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Home , Organ dysfunction, Sepsis, Septic shock

REVIEW ARTICLE Martin Mateos and Albillos

Sepsis in Patients With Awaiting Liver Transplantation: New Trends and Management Rosa Martin Mateos and Agustín Albillos Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain

Bacterial are more frequent and severe in patients with advanced liver disease and, therefore, in liver transplant candidates. The increased risk of in these patients parallels the severity of the immune dysfunction associated with cirrhosis, which is related to systemic and progressive . Other factors contribute to this risk, such as genetic polymorphisms, proton pump inhibitor overuse, the numerous invasive procedures and hospitalizations these patients go through, or the immunosuppressive effects of malnutrition or . Bacterial infections have a great impact on disease progression and significantly increase mortality rates before and after liver transplantation. Mechanisms leading to failure in are associated not only with the hemodynamic derangement but also with an excessive inflam- matory response triggered by infection. Furthermore, prophylactic and empirical treatment strategies in patients with cirrhosis are being modified according to the growing prevalence of multidrug-resistant in the past decade. Also, new criteria have been introduced for the diagnosis of sepsis and septic . These new definitions have been validated in patients with cirrhosis and show a better accuracy to predict in-hospital mortality than previous criteria based on systemic inflammatory response syndrome. Accurate prophylaxis and early identification and treatment of bacterial infections are key to reducing the burden of sepsis in patients with cirrhosis awaiting liver transplantation. Liver Transplantation 25 1700‒1709 2019 AASLD. Received April 4, 2019; accepted August 6, 2019.

Patients with cirrhosis present an increased risk of decreasing, the risk of sepsis-related has increased developing bacterial infections,(1) which are, in addition, over the past few years ( risk ratio, 4.70; 95% more severe than in the general population (estimated confidence interval, 4.61-4.79).(5) Bacterial infections overall mortality of 38%(2) and up to 70% in case of sep- are the most identifiable triggers of -on-chronic tic shock versus 10% and 40%, respectively, for a gen- (ACLF), accounting for 32% of the precipi- eral hospital population).(3,4) Notably, although overall tating events.(6) Spontaneous bacterial (SBP) mortality among hospitalized patients with cirrhosis is and urinary tract infections (UTIs) are the most fre- quent type, followed by and . Several changes in the epidemiology of bacterial Abbreviations: ACLF, acute-on-chronic liver failure; AKI, acute kidney infections have occurred over the past decade. The

injury; CAID, cirrhosis-associated immune dysfunction; DAMP, most relevant is the increasing prevalence of mul- damage-associated molecular pattern; EASL, European Association for the Study of the Liver; ESBLE, extended-spectrum ß-lactamase– tidrug-resistant (MDR) bacteria both in Europe (7) (8) producing Enterobacteriaceae; HRS, hepatorenal syndrome; ICU, (29%) and worldwide (34%). MDR pathogens ; IV, intravenous; MDR, multidrug-resistant; are resistant to at least 1 agent in 3 or more antimi- NOD2, nucleotide-binding oligomerization domain containing protein 2; PAMP, pathogen-associated molecular pattern; PMN, crobial categories. When bacteria are resistant to at polymorphonuclear leukocyte; PRR, pattern recognition receptor; least 1 agent in all but 2 or fewer cate- qSOFA, quick Sequential Organ Failure Assessment; SBP, spontaneous gories, they are considered extensively drug resistant, bacterial peritonitis; SIRS, systemic inflammatory response syndrome; and when not susceptible to any currently available SOFA, Sequential Organ Failure Assessment; TLR2, toll-like receptor (9) 2; UTI, ; VATS, video-assisted thoracoscopic agent, they are defined as pandrug-resistant bacteria. ; VRE, -resistant enterococci; WBC, white cell. The most common MDR pathogens are extended- spectrum ß-lactamase–producing Enterobacteriaceae

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(ESBLE; ie, and pneumoniae), interactions between the gut and the liver. The intes- AmpC ß-lactamase–producing Enterobacteriaceae tinal surface is formed by physical defenses, includ- (ie, Enterobacter and spp.), carbapene- ing a layer of epithelial cells interconnected by tight mase-producing Enterobacteriaceae (ie, Klebsiella spp., junctions, and functional defenses, such as the mucous E. Coli, and Enterobacter spp.), methicillin-resistant layer. The intestinal barrier displays a unique immune aureus, and vancomycin-resistant entero- system capable of distinguishing between regular nu- cocci (VRE; ie, Enterococcus faecium). trient flux, self-, a diverse milieu of commen- A higher susceptibility to infections significantly sal bacteria, and invading pathogens. increases morbidity and mortality and, thus, deterio- Cirrhosis is associated with profound alterations rates the quality of life of patients with cirrhosis await- at different levels of the intestinal barrier. Dysbiosis ing liver transplantation. Strategies aimed at improving (reduced abundance of protective bacteria and diagnosis of infection, prophylaxis, and treatment are increased pathogenic species) and bacterial overgrowth therefore needed. This review examines the mecha- are a result of intestinal hypomotility, changes in bile nisms responsible for the high rate of bacterial infec- flow and composition, and impaired intestinal immu- tions in patients with cirrhosis and provides an overview nity. Disruption of the epithelial and vascular intestinal of the key clinical features and prognostic implications barriers enables passage of viable bacteria and patho- of sepsis in patients awaiting liver transplantation. gen-associated molecular patterns (PAMPs) through the vascular and lymphatic routes to the systemic cir- culation. Bacterial translocation is further aggravated Altered in sepsis due to alterations in , vascular tone, and that lead to a hypoxic microenviron- in Cirrhosis and Sepsis ment of the intestinal tissue. PATHOLOGICAL BACTERIAL CIRRHOSIS-ASSOCIATED IMMUNE TRANSLOCATION DYSFUNCTION The mucosa of the intestine is a highly organized Systemic inflammation due to persistent immune sys- and compartmentalized structure that controls the tem stimulation and progressive immunodeficiency characterize what is known as cirrhosis-associated (1) immune dysfunction (CAID). Immunodeficiency Address reprint requests to Agustín Albillos, M.D., Ph.D., Gastroenterology and Hepatology Department, Hospital Universitario affects cellular and soluble components of the immune Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal system both at the liver and systemically. The abnor- de Investigación Sanitaria, Centro de Investigación Biomédica en malities include the following: Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Carretera de Colmenar Viejo km 9100, 28034 Madrid, 1. Compromise of the immune surveillance function Spain. Telephone: +34 913368592; FAX: +34 913368592; E-mail: of the liver through damage of the reticuloen- [email protected] dothelial system. Supported by grants from the Spanish Ministerio de Ciencia, Innovación 2. Impaired synthesis of innate immunity proteins. y Universidades, Instituto de Salud Carlos III (number PI14/00876), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas 3. Altered functions of circulating and intestinal y Digestivas (CB06/04/0024), and Ministerio de Economía, Industria populations of immune cells (specifically reduced y Competitividad (SAF 2017-86343-R) awarded to Agustín Albillos. chemotaxis and oxidative burst of ), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas is funded by the Instituto de Salud Carlos III. Grants impaired phagocytic activity of -presenting were cofinanced by the European Development Regional Fund “A way cells, and exhaustion of the adaptive immune to achieve Europe.” response.(1,10) Copyright © 2019 by the American Association for the Study of Liver On the other hand, systemic inflammation is

Diseases. prompted by increased intestinal permeability, bac- View this article online at wileyonlinelibrary.com. terial overgrowth, and dysbiosis, which favors trans-

DOI 10.1002/lt.25621 location of bacteria and PAMPs. Specific receptors activated by PAMPs (also called pattern recognition Potential conflict of interest: Nothing to report. receptors [PRRs]) amplify proinflammatory signaling. Intracellular molecules released by injured or dead cells

Review Article | 1701 Martin Mateos and Albillos Liver Transplantation, November 2019

(damage-associated molecular patterns [DAMPs]) are Because the new definition of sepsis requires a base- also recognized by PRRs, and they contribute to per- line calculation of the SOFA score, an easy-to-use sistent systemic inflammation in cirrhosis. bedside tool called the quick Sequential Organ Failure Assessment (qSOFA) has been proposed for the prompt recognition of sepsis in patients outside ICUs. DYSFUNCTIONAL IMMUNE This score identifies patients with suspected infec- RESPONSE IN SEPSIS tion who are likely to have a poor outcome, and it is The severity of CAID parallels the severity of cir- based on the presence of at least 2 of the following rhosis, and it worsens critically with acute events. In criteria: of 22 breaths per minute or sepsis-induced ACLF, PAMPs, such as bacterial lipo- greater, altered mentation, or systolic of polysaccharides, bind to PRRs. Receptor engagement 100 mm Hg or lower.(4) activates downstream signaling pathways, which leads Piano et al. have recently validated Sepsis-3 and to increased transcription and the release of inflam- qSOFA criteria in patients with cirrhosis.(12) These new matory as well as the activation of innate scores were significantly better at predicting in-hospital immune cells. Sepsis triggers massive immune cell mortality than SIRS (area under the receiver operat- activation and overproduction of cytokines. This situ- ing characteristic curve = 0.78 for Sepsis-3, 0.73 for ation is further amplified and perpetuated by DAMPs qSOFA, and 0.61 for SIRS). In addition, patients who released by cells damaged by hypoperfusion, necrosis, met the Sepsis-3 criteria had a significantly higher and . incidence of ACLF, , and ICU admissions. Accordingly, Sepsis-3 and qSOFA are now recom- mended in clinical practice guidelines for the manage- Sepsis in Cirrhosis: Burden ment of patients with decompensated cirrhosis.(13) and Definitions

BURDEN OF SEPSIS IN CIRRHOSIS Mechanisms of Organ AND LIVER TRANSPLANT Failure in Sepsis and Clinical CANDIDATES Patients with cirrhosis are at increased risk of sepsis Approach and sepsis-related mortality.(2) Septic shock is associ- Hepatic and/or extrahepatic organ failure is the hall- ated with higher mortality rates in intensive care units mark of ACLF and serves to differentiate this syn- (ICUs) for these patients compared with patients with- drome from acute decompensation of cirrhosis. In out cirrhosis (71% versus 49%).(3) Conversely, cirrhosis sepsis-induced ACLF, the mechanisms underlying is an independent for sepsis and death.(11) organ failure are related not only to the hemodynamic derangement but also to cell dysfunction and cell death

mechanisms induced by the exacerbated inflammatory SEPSIS: A RENOVATED CONCEPT response. The number of organ failures is highly pre- In an effort to improve the diagnostic accuracy of dictive of the risk for delisting or death in liver trans- the previous definition of sepsis based on systemic plant candidates hospitalized with an infection.(14) inflammatory response syndrome (SIRS), new diag- (4) nostic criteria (Sepsis-3) have been proposed. Sepsis CARDIOVASCULAR DYSFUNCTION is now defined as a life-threatening situation because of caused by a dysregulated response Portal hypertension induces a profound hemodynamic to infection. Organ dysfunction is defined as an acute alteration characterized by peripheral , hy- change in total Sequential Organ Failure Assessment perdynamic circulation, high , and low (SOFA) score ≥2 points from baseline. Septic shock systemic vascular resistances. In sepsis-related ACLF, can be clinically identified if vasopressors are required -induced release of and reactive to maintain a ≥65 mm Hg and oxygen species contribute to arterial vasodilation, if serum lactate levels are ≥18 mg/dL in the absence of which further reduces mean arterial pressure and im- . pairs left ventricular function and tissue perfusion.(15)

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In a recent study analyzing factors associated with sur- terlipressin was as effective as , and it vival in transplanted patients with severe ACLF, it was also provided an early survival benefit (at 48 hours) found that 1-year survival was associated with a sig- and reduced the risk of variceal .(25) Therefore, nificantly lower prevalence of pretransplant circulatory or terlipressin may be used as second-line failure (50% versus 61%), which confirms the negative treatments for persistent in patients with impact of the hemodynamic dysfunction on posttrans- cirrhosis who have sepsis. plant mortality.

Fluid RENAL FAILURE Bacterial infections are the most frequent triggers of Current guidelines recommend crystalloid solutions renal failure in cirrhosis.(26) The hemodynamic dys- (normal 0.9% or pH balanced in case of hyper­ function is worsened by sepsis, which further activates chloremia) as the initial fluid of choice (10-20 mL/kg).(16) neurohumoral compensatory mechanisms that result In addition, has shown beneficial effects not in arterial renal , hypoperfusion, and only as a plasma expander but also as immunomod- renal failure. On the other hand, the excessive inflam- ulatory therapy. Albumin may counteract systemic matory response contributes to the activation of cell inflammation by binding and inactivating PAMPs, apoptosis mechanisms and mitochondrial injury, acute prostaglandins, and reactive oxygen and nitrogen spe- tubular necrosis due to capillary leukocyte infiltration, cies.(17) Low levels and altered function of albumin in and microthrombosis related to cytokine-mediated cirrhosis is associated with a higher risk of infection microvascular dysfunction.(27) The term acute kid- and death.(18) Conversely, albumin infusion improves ney injury (AKI) is now used to define renal failure survival in patients with SBP, hepatorenal syndrome in cirrhosis, including prerenal, HRS, intrinsic (acute (HRS), and circulatory dysfunction after large-volume tubular necrosis), and postrenal injury. Differentiating paracentesis.(19,20) Despite these well-known benefits, HRS-AKI (previously known as type 1 HRS) from albumin failed to improve renal function or survival in acute tubular necrosis may be challenging, and there- infections other than SBP.(21,22) Until more evidence fore, serum diagnostic are currently under supporting the use of albumin becomes available, early evaluation. Among them, urinary gelati- initiation of volume resuscitation, independently of nase-associated lipocalin, a marker of tubular injury, fluid type, will be the key factor for the hemodynamic has shown promising results.(28) management in patients with cirrhosis and sepsis. Prompt recognition and treatment of AKI is key to improving survival. Reduction or discontinuation Vasopressors of diuretics, withdrawal of all potentially nephrotoxic Vasopressor agents counteract arterial vasodilation, drugs, and plasma volume expansion if hypovolemia is increasing mean arterial pressure, cardiac preload, and suspected are the initial measures in patients presenting tissue perfusion. In cirrhosis, a mean arterial pressure with AKI.(29) In case of progression of the AKI stage, of 60 mm Hg or higher is recommended, along with complete withdrawal of diuretics and volume expan- adequate hemodynamic with arterial cath- sion with albumin (1 g/kg body weight for 2 days) are eters, central venous access, and initial echocardio- recommended to treat prerenal AKI and to perform graphic assessment in patients with circulatory shock. the . If HRS-AKI is diagnosed, A pulmonary artery should be placed in cases first-line treatment consists of terlipressin (1 mg every of or hemodynamic instability.(16) 4-6 hours) and albumin (20-40 g/day).(30) Recently, Norepinephrine has vasopressor as well as positive terlipressin infusion has shown an earlier response and inotropic effects, and it is considered the drug of choice improved survival rate when compared with norepi- for septic shock in cirrhosis and in the general pop- nephrine in patients with ACLF and HRS-AKI.(31) ulation.(23) This recommendation is based on a lower However, norepinephrine is an acceptable option mortality and incidence of arrhythmic events associ- when terlipressin is not available. Vasopressors offset ated with the use of norepinephrine as compared with the splanchnic arterial vasodilation and the activa- .(24) Terlipressin, an analogue of vasopres- tion of compensatory mechanisms that result in renal sin with a predominant vasoconstrictor effect on the vasoconstriction. The additional benefits of albumin splanchnic circulation, has also been tested in patients administration are beyond the hemodynamic effects with cirrhosis and septic shock. In a small clinical trial, and are related to its anti-inflammatory properties.(17)

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Liver transplant is the definitive treatment for accounted for 38% (S. aureus and Enterococci), and patients with HRS-AKI, which resolves in most cases fungal infections were found in 4% of patients. The after surgery (76% of patients at a mean of 13 ± 2 days most commonly isolated MDR bacteria were ESBLE, after transplant).(32) Treatment with vasoconstrictors methicillin-resistant S. aureus, VRE, Pseudomonas and albumin is recommended because improved renal aeruginosa, and . It should be function prior to transplant increases survival. Renal noted that the prevalence and type of MDR bacteria replacement therapies should be considered in non- is highly variable among centers, and so, the local epi- responding patients presenting with AKI and volume demiology must be considered before prophylaxis and overload, , hyperkalemia, or hypo- treatment strategies are implemented.(7) natremia, especially if they are potential candidates for Fungal isolation in patients with cirrhosis is an liver transplantation. infrequent event, but it entails a very poor : mortality rates associated with invasive fungal infec-

tion and colonization are 71% and 67%, respectively, at OTHER ORGAN FAILURES AND 90 days of ACLF diagnosis.(37) The incidence of fun- RELATED COMPLICATIONS gal infections increases in second infections and during (8) Sepsis not only favors cardiovascular and renal failure, the follow-up period after ACLF diagnosis, which but it also increases the risk of acute variceal bleed- reflects the progressive impairment and exhaustion of ing,(33) hepatic ,(34) and coagulation the . disorders.(35) is frequent in patients with cirrhosis who have sepsis and is associ- EMPIRICAL ANTIBIOTIC ated with hemodynamic instability, renal dysfunction, TREATMENT reduced response to norepinephrine, and poor out- comes.(36) However, it has been also described in acute Timely initiation of an adequate empirical antibiotic decompensations due to causes other than sepsis and treatment is key to improving survival in patients with (38) in nondecompensated patients. The administration sepsis. The growing incidence of MDR pathogens of has shown a significant reduction in has progressively compromised treatment success (39) vasopressor requirements and a higher rate of shock with the standard strategies, and thus, empirical reversal, so in cases of refractory hypotension, hydro- broad-spectrum , particularly in health cortisone 200-300 mg/day in divided doses has been care–related infections, are associated with higher (40) suggested.(16) The SCOTCH trial is currently testing survival rates than standard therapies. To counter- the safety and efficacy of in cirrhotic act the risk of possible antibiotic resistances, once the hypotensive patients with suspicion of sepsis (clinical- pathogen is identified, treatment should be tailored trials.gov, NCT02602210). according to microbial sensitivity. In patients who fail to respond to a broad-spectrum antibiotic course, a fungal infection should be suspected and investi- gated.(13) The empirical antibiotic treatment recom- Antibiotic Treatment mended according to the European Association for the Study of the Liver (EASL) guidelines is shown TRENDS IN EPIDEMIOLOGY: MDR PATHOGENS in Table 1. Known risk factors for MDR infections are the use The increasing prevalence of MDR bacterial infec- of systemic antibiotics, invasive procedures or expo- tions is attributed to antibiotic overuse and failure to sure to the health care environment in the previous control the spread of resistant bacteria. The problem is months,(8) presence of certain genetic polymorphisms aggravated by the scarce therapeutic options available. of proteins involved in antigen recognition,(41) overuse The global epidemiology of MDR bacterial infections of proton pump inhibitors,(42) malnutrition, and alco- in cirrhosis has been recently addressed.(8) Estimated hol abuse (Fig. 1).(43) For antibiotic selection, besides overall prevalence was 34%, yet values ranged widely the type of infection and context (community or from 73% in India to 16% in US centers. The most hospital acquired), other factors to consider are local frequent isolated pathogens were gram-negative bac- resistance rates, previous prophylactic antibiotic treat- teria (57%), mainly Enterobacteriaceae, such as E. coli ments, and prior colonization or episodes of MDR and K. pneumoniae. Gram-positive bacterial infections.

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TABLE 1. Recommended Empirical Antibiotic Treatment According to EASL Guidelines

Infection Type Community-Acquired Infection Hospital-Acquired Infection

SBP or spontaneous bacterial Third-generation cephalosporin alone or combined with daptomycin, empyema piperacillin-tazobactam, or * vancomycin, or linezolid** UTI Uncomplicated: ciprofloxacin or cotrimoxazole Uncomplicated: nitrofurantoin or fosfomycin If sepsis: third-generation cephalosporin or If sepsis: plus or vancomycin piperacillin-tazobactam Pneumonia Piperacillin-tazobactam or plus or meropenem plus levofloxacin with or without or levofloxacin or moxifloxacin glycopeptides or linezolid** Cellulitis Piperacillin-tazobactam or third-generation Third-generation cephalosporin or meropenem plus oxacillin or cephalosporin plus oxacillin glycopeptides or daptomycin or linezolid

NOTE: See Angeli et al.(13) (2018). *In countries with high rates of bacterial resistance. **If high prevalence of MDR gram positive bacteria or sepsis.

FIG. 1. Factors associated with an increased risk of infection in patients with cirrhosis awaiting liver transplantation. As cirrhosis progresses, the immune dysfunction compromises the effector response against pathogens. Patients with decompensated cirrhosis are frequently hospitalized and subjected to invasive procedures, which increases the risks of nosocomial hospital-acquired infections and bacterial translocation. Specific polymorphisms in genes related to antigen recognition have been linked to a higher infection susceptibility. Alcohol alters the quantity and composition of the and directly contributes to increased intestinal permeability. Malnutrition due to alcoholism or end-stage liver disease compromises intestinal and skin barrier integrity, alters gut microbiota, and leads to reduced levels of proteins involved in immune functions.

CURRENT STRATEGIES FOR during the postoperative period.(45-48) Rectal and

INFECTION PROPHYLAXIS nasal surveillance cultures have detected methicillin- resistant and vancomycin-resistant bacteria in 7% and Screening 15%, respectively, of liver transplant candidates.(49) Rectal swabs may serve as noninvasive screening tools In liver transplant candidates, a previous episode of to identify patients colonized by MDR pathogens who SBP or ESBLE infection and/or recent exposure to are, therefore, at a higher risk of presenting MDR in- β-lactam agents have been found to increase the risk fections in the postoperative period.(50) (44) of preoperative ESBLE colonization. On the other Recipient colonization by MDR bacteria is not a hand, pretransplant methicillin-resistant, vancomycin- contraindication for transplantation; however, contact resistant, or carbapenemase-producing bacteria col- isolation precautions, hand hygiene compliance, and onization is a strong risk factor for MDR infections antibiotic control policies are recommended.(51) Intestinal

Review Article | 1705 Martin Mateos and Albillos Liver Transplantation, November 2019 decontamination significantly reduces rectal colonization with norfloxacin (400 mg/day), which has shown to re- by gram-negative bacteria; however, the longterm benefit duce the incidence of SBP, to delay the development of is uncertain, and in addition, concerns over the poten- HRS-AKI, and to increase 3-month survival rates.(56) tial risk of selecting highly resistant strains have been Patients recovering from a first episode of SBP should raised.(52) Currently, a randomized multicenter clinical be considered for liver transplantation because survival trial aims to analyze the impact of intestinal MDR bac- drops to 30%-50% in the first year and to 25%-30% in terial colonization in liver and kidney transplant recip- the second year. In these cases, secondary prophylaxis ients, and the effect of decontamination strategies with with norfloxacin 400 mg/day is recommended to re- colistin and neomycin on reducing posttransplant infec- duce the risk of recurrence.(57) Despite promising re- tions (ENTHERE Study, EudraCT: 2013-004838-15). sults, rifaximin cannot be yet considered an alternative to norfloxacin for secondary prophylaxis.(13)

Translocation of bacteria increases the risk of infections, General Prophylaxis and thus, the use of prophylactic antibiotics may be ef- In a randomized placebo-controlled trial by Moreau fective at decreasing bacterial concentrations in the gut. et al.,(58) norfloxacin (400 mg/day) failed to reduce However, due to the potential risk of selecting highly 6-month overall mortality in patients with advanced resistant pathogens, prophylaxis should be strictly re- cirrhosis (Child C). However, a survival benefit was stricted to patients with a high risk of infection, such as found in those with an ascitic fluid protein concentra- those patients with gastrointestinal bleeding, advanced tion of <1.5 g/dL. In addition, norfloxacin significantly cirrhosis, or a previous episode of SBP. decreased the incidence of bacterial infections without increasing the risk of difficile or MDR in- Acute Gastrointestinal Bleeding fections (NORFLOCIR trial, NCT01037959). The risk of bacterial infections is greater in patients with cirrhosis presenting with acute gastrointestinal Nonantibiotic Prophylaxis bleeding than in those hospitalized for other reasons Longterm administration of albumin (40 g twice weekly (44%-66% versus 32%-34%).(53) Antibiotic prophy- for 2 weeks, and then 40 g weekly for up to 18 months) laxis decreases the risk of infection, rebleeding, and has been recently shown to increase overall survival in all-cause mortality.(53) Ceftriaxone (1 g/24 hours) is patients with cirrhosis and uncomplicated ascites.(59) recommended in patients with at least 2 of the fol- However, other authors recently showed that treatment lowing conditions: ascites, hepatic encephalopathy, with albumin and midodrine in patients awaiting liver , or severe malnutrition.(54) Ceftriaxone is transplantation failed to prevent complications (includ- also recommended in patients with active bleeding, ing infections, renal failure, hyponatremia, hepatic en- on quinolone prophylaxis on admission, with previous cephalopathy, or gastrointestinal bleeding) or improve quinolone-resistant infections, or in areas of high prev- survival.(60) Thus, feasibility, timing, and exact doses of alence of quinolone-resistant bacteria (≥20%). Oral albumin for preventing infections and improving survival quinolones (norfloxacin 400 mg/12 hours) are appro- in cirrhosis need to be further addressed. priate for all remaining cases. Guidelines suggest 7 days of antibiotic therapy; however, a shorter course may be acceptable in Child A patients or as guided by bacterial (55) Specific Considerations for cultures collected just before starting prophylaxis. Liver Transplant Candidates Spontaneous Bacterial Peritonitis Patients with advanced cirrhosis—defined as Child With Sepsis score ≥9 and serum ≥3 mg/dL, low ascitic Septic shock within 1 month before liver transplanta- fluid protein concentrations (<15 g/L), and either tion is associated with a 2.4-fold increase in transplant impaired renal function or hyponatremia—have an futility.(61) Furthermore, several studies have shown that increased risk of developing a first episode of SBP peritransplant infections and sepsis significantly increase (1-year probability of 61%). In these patients, current 90-day mortality.(61,62) However, other authors did not guidelines recommend longterm primary prophylaxis find differences in mortality if pretransplant infections

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TABLE 2. Considerations for Management and Relisting were adequately treated.(63) Therefore, careful individual Patients for Liver Transplantation After Common Bacterial and Fungal Infections assessment and a multidisciplinary approach are recom- mended to decide when a patient should be provisionally Infection Recommendations or definitively removed from the waiting list or reacti-

Asymptomatic bacteriuria or Not a contraindication vated for liver transplantation. So far, only uncontrolled (64) candiduria sepsis is considered a formal contraindication and suc- UTI with negative blood Not a contraindication; peritransplant cessfully treated prior sepsis or septic shock should not cultures antibiotic treatment preclude the intervention. Bacterial SBP 5 days of treatment Table 2 shows current recommendations for the Reactivate if repeated paracentesis management of patients on the waiting list presenting shows a 25% decrease in PMN count > bacterial or fungal infections.(16) UTIs do not generally ≥48 hours after treatment initiation contraindicate transplantation. However, pneumonia, Fungal SBP Requires a full course of therapy and a PMN count <250 cells/mm3 off bacteremia, and C. difficile diarrhea require at least 7 days treatment; always rule out secondary of antibiotic treatment and signs of clinical improve- causes ment before relisting the candidate for transplantation. Pneumonia Reactivate patients after 7 days of ≥ In the case of bacterial SBP, it is suggested to reactivate therapy when clinical improvement is documented the patient on the waiting list 48 hours after treatment ICU patients: clinical improvement is initiation if there is also a decrease in polymorphonu- required to achieve oxygen levels above clear leukocyte (PMN) count >25% in the ascitic fluid. local standards Pleural effusion requires a thoracentesis. Parapneumonic effusion requires no additional intervention Conclusions Empyema requires drainage; complete Patients with advanced liver disease are at significant course of antibiotics and VATS is sometimes required risk of bacterial infections, which has a profound clin- Central line spontaneous Antibiotics for 7-14 days ical impact and worsens prognosis. The growing inci- bacteremia Reactivation can be considered before dence of MDR bacterial infections has become a major completion of antibiotics if patient has concern. Organ failure in sepsis is related not only to documented rapid clinical improvement exces- with negative repeat blood cultures for the hemodynamic derangement but also to an ≥48 hours sive inflammatory response against pathogens. A key Completion of a course of treatment component of the management of patients with cir- with repeat negative blood cultures off rhosis who have sepsis while awaiting liver transplan- therapy is required in addition to exclusion of a secondary source tation should be to prioritize early empiric antibiotic

C. difficile diarrhea Therapy for at least 7 days is required therapy and hemodynamic resuscitation. in addition to clinical improvement and normalization of WBCs prior to reactivation. A sigmoidoscopy can be REFERENCES performed to assess mucosal healing. 1) Albillos A, Lario M, Álvarez-Mon M. Cirrhosis-associated Consider fidaxomicin or fecal microbiota immune dysfunction: distinctive features and clinical relevance. transplantation to decrease relapse rate J Hepatol 2014;61:1385-1396. and VRE colonization 2) Arvaniti V, D’Amico G, Fede G, Manousou P, Tsochatzis E, Cholecystitis Surgical intervention Pleguezuelo M, Burroughs AK. Infections in patients with cirrho- Nonoperative candidates IV antibiotics are first-line therapy sis increase mortality four-fold and should be used in determining

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1708 | Review Article Liver Transplantation, Vol. 25, No. 11, 2019 Martin Mateos and Albillos

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