Infectious Complications in Critically Ill Liver Failure Patients

Amanda Cheung, MD; Sajal Tanna, MD, MPH; Michael G. Ison, MD, MS

Disclosures

Semin Respir Crit Care Med. 2018;39(5):578-587. 

In This Article

Identification and Treatment of Infections

Infections in cirrhotic patients admitted to an intensive care unit (ICU) are a significant cause of mortality (80.8% with infection vs. 32% without infection; p < 0.001) particularly in those with elevated bilirubin at admission, respiratory failure requiring mechanical ventilation, and vasopressor requirements.[34] One of the most important steps in sepsis management is the timely initiation of care including appropriate administration of antibiotics.[35] In fact, the delay of antimicrobials in a cohort of cirrhotic patients was found to increase the mortality risk by 10% per hour of delay.[36]

The most common infections identified in hospitalized cirrhotic patients are urinary tract infections (UTIs), SBP, and pneumonia.[19,37] Enterobacteriaceae and streptococci are the most common organisms causing infection in cirrhotic patients.[14,37] Of note, infections due to multidrug-resistant (MDR) bacteria, including extended-spectrum β-lactamase-producing (ESBL) Enterobacteriaceae, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium, are reported at increasing rates and associated with higher mortality rates.[38] This highlights the need for appropriate selection of antibiotics for identified infections and empiric treatment in sepsis without an identified source.

Bloodstream Infections

Bloodstream infections (BSIs) are common in patients with liver failure due to impaired immunity, increased gut permeability leading to bacterial translocation, and invasive procedures such as transjugular intrahepatic portosystemic shunt (TIPS) and central venous catheter (CVC) placement that allow a portal of entry for infection.[39] The incidence of bacteremia in cirrhotic patients in one population-based study in Denmark was 10 times greater than in the general population with a case fatality rate of 0.53.[40] In a multicenter study of cirrhotic patients with BSI, the causative organism was gram-negative bacteria in 53%, gram-positive bacteria in 47%, and Candida species in 7%; moreover, MDR organisms accounted for 31% of BSIs.[41] Long-term CVCs should be removed in patients with severe sepsis, infective endocarditis, suppurative thrombophlebitis, persistent BSI despite 72 hours of appropriate antimicrobial therapy, or certain causative pathogens including S. aureus, P. aeruginosa, mycobacteria, Candida species, or other fungi.[42,43] Sustained bacteremia despite line removal and appropriate antimicrobial therapy should be further investigated and include transesophageal echocardiogram (TEE) to evaluate for infective endocarditis and endoscopic retrograde cholangiopancreatography (ERCP) to investigate endotipsitis, an infection involving the TIPS. Given the risk of GI bleeding and bacteremia, TEE should be used only for cases in which it would be essential to change medical therapy. Fortunately, endocarditis remains a rare complication of bacteremia, occurring in only 0.24% of cirrhotic patients in one study.[44] Due to the morbidity and mortality associated with bacteremia in this population, antibacterial therapy should be initiated promptly.[45] Transplantation should be delayed until blood cultures are negative for 48 hours and until therapy is completed for most patients, unless the patient is unlikely to survive until the end of therapy. Therapy for BSI in cirrhotic patients should target the responsible pathogen, and duration should be determined based on the type of organism, the extent of disease, and the presence of retained prosthetic material or satellite foci of infection.

Pneumonia and Empyema

Pneumonia is a frequent infection in decompensated cirrhotic patients, with an incidence rate of 21.4%.[46] In one investigation of cirrhotic patients with ascites, patients with pneumonia had the highest mortality rates of all infections reported, with 30- and 90-day mortality rates of 32 and 51%, respectively.[47] In a prospective study of cirrhotic patients with bacterial infections, the most common organisms isolated in pneumonia were Streptococcus pneumoniae, methicillin-resistant S. aureus, P. aeruginosa, and Escherichia coli.[11] Guidelines for therapy in this population are the same as those in other critically ill, hospitalized patients.[48,49] Management of patients with community-acquired pneumonia (CAP) typically includes a β-lactam antibiotic plus a macrolide or respiratory fluoroquinolone for hospitalized ICU patients with liver failure.[49] Empiric therapy for hospital-acquired pneumonia (HAP) or ventilator-acquired pneumonia (VAP) should include coverage for methicillin-sensitive S. aureus, P. aeruginosa, and other gram-negative bacilli; furthermore, additional coverage with linezolid or vancomycin is recommended if the patient has risk factors for methicillin-resistant S. aureus or in hospitals with >10 to 20% of S. aureus isolates that are methicillin-resistant.[48] Antibiotics should be de-escalated as soon as the causative organisms are identified. Seven days of antibiotic therapy is generally adequate for CAP, HAP, and VAP.[50,51] Historically, longer courses have been used for more challenging bacteria, including Pseudomonas and Acinetobacter.

Pleural effusions adjacent to bacterial pneumonia should be sampled with diagnostic thoracentesis to evaluate for parapneumonic effusion or empyema.[52] Patients with cirrhosis can also develop spontaneous bacterial empyema (SBEM), infected pleural fluid in the absence of pneumonia. Mortality in patients with SBEM is high, ranging from 20 to 38%.[53,54] SBEM is diagnosed by the presence of polymorphonuclear leukocyte (PMN) count of >250 cells/microliter with positive pleural fluid cultures or >500 PMN/microliter with negative pleural fluid cultures.[55] Although SBEM is often related to the seeding of hepatic hydrothorax from SBP, 43% of SBEM episodes were seen in the absence of SBP.[54] SBEM is treated similar to SBP, with 7 to 10 days of a third-generation cephalosporin intravenously; of note, administration of albumin has proven mortality benefit in SBP treatment but has not been studied specifically in SBEM.[56] Unlike treatment for empyemas secondary to pneumonia, chest tube drainage is not recommended in SBEM as this can lead to protein loss, fluid loss, and electrolyte imbalances.[57]

There are no clinical trials on viral pneumonia in patients with liver failure. However, published case series report high mortality rates in patients with influenza infection and secondary bacterial infections despite antiviral treatment.[58,59] Strict adherence of yearly influenza vaccination, a high level of suspicion, and prompt initiation of antiviral therapy and supportive care are crucial in cirrhotic patients.

Urinary Tract Infections

UTIs are the second most common infection in advanced liver disease and increase mortality in this population.[11,46,60] The most commonly isolated organisms for UTIs in cirrhotic patients are E. coli, Enterococcus faecalis, Klebsiella pneumoniae, E. faecium, and Proteus mirabilis.[11] In the critically ill patient, indwelling catheters are an additional risk factor for UTI. Signs and symptoms of UTI include fever, altered mental status, increased urinary frequency, dysuria, urgency, flank pain, and suprapubic tenderness. Diagnosis of UTI is based on the presence of signs or symptoms in addition to a catheterized or clean catch urine sample with at least 1,000 CFU/mL of one or more bacterial species.[61] Asymptomatic bacteruria or funguria do not require antimicrobial therapy, but indwelling catheters should be exchanged or removed in this setting.

Empiric therapy for community-acquired uncomplicated UTI include third-generation cephalosporins or amoxicillin/clavulanate; however, additional coverage may be considered in critically ill patients for MDR organisms such as ESBL Enterobacteriaceae, vancomycin-resistant E. faecium, and, in catheterized patients, S. aureus.[15,62] Empiric fluoroquinolone therapy should not be used in patients on long-term fluoroquinolone prophylaxis. Once the causative organism has been identified, antibiotics should be promptly tailored to the responsible pathogen. Duration of therapy for a complicated UTI or pyelonephritis should be 7 to 14 days, but it may be extended if there is a focus of infection, such as an infected stone or stent, that cannot be removed.[63]

Spontaneous Bacterial Peritonitis

Due to the high prevalence of SBP without symptoms and a high risk of mortality, clinical practice guidelines recommend a diagnostic paracentesis for every cirrhotic patient with ascites who is admitted to the hospital.[64] Delaying paracentesis and initiation of antibiotics is associated with higher in-hospital and three-month mortality; more specifically, each hour delay in paracentesis increases in-hospital mortality by 3.3% per hour.[65]

SBP is diagnosed based on an absolute PMN count of >250 cells/mm3 in the ascitic fluid.[66] SBP may be present in the absence of clinical signs or symptoms; in fact, physicians are able to identify SBP in <50% of cases based on clinical suspicion alone.[67] In-hospital mortality in patients with SBP is 18 to 38%, with greater rates in patients with advanced age, renal impairment, ICU level care, and advanced liver disease.[68–71] Furthermore, patients with an MELD (model of end-stage liver disease) score of 22 or higher who are diagnosed with SBP have significantly increased mortality.[72,73]

Five days of empiric treatment for SBP with a third-generation cephalosporin is adequate coverage for the main organisms known to cause SBP, E. coli, K. pneumoniae, and S. pneumoniae.[74,75] Of note, there has been a shift in pathogenic organisms including gram-positive and ESBL Enterobacteriaceae due to the widespread use of fluoroquinolone prophylaxis.[38] Administration of intravenous (IV) albumin (1.5 g/kg at the time of diagnosis and 1 g/kg 3 days after diagnosis) as part of the routine treatment regimen for SBP significantly decreases the risk of hepatorenal syndrome and in-hospital and overall mortality.[76]

Secondary peritonitis should be considered if ascitic fluid cultures have multiple organisms, patients fail to improve on empiric antibiotic therapy, or initial ascitic fluid culture has a total protein of >1 g/dL, glucose of <50 mg/dL, or lactate dehydrogenase is greater than the upper limit of normal for serum.[77] A repeat paracentesis with ascitic fluid analysis to document a downtrend in PMN count should be considered in patients with inadequate response to treatment, an atypical organism in the fluid culture, or suspected secondary peritonitis.[66]

Biliary Tract Infections

Cholecystitis. Acute cholecystitis, or inflammation of the gallbladder, occurs in the setting of an obstructed cystic duct typically due to gallstones or biliary sludge and classically presents with abdominal pain, fever, and right upper quadrant pain.[78] In critically ill patients, acalculous cholecystitis is more commonly seen, but symptoms may be difficult to obtain in a sedated or otherwise altered patient. As a result, diagnosis may depend on ultrasonography showing gallbladder wall thickening of >3 mm, pericholecystic fluid, gallbladder distension with a short-axis diameter of >40 mm, or sonographic Murphy's sign.[79] Although acalculous cholecystitis is initially because of gallbladder stasis, ischemia, and inflammation, there may be secondary bacterial infection from enteric organisms that can ultimately lead to sepsis. Thus, acalculous cholecystitis should remain high on the differential in a critically ill patient with sepsis without an identified source.

Though the ultimate and most definitive treatment for acute cholecystitis is cholecystectomy,[78] the critically ill patient is unlikely to tolerate such an operation, particularly liver failure patients who have high operative mortality risks. In comparison with cholecystectomy, treatment with percutaneous cholecystostomy has been associated with decreased morbidity, shorter ICU and overall hospital length of stay, and reduced cost.[80] Furthermore, patients require empiric broad-spectrum antibiotics with anaerobic coverage (i.e. piperacillin–tazobactam or ceftriaxone plus metronidazole). In patients with known MDR organism colonization or those who are initially critically ill, broader coverage including meropenem or cefepime plus metronidazole can be considered, with vancomycin added in patients who develop the infection while being hospitalized. For penicillin-allergic patients, vancomycin, aztreonam, and metronidazole can be considered.

Cholangitis. Acute cholangitis occurs in the setting of biliary obstruction or stasis with bacterial infection and classically presents with right upper quadrant pain, fevers, and jaundice.[78] The most common causes of cholangitis are choledocholithiasis, malignancy, and benign stenosis.[81] A notable risk factor in liver failure patients are those with primary sclerosing cholangitis. Due to the significant morbidity and mortality associated with cholangitis, patients require broad-spectrum antibiotic coverage as the most common organisms present in infected bile fluid, including E. coli, K. pneumoniae, enterococcus, and anaerobes.[78] Patients with cholangitis due to choledocholithiasis should be managed with endoscopic drainage through ERCP, which is superior to surgical intervention.[82] In cases of patient instability, however, endoscopic intervention may not be feasible and therefore percutaneous drainage may be required. Early empiric antibiotics should be started as well with regimens similar to those recommended for cholecystitis.

Transjugular Intrahepatic Portosystemic Shunt Infections

The TIPS procedure was first described in 1971[83] and is now widely used to treat complications of portal hypertension, including refractory or recurrent variceal bleeding and refractory ascites or hepatic hydrothorax. Infection of the TIPS, also termed endotipsitis, is rare and defined by the presence of a vegetation or thrombus in the TIPS that is thought to be the source of otherwise unexplained bacteremia.[84,85] The source of bacterial infection in these patients may be related to bacterial translocation, which is then able to access the TIPS hematogenously. Infections due to S. aureus and Candida species have significantly higher mortality.[86] The optimal antibiotic regimen and length of treatment remain unclear given the rarity of this type of infection. However, the overarching principle is to treat similar to a prosthetic valve endocarditis with more prolonged courses of therapy directed at the causative pathogen. Long-term suppressive antibiotics are often needed as clearance of infection on the foreign body may be difficult. Since a TIPS cannot be removed once placed, liver transplantation may ultimately be needed to prevent recurrent episodes, although this can only be performed if the infection is under adequate control at the time of transplant.[87]

Clostridioides difficile Infection. CDI is the most commonly reported health care associated pathogen.[88] In 2011, there were an estimated 453,000 CDIs in the United States, resulting in 29,300 deaths.[89] Patients with advanced liver disease have many common risk factors for CDI, including advanced age, prolonged hospitalizations, increased exposure to antibiotics for prophylaxis, and frequent use of PPIs.[90] Cirrhotic patients with CDI have significantly increased in-hospital mortality, with at least two times greater length of stay and hospital costs compared with cirrhotic patients without CDI.[33]

Diagnosing CDI in patients with liver failure can be challenging as many are taking lactulose or other laxatives. Thus, in these patients, CDI should be suspected if the patient has a change in typical stool pattern such as increased frequency of bowel movements or change in consistency of stool to a more liquid form. Only patients who fit this clinical definition should be tested for CDI. Laboratory diagnosis involves a multistep algorithm that includes testing for the toxins or the toxin gene (NAAT). Formed stool from asymptomatic patients should not be sent for CDI testing and do not warrant treatment. CDI is classified as severe if patients have a white blood cell count of >15,000 cells/mL or a creatinine of >1.5 mg/dL.[91,92]

If possible, unnecessary antibiotics should be discontinued in all patients diagnosed with CDI. Of note, metronidazole is no longer recommended as first-line therapy for nonsevere CDI. A randomized controlled trial (RCT) demonstrated that metronidazole was inferior to oral vancomycin with regard to symptomatic clinical success among all severity groups.[93] A prior double-blinded, placebo-controlled RCT demonstrated that vancomycin was superior to metronidazole in severe CDI.[94]

Treatment for the initial episode of CDI is a 10-day course of oral vancomycin 125 mg four times daily or fidaxomicin 200 mg twice daily.[91] Fidaxomicin is noninferior to oral vancomycin in achieving clinical cure of CDI and has significantly lower recurrence rates of CDI.[95] A recent meta-analysis further supported this data with 61 and 71% of patients achieving symptomatic cure when treated with vancomycin and fidaxomicin, respectively (relative ratio: 1.17; 95% CI: 1.04–1.31).[96] For patients with a history of recurrent CDI who require systemic antibiotics with finite duration, oral vancomycin prophylaxis should be considered. Although not studied specifically in patients with liver failure, a retrospective cohort study demonstrated a significant reduction in CDI with oral vancomycin prophylaxis (4.2 vs. 26.6% in patients with vs. without prophylaxis).[97]

Fulminant CDI presents with hypotension, shock, ileus, or megacolon; ileus can present with little to no diarrhea.[91] These patients should be treated with IV metronidazole in addition to vancomycin orally, through nasogastric tube, or per rectum. General surgery consultation should also be obtained.

Unfortunately, recurrent CDI is not an infrequent challenge. Therapy for the first recurrence of CDI should be based on the initial therapy given. Options include standard 10 days od vancomycin, standard 10 days of fidaxomicin, or pulsed vancomycin taper. If a patient has more than two CDI recurrences, fecal microbiota transplantation (FMT) should be considered.[91] While there are limited data on the safety and efficacy of FMT in cirrhotic patients, ongoing studies of FMT's role in managing hepatic encephalopathy will provide data on the safety of this approach.

Fungal Infections

Patients with chronic liver disease are at a risk of fungal infections in part due to the use of medications (i.e., steroids in alcoholic hepatitis, immunomodulators in autoimmune hepatitis) and severity of illness with a functionally immunosuppressed state. Nearly all fungal infections are hospital acquired and most commonly preceded by bacterial infection or antibiotic use, which ultimately leads to a worse overall prognosis.[98] However, patients with cirrhosis also appear to be at an increased risk of developing Cryptococcal infections and aspergillus infections compared with patients without cirrhosis; these are often community-acquired infections.

Two of the more common sites of fungal growth are the respiratory (sputum or bronchial lavage) and urinary tracts, which may be related to colonization or indwelling catheters. Treatment of positive fungal cultures from these sites is recommended only if the fungus is isolated from an additional site. Specific recommendations for antifungal therapy can be found in the published Infectious Diseases Society of America (IDSA) guidelines.[42] Positive fungal blood cultures should always be treated as patients with candidemia have a significantly increased mortality risk (OR: 2.2) particularly in those with associated septic shock (OR: 3.2).[99] Empiric antifungal therapy may be considered in patients with no improvement or worsening status after 48 hours of antibacterial treatment for severe sepsis.[100]

Biomarkers of Infection

Bacterial translocation and its downstream inflammatory effects play an important role in the development of ACLF. Thus, biomarkers for the presence of bacteria or its byproducts may be able to identify infection early before culture data is available or in cases of sepsis without an identified source. Leukocytosis is a classic marker for inflammation or infection in patients but is not a reliable marker in cirrhotic patients due to impaired neutrophil recruitment and activity.[101]

Proposed biomarkers that have been shown to predict the presence of bacterial infection, complications of cirrhosis, and short-term mortality include bacterial DNA, C-reactive protein, procalcitonin, and lipopolysaccharide-binding protein.[102–105] Procalcitonin has been widely studied and found to be useful for the diagnosis of sepsis in critically ill patients (pooled sensitivity of 0.77 and specificity of 0.79 with a median cutoff of 1.1 ng/mL).[106] Furthermore, procalcitonin trends may be used to determine the length of antibiotic therapy.[107] A meta-analysis on the use of procalcitonin to diagnose SBP found similar positive results, and a subgroup analysis using the procalcitonin cutoff of 0.5 ng/mL had a sensitivity of 0.81 and specificity of 0.95.[108] However, cutoff values to use any of these biomarkers for diagnosis or prognostication remain undetermined and require further validation, particularly in liver failure patients.

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