiz I, Levesque E, Labreuche J, Ursic-Bedoya J, et al. Liver transplantation in the most severely ill cirrhotic patients: A multicenter study in acute-onchronic liver failure grade 3. Journal of Hepatology. 2017;**67**:708-715

[38] Finkenstedt A, Nachbaur K, Zoller H, Joannidis M, Pratschke J, Graziadei IW, et al. Acute-on-chronic liver failure: Excellent outcomes after liver transplantation but high mortality on the wait list. Liver Transplantation. 2013;**19**:879-886

[39] Jalan R, Gines P, Olson JC, Mookerjee RP, Moreau R, Garcia-Tsao G, et al. Acute-on chronic liver failure. Journal of Hepatology. 2012;**57**:1336-1348

[40] Bahirwani R, Shaked O, Bewtra M, Forde K, Reddy KR. Acute-on-chronic liver failure before liver transplantation: Impact on post-transplant outcomes. Transplantation. 2011;**92**:952-957

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Hepatology. 2016;**64**:717-735

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2000;**28**:2729-2732

2014;**60**:250-256

liv.14433

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[47] Zheng Z, Li X, Li Z, Ma X. Artificial and bioartificial liver support systems for acute and acute-on-chronic hepatic failure: Meta-analysis and meta-regression. Experimental and Therapeutic Medicine. 2013;**6**:929-936

Thomsen KL, Mehta G, Macnaughtan J, Bendtsen F, et al. Treatment with non-selective beta-blockers associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. Journal of Hepatology.

[49] Kumar M, Kainth S, Choudhury A, Maiwall R, Mitra LG, Saluja V, et al. Treatment with carvedilol improves survival of patients with acute-onchronic liver failure: A randomized controlled trial. Hepatology International. 2019;**13**:800-813

[50] Nadim MK, Durand F, Kellum JA, Levitsky J, O'Leary JG, Karvellas CJ,

[48] Mookerjee RP, Pavesi M,

2016;**64**:574-582

International. 2015;**9**:534-542

2013;**57**:1153-1162

2012;**142**:782-789

**120**

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[60] Brandstrup B, Tonnesen H, Beier-Holgersen R, Hjortso E, Ording H, Lindorff-Larsen K, et al. Effects of intravenous fluid restriction on postoperative complications: Comparison of two perioperative fluid regimens: A randomized assessorblinded multicenter trial. Annals of Surgery. 2003;**238**:641-648

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[62] Humphrey H, Hall J, Sznajder I, Silverstein M, Wood L. Improved survival in ARDS patients associated with a reduction in pulmonary capillary wedge pressure. Chest. 1990;**97**:1176-1180

[63] Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. The New England Journal of Medicine. 2004;**350**:2247-2256

[64] Myburgh JA, Mythen MG. Resuscitation fluids. The New England Journal of Medicine. 2013;**369**:1243-1251

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[66] Banares R, Bernardi M. Long-term albumin administration in patients with decompensated cirrhosis. It is time for a reappraisal. Liver International. 2019;**39**:45-48

[67] Ortega R, Gines P, Uriz J, Cardenas A, Calahorra B, De Las HD, et al. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: Results of a prospective, nonrandomized study. Hepatology. 2002;**36**:941-948

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Hepatology. 2002;**35**:140-148

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[91] Fernández J, Acevedo J, Wiest R, Gustot T, Amoros A, Deulofeu C, et al. Bacterial and fungal infections in acuteon-chronic liver failure: Prevalence, characteristics and impact on prognosis.

[93] Blasco-Algora S, Masegosa-Ataz J, Gutiérrez-García ML, Alonso-López S, Fernández-Rodríguez C. Acute-onchronic liver failure: Pathogenesis, prognostic factors and management. World Journal of Gastroenterology.

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2014;**21**:12125-12140

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Disease. 2001;**33**:41-48

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Bacterial infection in patients with advanced cirrhosis: A multicentre prospective study. Digestive and Liver Disease. 2001;**33**:41-48

*Liver Pathology*

2012;**57**:759-765

[72] Sola-Vera J, Minana J, Ricart E, Planella M, Gonzalez B, Torras X, et al. Randomized trial comparing albumin and saline in the prevention of paracentesis-induced circulatory dysfunction in cirrhotic patients with ascites. Hepatology. 2003;**37**:1147-1153

septic shock patients. Critical Care.

Dabbagh O, Tamim HM, Rishu AH, Al-Abdulkareem A, et al. Low-dose hydrocortisone in patients with cirrhosis

[81] Harry R, Auzinger G, Wendon J. The effects of supraphysiological doses of corticosteroids in hypotensive liver failure. Liver International.

Wendon J. The clinical importance of adrenal insufficiency in acute hepatic dysfunction. Hepatology.

[83] Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;**288**:862-871

[84] Tsai MH, Peng YS, Chen YC, Liu NJ, Ho YP, Fang JT, et al. Adrenal insufficiency in patients with cirrhosis,

severe sepsis and septic shock. Hepatology. 2006;**43**:673-681

and risk of hospitalisation for

[85] Gronbaek H, Johnsen SP, Jepsen P, Gislum M, Vilstrup H, Tage-Jensen U, et al. Liver cirrhosis, other liver diseases,

intracerebral haemorrhage: A Danish population-based case-control study. BMC Gastroenterology. 2008;**8**:16

[86] Vilstrup H, Gluud C, Hardt F, Kristensen M, Kohler O, Melgaard B, et al. Branched chain enriched amino acid versus glucose treatment of hepatic encephalopathy. A double-blind study of 65 patients with cirrhosis. Journal of

Hepatology. 1990;**10**:291-296

[87] Borzio M, Salerno F, Piantoni L, Cazzaniga M, Angeli P, Bissoli F, et al.

and septic shock: A randomized

[80] Arabi YM, Aljumah A,

controlled trial. CMAJ. 2010;**182**:1971-1977

[82] Harry R, Auzinger G,

2005;**9**:212-222

2003;**23**:71-77

2002;**36**:395-402

[73] Guevara M, Terra C, Nazar A, Sola E, Fernandez J, Pavesi M, et al. Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study. Journal of Hepatology.

[74] Thevenot T, Bureau C, Oberti F, Anty R, Louvet A, Plessier A, et al. Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial. Journal of Hepatology. 2015;**62**:822-830

[75] De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, et al.

Comparison of dopamine and norepinephrine in the treatment of shock. New England Journal of Medicine. 2010;**362**:779-789

[76] Albanese J, Leone M,

2005;**33**:1897-1902

2002;**359**:1209-1210

2004;**30**:597-604

Delmas A, Martin C. Terlipressin or norepinephrine in hyperdynamic septic shock: A prospective, randomized study. Critical Care Medicine.

[77] O'Brien A, Clapp L, Singer M. Terlipressin for norepinephrineresistant septic shock. Lancet.

[78] Morelli A, Rocco M, Conti G, Orecchioni A, De Gaetano A, Cortese G, et al. Effects of terlipressin on systemic and regional haemodynamics in catecholamine-treated hyperkinetic septic shock. Intensive Care Medicine.

[79] Delmas A, Leone M, Rousseau S, Albanese J, Martin C. Clinical review: Vasopressin and terlipressin in

**122**

[88] Jalan R, Fernández J, Wiest R, Schnabl B, Moreau R, Angeli P, et al. Bacterial infections in cirrhosis: A position statement based on the EASL special conference 2013. Journal of Hepatology. 2014;**60**:1310-1324

[89] Fernández J, Navasa M, Gómez J, Colmenero J, Vila J, Arroyo V, et al. Bacterial infections in cirrhosis: Epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology. 2002;**35**:140-148

[90] Merli M, Lucidi C, Giannelli V, Giusto M, Riggio O, Falcone M, et al. Cirrhotic patients are at risk for health care-associated bacterial infections. Clinical Gastroenterology and Hepatology. 2010;**8**:979-985

[91] Fernández J, Acevedo J, Wiest R, Gustot T, Amoros A, Deulofeu C, et al. Bacterial and fungal infections in acuteon-chronic liver failure: Prevalence, characteristics and impact on prognosis. Gut. 2018;**67**:1870-1880

[92] Arvaniti V, D'Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology. 2010;**139**:1246-1256

[93] Blasco-Algora S, Masegosa-Ataz J, Gutiérrez-García ML, Alonso-López S, Fernández-Rodríguez C. Acute-onchronic liver failure: Pathogenesis, prognostic factors and management. World Journal of Gastroenterology. 2014;**21**:12125-12140

[94] Hernaez R, Solà E, Moreau R, Ginès P. Acute-on-chronic liver failure: An update. Gut. 2017;**66**:541-553

[95] Gupta T, Dhiman R, Rathi S, Agrawal S, Duseja A, Taneja S, et al. Impact of hepatic and extrahepatic insults on the outcome of acuteon-chronic liver failure. Journal of Clinical and Experimental Hepatology. 2017;**7**:9-15

[96] Chaulk J, Charbonneau M, Qamar H, Keough A, Chang HJ, Ma M, et al. Third-generation cephalosporinresistant spontaneous bacterial peritonitis: A single-center experience and summary of existing studies. Canadian Journal of Gastroenterology & Hepatology. 2014;**28**:83-88

[97] Campillo B, Richardet JP, Kheo T, Dupeyron C. Nosocomial spontaneous bacterial peritonitis and bacteremia in cirrhotic patients: Impact of isolate type on prognosis and characteristics of patients. Clinical Infectious Diseases. 2002;**35**:1-10

[98] Tandon P, Delisle A, Topal JE, Garcia-Tsao G. High prevalence of antibiotic-resistant bacterial infections among patients with cirrhosis at a US liver center. Clinical Gastroenterology and Hepatology. 2012;**10**:1291-1298

[99] Piano S, Singh V, Caraceni P, Maiwall R, Alessandria C, Fernandez J, et al. Epidemiology and effects of bacterial infection in cirrhosis worldwide. Gastroenterology. 2019;**156**:1368-1380

[100] Nahon P, Lescat M, Layese R, Bourcier V, Talmat N, Allam S, et al. Bacterial infection compensated viral cirrhosis impairs 5-year survival (ANRS CO12 Cir Vir prospective cohort). Gut. 2017;**66**:330-341

[101] Dionigi E, Garcovich M, Borzio M, Leandro G, Majumdar A, Tsami A, et al. Bacterial infections change natural history of cirrhosis irrespective of liver disease severity. The American Journal of Gastroenterology. 2017;**112**:588-596

[102] Salerno F, Borzio M, Pedicino C, Simonetti R, Rossini A, Boccia S, et al. The impact of infection by multidrugresistant agents in patients with cirrhosis: A multicenter prospective study. Liver International. 2017;**37**:71-79

[103] Park JK, Lee CH, Kim HI, Kim SM, Jang JW, Kim SH, et al. Clinical characteristics and prognostic impact of bacterial infections in hospitalized patients with alcoholic liver disease. Journal of Korean Medical Science. 2015;**30**:598-605

[104] Jain M, Varghese J, Michael T, Kedarishetty CKGB, Swaminathan S, Venkataraman J. An insight into antibiotic resistance to bacterial infection in chronic liver disease. Journal of Clinical and Experimental Hepatology. 2017;**7**:305-309

[105] Zhao R, Ma J, Li P, Fang H, Sun S, Wu W, et al. Multidrug-resistant bacterial infections in cirrhotic patients: An epidemiological study. Expert Review of Gastroenterology & Hepatology. 2018;**5**:1-8

[106] Fernández J, Prado V, Trebicka J, Amoros A, Gustot T, Wiest R, et al. Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe. Journal of Hepatology. 2019;**70**:398-411

[107] Verma N, Singh S, Taneja S, Duseja A, Singh V, Dhiman RK, et al. Invasive fungal infections amongst patients with acute-on-chronic liver failure at high risk for fungal infections. Liver International. 2019;**39**:503-513

[108] Galbois A, Aegerter P, Martel-Samb P, Housset C, Thabut D, Offenstadt G, et al. Improved prognosis of septic shock inpatients with cirrhosis: A multicenter study. Critical Care Medicine. 2014;**42**:1666-1675

[109] Gravito-Soares M, Gravito-Soares E, Lopes S, Ribeiro G, Figueiredo P. Spontaneous fungal peritonitis: A rare but severe complication of liver cirrhosis. European Journal of Gastroenterology & Hepatology. 2017;**29**:1010-1016

[110] Hwang SY, Yu SJ, Lee JH, Kim JS, Yoon JW, Kim YJ, et al. Spontaneous fungal peritonitis: A severe complication in patients with advanced liver cirrhosis. European Journal of Clinical Microbiology & Infectious Diseases. 2014;**33**:259-264

[111] Bassetti M, Peghin M, Carnelutti A, Righi E, Merelli M, Ansaldi F, et al. Clinical characteristics and predictors of mortality in cirrhotic patients with candidemia and intraabdominal candidiasis: A multicenter study. Intensive Care Medicine. 2017;**43**:509-518

[112] Fernández J, Tandon P, Mensa J, Garcia-Tsao G. Antibiotic prophylaxis in cirrhosis: Good and bad. Hepatology. 2016;**63**:2019-2031

[113] Fernández J, Acevedo J, Castro M, Garcia O, Rodríguez de Lope C, Roca D, et al. Prevalence and risk factors of infections by multi resistant bacteria in cirrhosis: A prospective study. Hepatology. 2012;**55**:1551-1561

[114] Fernández J, Bert F, Nicolas-Chanoine MH. The challenges of multi- drug-resistance in hepatology. Journal of Hepatology. 2016;**65**:1043-1054

[115] Di Gregorio V, Lucidi C, Giannelli V, Lattanzi B, Giusto M, Iacovone G, et al. Bacterial infections in cirrhotic patients: Risk factors and rate of failure of the empirical antibiotic therapy. Journal of Hepatology. 2014;**60**:S227

[116] Merli M, Lucidi C, Di Gregorio V, Falcone M, Giannelli V, Lattanzi B, et al. The spread of multi drug resistant infections is leading to an increase in the

**125**

*Acute on Chronic Liver Failure: Role of the Bacterial Infections*

A prospective multicentre study of the epidemiology and outcomes of bloodstream infection in cirrhotic patients. Clinical Microbiology and Infection. 2018;**24**:546 e1-546 e8

[124] Laxminarayan R, Chaudhury RR. Antibiotic resistance in India: Drivers and opportunities for action. Plo S Med.

[125] Piroth L, Pechinot A, Minello A, Jaulhac B, Patry I, Hadou T, et al. Bacterial epidemiology and antimicrobial resistance in ascitic fluid: A 2-year retrospective study. Scandinavian Journal of Infectious

[126] Novovic S, Semb S, Olsen H, Moser C, Knudsen JD, Homann C. First-line treatment with cephalosporins

peritonitis provides poor antibiotic coverage. Scandinavian Journal of Gastroenterology. 2012;**47**:212-216

Miedaner M, Schmid RM, Huber W. Failure of current antibiotic first-line regimens and mortality in hospitalized patients with spontaneous bacterial peritonitis. Infection. 2009;**37**:2-8

[128] Alexopoulou A, Vasilieva L, Agiasotelli D, Siranidi K, Pouriki S, Tsiriga A, et al. Extensively drug-resistant bacteria are an independent predictive factor of mortality in 130 patients with spontaneous bacterial peritonitis or spontaneous bacteremia. World Journal of Gastroenterology. 2016;**22**:4049-4055

[129] Sargenti K, Prytz H, Strand A, Nilsson E, Kalaitzakis E. Healthcareassociated and nosocomial bacterial infections in cirrhosis: Predictors and impact on outcome. Liver International.

[130] Yang et al. Bacterial infections in acute-on-chronic liver failure. Seminars in Liver Disease. 2018;**38**:121-133

2015;**35**:391-400

2016;**13**(3):e1001974

Diseases. 2009;**37**:2-8

in spontaneous bacterial

[127] Umgelter A, Reindl W,

*DOI: http://dx.doi.org/10.5772/intechopen.93440*

[117] Ariza X, Castellote J, Lora-Tamayo J, Girbau A, Salord S, Rota R, et al. Risk factors for resistance to ceftriaxone and its impact on mortality in community, healthcare and nosocomial spontaneous

bacterial peritoni tis. Journal of Hepatology. 2012;**56**:825-832

[118] Carlet J, Pulcini C, Piddock LJV. Antibiotic resistance: a geopolitical issue. Clinical Microbiology and Infection. 2014;**20**:949-953

[119] Magiorakos A-P, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrugresistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clinical Microbiology and Infection.

[120] Song KH, Jeon JH, Park WB, Park SW, Kim HB, Oh MD, et al. Clinical outcomes of spontaneous bacterial peritonitis due to extended-spectrum beta-lactamase-producing *Escherichia coli* and *Klebsiella* species: A retrospective matched case-control study. BMC Infectious Diseases. 2009;**9**:41-46

[121] Cheong HS, Kang CI, Lee JA, Moon SY, Joung MK, Chung DR, et al. Clinical significance and outcome of nosocomial acquisition of spontaneous bacterial peritonitis in patients with liver cirrhosis. Clinical Infectious Diseases. 2009;**48**:1230-1236

[122] Bartoletti M, Giannella M,

Hepatology. 2014;**61**:51-58

Caraceni P, Domenicali M, Ambretti S, Tedeschi S, et al. Epidemiology and outcomes of bloodstream infection in patients with cirrosis. Journal of

[123] Bartoletti M, Giannella M, Lewis R, Caraceni P, Tedeschi S, Paul M, et al.

2012;**18**:268-281

empirical antibiotic treatment failure in cirrhosis: A prospective survey. PLoS

One. 2015;**10**:e0121448

*Acute on Chronic Liver Failure: Role of the Bacterial Infections DOI: http://dx.doi.org/10.5772/intechopen.93440*

empirical antibiotic treatment failure in cirrhosis: A prospective survey. PLoS One. 2015;**10**:e0121448

*Liver Pathology*

[102] Salerno F, Borzio M, Pedicino C, Simonetti R, Rossini A, Boccia S, et al. The impact of infection by multidrugresistant agents in patients with cirrhosis: A multicenter prospective study. Liver International. 2017;**37**:71-79 Ribeiro G, Figueiredo P. Spontaneous fungal peritonitis: A rare but severe complication of liver cirrhosis.

European Journal of Gastroenterology & Hepatology. 2017;**29**:1010-1016

[110] Hwang SY, Yu SJ, Lee JH, Kim JS, Yoon JW, Kim YJ, et al. Spontaneous fungal peritonitis: A severe complication

cirrhosis. European Journal of Clinical Microbiology & Infectious Diseases.

[111] Bassetti M, Peghin M, Carnelutti A, Righi E, Merelli M, Ansaldi F, et al. Clinical characteristics and predictors of mortality in cirrhotic patients with candidemia and intra-

abdominal candidiasis: A multicenter study. Intensive Care Medicine.

[112] Fernández J, Tandon P, Mensa J, Garcia-Tsao G. Antibiotic prophylaxis in cirrhosis: Good and bad. Hepatology.

[113] Fernández J, Acevedo J, Castro M, Garcia O, Rodríguez de Lope C, Roca D, et al. Prevalence and risk factors of infections by multi resistant bacteria in cirrhosis: A prospective study. Hepatology. 2012;**55**:1551-1561

Nicolas-Chanoine MH. The challenges

in patients with advanced liver

2014;**33**:259-264

2017;**43**:509-518

2016;**63**:2019-2031

[114] Fernández J, Bert F,

2016;**65**:1043-1054

2014;**60**:S227

of multi- drug-resistance in hepatology. Journal of Hepatology.

[115] Di Gregorio V, Lucidi C, Giannelli V, Lattanzi B, Giusto M, Iacovone G, et al. Bacterial infections in cirrhotic patients: Risk factors and rate of failure of the empirical antibiotic

therapy. Journal of Hepatology.

[116] Merli M, Lucidi C, Di Gregorio V, Falcone M, Giannelli V, Lattanzi B, et al. The spread of multi drug resistant infections is leading to an increase in the

[103] Park JK, Lee CH, Kim HI,

[104] Jain M, Varghese J, Michael T, Kedarishetty CKGB, Swaminathan S, Venkataraman J. An insight into antibiotic resistance to bacterial infection in chronic liver disease. Journal of Clinical and Experimental Hepatology. 2017;**7**:305-309

[105] Zhao R, Ma J, Li P, Fang H,

bacterial infections in cirrhotic patients: An epidemiological study. Expert Review of Gastroenterology &

Hepatology. 2018;**5**:1-8

Sun S, Wu W, et al. Multidrug-resistant

[106] Fernández J, Prado V, Trebicka J, Amoros A, Gustot T, Wiest R, et al. Multidrug-resistant bacterial infections

in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe. Journal of Hepatology. 2019;**70**:398-411

[107] Verma N, Singh S, Taneja S, Duseja A, Singh V, Dhiman RK, et al. Invasive fungal infections amongst patients with acute-on-chronic liver failure at high risk for fungal infections. Liver International. 2019;**39**:503-513

[108] Galbois A, Aegerter P,

[109] Gravito-Soares M, Gravito-Soares E, Lopes S,

Martel-Samb P, Housset C, Thabut D, Offenstadt G, et al. Improved prognosis of septic shock inpatients with cirrhosis: A multicenter study. Critical Care Medicine. 2014;**42**:1666-1675

2015;**30**:598-605

Kim SM, Jang JW, Kim SH, et al. Clinical characteristics and prognostic impact of bacterial infections in hospitalized patients with alcoholic liver disease. Journal of Korean Medical Science.

**124**

[117] Ariza X, Castellote J, Lora-Tamayo J, Girbau A, Salord S, Rota R, et al. Risk factors for resistance to ceftriaxone and its impact on mortality in community, healthcare and nosocomial spontaneous bacterial peritoni tis. Journal of Hepatology. 2012;**56**:825-832

[118] Carlet J, Pulcini C, Piddock LJV. Antibiotic resistance: a geopolitical issue. Clinical Microbiology and Infection. 2014;**20**:949-953

[119] Magiorakos A-P, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrugresistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clinical Microbiology and Infection. 2012;**18**:268-281

[120] Song KH, Jeon JH, Park WB, Park SW, Kim HB, Oh MD, et al. Clinical outcomes of spontaneous bacterial peritonitis due to extended-spectrum beta-lactamase-producing *Escherichia coli* and *Klebsiella* species: A retrospective matched case-control study. BMC Infectious Diseases. 2009;**9**:41-46

[121] Cheong HS, Kang CI, Lee JA, Moon SY, Joung MK, Chung DR, et al. Clinical significance and outcome of nosocomial acquisition of spontaneous bacterial peritonitis in patients with liver cirrhosis. Clinical Infectious Diseases. 2009;**48**:1230-1236

[122] Bartoletti M, Giannella M, Caraceni P, Domenicali M, Ambretti S, Tedeschi S, et al. Epidemiology and outcomes of bloodstream infection in patients with cirrosis. Journal of Hepatology. 2014;**61**:51-58

[123] Bartoletti M, Giannella M, Lewis R, Caraceni P, Tedeschi S, Paul M, et al.

A prospective multicentre study of the epidemiology and outcomes of bloodstream infection in cirrhotic patients. Clinical Microbiology and Infection. 2018;**24**:546 e1-546 e8

[124] Laxminarayan R, Chaudhury RR. Antibiotic resistance in India: Drivers and opportunities for action. Plo S Med. 2016;**13**(3):e1001974

[125] Piroth L, Pechinot A, Minello A, Jaulhac B, Patry I, Hadou T, et al. Bacterial epidemiology and antimicrobial resistance in ascitic fluid: A 2-year retrospective study. Scandinavian Journal of Infectious Diseases. 2009;**37**:2-8

[126] Novovic S, Semb S, Olsen H, Moser C, Knudsen JD, Homann C. First-line treatment with cephalosporins in spontaneous bacterial peritonitis provides poor antibiotic coverage. Scandinavian Journal of Gastroenterology. 2012;**47**:212-216

[127] Umgelter A, Reindl W, Miedaner M, Schmid RM, Huber W. Failure of current antibiotic first-line regimens and mortality in hospitalized patients with spontaneous bacterial peritonitis. Infection. 2009;**37**:2-8

[128] Alexopoulou A, Vasilieva L, Agiasotelli D, Siranidi K, Pouriki S, Tsiriga A, et al. Extensively drug-resistant bacteria are an independent predictive factor of mortality in 130 patients with spontaneous bacterial peritonitis or spontaneous bacteremia. World Journal of Gastroenterology. 2016;**22**:4049-4055

[129] Sargenti K, Prytz H, Strand A, Nilsson E, Kalaitzakis E. Healthcareassociated and nosocomial bacterial infections in cirrhosis: Predictors and impact on outcome. Liver International. 2015;**35**:391-400

[130] Yang et al. Bacterial infections in acute-on-chronic liver failure. Seminars in Liver Disease. 2018;**38**:121-133

[131] European Center for Disease Prevention and Control. Antimicrobial Resistance Surveillance in Europe. 2013. Avaialble from: http://ecdc.europa.eu/en/ publi-cations/Publications/antimicrobialresistance-europe-2013.pdf

[132] Arabi YM, Dara SI, Memish Z, et al. Antimicrobial therapeutic determinants of outcomes from septic shock among patients with cirrhosis. Hepatology. 2012;**56**:2305-2315

[133] Acevedo J. Multiresistant bacterial infections in liver cirrhosis: Clinical impact and new empirical antibiotic treatment policies. World Journal of Hepatology. 2015;**7**(7):916

[134] Dupeyron C, Campillo B, Mangeney N, Bordes M, Richardet JP, Leluan G. Carriage of *Staphylococcus aureus* and gram-negative bacilli resistant to third generation cephalosporins in cirrhotic patients a prospective assessment of hospitalacquired infections. Infection Control and Hospital Epidemiology. 2001;**22**:427-432

[135] Bassetti M, Merelli M, Temperoni C, Astilean A. New antibiotics for bad bugs: Where are we? Annals of Clinical Microbiology and Antimicrobials. 2013;**12**:22

[136] Wieser A, Li H, Zhang J, Liss I, Markwardt D, Hornung R, et al. Evaluating the best empirical antibiotic therapy in patients with acute-onchronic liver failure and spontaneous bacterial peritonitis. Digestive and Liver Disease. 2019;**51**:1300-1307

[137] Dryden M. Linezolid pharmacokinetics and pharmacodynamics in clinical treatment. The Journal of Antimicrobial Chemotherapy. 2011;**66**(Suppl. 4):iv7-iv15

[138] Marsot A, Boulamery A, Bruguerolle B, Simon N. Vancomycin: A review of population pharmacokinetic

analyses. Clinical Pharmacokinetics. 2012;**51**:1-13

[139] Cardone KE, Lodise TP, Patel N, Hoy CD, Meola S, Manley HJ, et al. Pharmacokinetics and pharmacodynamics of intravenous daptomycin during continuous ambulatory peritoneal dialysis. Clinical Journal of the American Society of Nephrology. 2011;**6**:1081-1088

[140] Ulldemolins M, Vaquer S, Llauradó-Serra M, Pontes C, Calvo G, Soy D, et al. Beta-lactam dosing in critically ill patients with septic shock and continuous renal replacement therapy. Critical Care. 2014;**18**:227

[141] Karjagin J, Lefeuvre S, Oselin K, Kipper K, Marchand S, Tikkerberi A, et al. Phar-macokinetics of meropenem determined by microdialysis in the peritoneal fluid of patients with severe peritonitis associated with septic shock. Clinical Pharmacology and Therapeutics. 2008;**83**:452-459

[142] Bert F, Larroque B, Dondero F, Durand F, Paugam-Burtz C, Belghiti J, et al. Risk factors associated with preoperative fecal carriage of extendedspectrum b-lactamase-producing Enterobacteriaceae in liver transplant recipients. Transplant Infectious Disease. 2014;**16**:84-89

[143] Crum-Cianflone NF, Sullivan E, Ballon-Landa G. Fecal microbiota transplantation and successful resolution of multidrug-resistant-organism colonization. Journal of Clinical Microbiology. 2015;**53**:1986-1989

[144] Naas T, Cuzon G, Truong H, Bernabeu S, Nordmann P. Evaluation of a DNA microarray, the checkpoints ESBL/KPC array, for rapid detection of TEM, SHV, and CTX-M extended-spectrum b-lactamases and KPC carbapenemases. Antimicrobial Agents and Chemotherapy. 2010;**54**:3086-3092

**127**

clinre

*Acute on Chronic Liver Failure: Role of the Bacterial Infections*

*DOI: http://dx.doi.org/10.5772/intechopen.93440*

[145] Mancini N, Infurnari L, Ghidoli N, Valzano G, Clementi N, Burioni R, et al. Potential impact of a microarray-based nucleic acid assay for rapid detection of Gram-negative bacteria and resistance markers in positive blood cultures. Journal of Clinical Microbiology.

[146] Perez KK, Olsen RJ, Musick WL, Cernoch PL, Davis JR, Peterson LE, et al. Integrating rapid diagnostics and antimicrobial stewardship improves outcomes in patients with antibiotic-resistant Gram-negative bacteremia. The Journal of Infection.

[147] Kaki R, Elligsen M, Walker S, Simor A, Palmay L, Daneman N. Impact of antimicrobial stewardship in critical care: A systematic review. The Journal of Antimicrobial Chemotherapy.

[148] Kollef M, Micek S, Hampton N, Doherty JA, Kumar A. Septicshock attributed to Candida infection: Importance of empiric therapy and source control. Clinical Infectious Diseases. 2012;**54**:1739-1746

[149] Allaire M et al. Management of infections in patients with cirrhosis in the context of increasing therapeutic resistance: A systematic review. Clinics and Research in Hepatology and Gastroenterology. 2019. DOI: 10.1016/j.

[150] Yeoh SF, Lee TJ, Chew KL,

Resistance. 2018;**11**:805-819

Lin S, Yeo D, Setia S. Echinocandins for management of invasive candidiasis in patients with liver disease and liver transplantation. Infection and Drug

2014;**52**:1242-1245

2014;**69**:216-225

2011;**66**:1223-1230

*Acute on Chronic Liver Failure: Role of the Bacterial Infections DOI: http://dx.doi.org/10.5772/intechopen.93440*

[145] Mancini N, Infurnari L, Ghidoli N, Valzano G, Clementi N, Burioni R, et al. Potential impact of a microarray-based nucleic acid assay for rapid detection of Gram-negative bacteria and resistance markers in positive blood cultures. Journal of Clinical Microbiology. 2014;**52**:1242-1245

*Liver Pathology*

[131] European Center for Disease Prevention and Control. Antimicrobial Resistance Surveillance in Europe. 2013. Avaialble from: http://ecdc.europa.eu/en/ publi-cations/Publications/antimicrobial-

[132] Arabi YM, Dara SI, Memish Z, et al. Antimicrobial therapeutic determinants of outcomes from septic shock among patients with cirrhosis. Hepatology.

analyses. Clinical Pharmacokinetics.

[139] Cardone KE, Lodise TP, Patel N,

ambulatory peritoneal dialysis. Clinical Journal of the American Society of Nephrology. 2011;**6**:1081-1088

Hoy CD, Meola S, Manley HJ, et al. Pharmacokinetics and pharmacodynamics of intravenous daptomycin during continuous

[140] Ulldemolins M, Vaquer S, Llauradó-Serra M, Pontes C, Calvo G, Soy D, et al. Beta-lactam dosing in critically ill patients with septic shock and continuous renal replacement therapy. Critical Care. 2014;**18**:227

[141] Karjagin J, Lefeuvre S, Oselin K, Kipper K, Marchand S, Tikkerberi A, et al. Phar-macokinetics of meropenem determined by microdialysis in the peritoneal fluid of patients with severe peritonitis associated with septic shock. Clinical Pharmacology and Therapeutics. 2008;**83**:452-459

[142] Bert F, Larroque B, Dondero F, Durand F, Paugam-Burtz C, Belghiti J, et al. Risk factors associated with preoperative fecal carriage of extendedspectrum b-lactamase-producing Enterobacteriaceae in liver transplant recipients. Transplant Infectious

[143] Crum-Cianflone NF, Sullivan E, Ballon-Landa G. Fecal microbiota transplantation and successful resolution of multidrug-resistant-organism colonization. Journal of Clinical Microbiology. 2015;**53**:1986-1989

[144] Naas T, Cuzon G, Truong H, Bernabeu S, Nordmann P. Evaluation of a DNA microarray, the checkpoints ESBL/KPC array, for rapid detection of TEM, SHV, and CTX-M extended-spectrum b-lactamases and KPC carbapenemases. Antimicrobial

Agents and Chemotherapy.

2010;**54**:3086-3092

Disease. 2014;**16**:84-89

2012;**51**:1-13

[133] Acevedo J. Multiresistant bacterial infections in liver cirrhosis: Clinical impact and new empirical antibiotic treatment policies. World Journal of

resistance-europe-2013.pdf

Hepatology. 2015;**7**(7):916

[134] Dupeyron C, Campillo B, Mangeney N, Bordes M, Richardet JP, Leluan G. Carriage of *Staphylococcus aureus* and gram-negative bacilli resistant to third generation

cephalosporins in cirrhotic patients a prospective assessment of hospitalacquired infections. Infection Control and Hospital Epidemiology.

antibiotics for bad bugs: Where are we? Annals of Clinical Microbiology and

Liss I, Markwardt D, Hornung R, et al. Evaluating the best empirical antibiotic therapy in patients with acute-onchronic liver failure and spontaneous bacterial peritonitis. Digestive and Liver

2012;**56**:2305-2315

2001;**22**:427-432

[135] Bassetti M, Merelli M, Temperoni C, Astilean A. New

Antimicrobials. 2013;**12**:22

[136] Wieser A, Li H, Zhang J,

Disease. 2019;**51**:1300-1307

[138] Marsot A, Boulamery A,

Bruguerolle B, Simon N. Vancomycin: A review of population pharmacokinetic

[137] Dryden M. Linezolid pharmacokinetics and pharmacodynamics in clinical treatment. The Journal of Antimicrobial Chemotherapy. 2011;**66**(Suppl. 4):iv7-iv15

**126**

[146] Perez KK, Olsen RJ, Musick WL, Cernoch PL, Davis JR, Peterson LE, et al. Integrating rapid diagnostics and antimicrobial stewardship improves outcomes in patients with antibiotic-resistant Gram-negative bacteremia. The Journal of Infection. 2014;**69**:216-225

[147] Kaki R, Elligsen M, Walker S, Simor A, Palmay L, Daneman N. Impact of antimicrobial stewardship in critical care: A systematic review. The Journal of Antimicrobial Chemotherapy. 2011;**66**:1223-1230

[148] Kollef M, Micek S, Hampton N, Doherty JA, Kumar A. Septicshock attributed to Candida infection: Importance of empiric therapy and source control. Clinical Infectious Diseases. 2012;**54**:1739-1746

[149] Allaire M et al. Management of infections in patients with cirrhosis in the context of increasing therapeutic resistance: A systematic review. Clinics and Research in Hepatology and Gastroenterology. 2019. DOI: 10.1016/j. clinre

[150] Yeoh SF, Lee TJ, Chew KL, Lin S, Yeo D, Setia S. Echinocandins for management of invasive candidiasis in patients with liver disease and liver transplantation. Infection and Drug Resistance. 2018;**11**:805-819

**Chapter 7**

**Abstract**

four variation types.

**1. Introduction**

in preventing serious complications.

tears.

**129**

Left Side Gallbladder: Clinical and

Left side gallbladder is a rare anatomical anomaly reported in the literature. It is associated with various anatomical variations of the biliary way and intrahepatic portal supply. Most of the time, it is discovered as an incidental finding during intervention for cholecystectomy, exposing patients and surgeons to high risk of complication. To prevent this, we analyze the critical aspects that must be known to perform safe interventions either in the normal setting or in the emergency setting. Different theories are proposed to describe this anomaly, but a debate is still open. Reviewing the literature and analyzing the different processes of formation, we create a classification that can explain how this anomaly can occur, dividing into

**Keywords:** left side, gallbladder, fusion of plans, liver resection, biliary, agenesis,

The left side gallbladder (LSG) is a very rare alteration defined by the attachment of the gallbladder to the left lobe of the liver at the right side of the ligament

Since Hochstetter's first description in 1886 [1], about 150 cases have been reported in the literature. The attempts to explain the cause of this anomaly have been different, but the numerous variations described do not allow a clear definition of its origin. Although this debate is still open, it is of considerable importance to know that LSG is frequently associated with alterations of both the portal branches and the intrahepatic biliary tree. The association of these anomalies, therefore, represents an important risk, especially if surgical treatment is necessary. There are two cases in which surgical treatment may be required: the first is gallbladder stones and in particular acute cholecystitis, and the second is the need for liver resection surgery. In the first case, the diagnosis of gallstones and cholecystitis is made only with ultrasound, but often this method does not describe the anomaly of the LSG. In fact, in most cases described, the diagnosis is made intraoperatively, making the surgical treatment problematic and risky due to the lack of correct anatomical knowledge. In the case of liver resection, the diagnosis is made before surgery, highlighting anatomical variations that require complex dissection strategies. Knowledge of the anomalies associated with a LSG can be of considerable help

abnormality, cholecystectomy, right umbilical vein, liver, hepatic

Anatomical Implication

*Filippo Banchini and Patrizio Capelli*

#### **Chapter 7**
