Fig. 24.1
Factors responsible for the susceptibility of cirrhotic patients to bacterial infections. NOD2 nucleotide-binding oligomerization domain containing 2, IgA immunoglobulin A, IBO intestinal bacterial overgrowth, HLA-DR human leukocyte antigen, TLR toll-like receptor
Cirrhotic patients also have altered defense against bacteria due to reduced bacterial clearance. Impairment of macrophage Fcγ-receptor-mediated clearance of antibody-coated bacteria, deficiencies in the complement system, downregulation of monocyte human leukocyte antigen (HLA-DR) expression, depressed neutrophil phagocytic and intracellular killing contributes to this altered defense [18, 19]. This immune defect facilitates BT [20]. Genetic immune defects could contribute to the high risk of bacterial infections in cirrhosis, particularly SBP. Cirrhotic patients carrying nucleotide-binding oligomerization domain containing 2 (NOD2) variants associated with impairment of recognition of bacterial product, muramyl dipeptide, have a higher risk of SBP and a decreased survival [21]. Mannose-binding lectin deficiency, inducing a defect in opsonophagocytosis of bacteria, also confers a higher risk of bacterial infections in patients with cirrhosis [22].
Besides this immune deficient state, in the early phase of bacterial sepsis, circulating levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 are significantly higher in infected patients with cirrhosis compared to those without [23]. This excessive pro-inflammatory response is recapitulated ex vivo with the stimulation of isolated peripheral blood mononuclear cells (PBMCs) or monocytes from patients with cirrhosis by LPS, which are part of the external membrane of Gram-negative bacteria. This hyper-response is in part explained by deficiency of negative feedbacks in toll-like receptor (TLR)-4 pathway [24]. This bacteria-induced “cytokine storm” contributes to sepsis-related organ failures. Indeed, there is a relationship between high plasma and ascitic levels of TNF-α and IL-6 and occurrence of renal dysfunction in SBP [25]. Moreover, enhanced neutrophil-induced oxidative stress and elastase production observed in cirrhosis could also participate in sepsis-related organ damages [26].
The Diagnostic Approach
The diagnosis of bacterial infection in cirrhosis is challenging for several reasons.
First, in the early phase of infection, cirrhotic patients may be totally asymptomatic. Second, the classical parameters assessing the inflammatory host response to infection systemic inflammatory response syndrome (SIRS) are not specific for the diagnosis of infection in cirrhosis. SIRS is defined as the presence of at least two of four clinical criteria: body temperature ≥ 38°C or ≤ 36°C; heart rate ≥ 90 beats/min; respiratory rate ≥ 20 breaths/min; or hyperventilation with a PaCO2 ≤ 32 mmHg; white blood cell count ≥ 12,000/mm3, ≤ 4000/mm3, or with > 10 % immature neutrophils. Decompensated cirrhosis may be associated with some degree of encephalopathy-related tachypnea, tachycardia, or hypersplenism-related leucopenia. SIRS thus has a low sensitivity (57–70 %) as a diagnostic tool of infection in patients with decompensated cirrhosis and low specificity (10–30 %) in those patients without infection [27, 28]. Common early markers of infection used in the general population such as C-reactive protein (CRP) and procalcitonin are not sufficiently adequate to distinguish infected from noninfected patients. Indeed, CRP > 2 mg/dL only has a sensitivity of 78 % and specificity of 68 % and procalcitonin > 3 ng/mL has sensitivity and specificity of 73 %.This poor diagnostic accuracy could be explained by a decreased production of acute-phase proteins in the liver, especially CRP. Low CRP values should be interpreted with caution in patients with severe liver insufficiency due to fact that hepatocytes are the main source of CRP. Some randomized-controlled trials have shown good results with the use of procalcitonin algorithms to guide decisions about the initiation and/or discontinuation of antibiotics in patients admitted in the intensive care unit (ICU) but the usefulness in cirrhotic patients has yet to be investigated [29].
Infection should be suspected in any decompensated cirrhotic patient or when a hospitalized patient deteriorates. Therefore, a thorough examination and workup including urinary sediment and culture, diagnostic paracentesis and ascitic fluid culture, blood cultures, and chest X-ray should be promptly performed in order to avoid a delay in the diagnosis and the administration of empiric antibiotics.
Principles for Management of Bacterial Infections in Cirrhosis
The early diagnosis of bacterial infections and the prompt initiation of adequate antibiotic treatment are the cornerstone of management. Each hour of delay in administering antibiotics, or the inappropriate initial choice of antibiotics drastically, worsens the prognosis of patients with septic shock [30]. The choice of initial empirical antibiotics should be based on the type, severity, and origin of infection (CA, nosocomial, or HCA) and on the local epidemiological data of antibiotic resistance. In general, third generation cephalosporins are still considered the gold standard for most infections acquired in the community. In contrast, the empirical treatment of nosocomial or HCA infections should be tailored according to the local epidemiological pattern of multiresistant bacteria.
Spontaneous Bacterial Peritonitis
SBP is defined as a spontaneous ascitic fluid infection without an evident abdominal source. It is the most frequent infection of cirrhotic patients (20–25 % of all infections) [3]. In outpatients without symptoms, the prevalence is low (< 3 %) [31, 32], but it increases to 8–36 % in hospitalized patients. The mortality for the first episode ranges from 10 to 25 % [33]. However, more important is the fact that 1-year mortality after the first SBP episode is reported to be at least 30 %, suggesting that the deterioration of liver function accelerates [34].
Diagnosis of SBP
Patients with SBP may have one of the following: local symptoms and/or signs of peritonitis (abdominal pain, abdominal tenderness, Blumberg sign, vomiting, diarrhea, ileus). However, it may be asymptomatic in some patients, particularly outpatients. The diagnosis of SBP is based on ascitic neutrophil count ≥ 250/mm3 [35]. Ascitic fluid neutrophil count is obtained by centrifugation of the ascitic fluid and then stained with Giemsa and differential cell counts are made with an optical microscope. Reagent strips have been assessed as method of rapid diagnosis, but given the high rate of false-negative results (around 50 %) their use has been abandoned [36]. Ascitic fluid lactoferrin levels have been suggested as an alternative method for the diagnosis of SBP. In one study, a cutoff value of 242 ng/mL had a sensitivity and specificity in the diagnosis of SBP of 95 and 97 %, respectively [37]. However, there are scarce data, and thus these results must be validated in other centers in order to consider the use of lactoferrin for the diagnosis of SBP in clinical practice. Pleural ascites could also be a site of infection. This infection is called spontaneous bacterial empyema (SBE), and the diagnostic criteria are the same than those for SBP.
Microbiology
Ascitic fluid cultures (10 mL injected into aerobic and anaerobic blood cultures), direct ascitic microscopic exam (to look for a potential polymicrobial infection in the case of secondary peritonitis), and blood cultures (50 % of SBP are associated with bacteremia) should also be obtained when SBP is suspected. The ascitic fluid culture is positive in approximately 40 % of cases. The most common pathogens are Gram-negative bacteria (GNB; mainly Escherichia coli, Klebsiella pneumonia, Enterobacter spp.) and Gram-positive cocci (GPC; mainly Streptococcus spp. and Enterococci). In Spain, 20 % of GNB are resistant to quinolones, and 70 % of these are also resistant to trimethoprim–sulfamethoxazole [1]. The long-term norfloxacin administration (see Prevention section) increases the rate of quinolone resistance to 60 % and the proportion of GPC. The rate of cephalosporin-resistant GNB is low in community-acquired SBP regardless of long-term norfloxacin prophylaxis. On the other hand, (at least in Spain), extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae are isolated in 30 % of nosocomial SBP and methicillin-resistant Staphylococcus aureus (MRSA) in 10 % of HCA SBP [3].
Some patients have bacterascites, a condition in which cultures are positive but there is an ascitic neutrophil count < 250/mm3. When this bacterascites is caused by only one microbe, it usually represents the colonization phase of ascitic fluid infection. It may progress to SBP or in the majority of cases (62–86 %) resolve spontaneously [38, 39]. Bacterascites with microorganisms similar to those of the skin flora are probably due to contaminants. If symptoms are present, a second paracentesis is recommended.
Antibiotics
For community-acquired SBP, third-generation cephalosporins (cefotaxime, ceftriaxone) are the gold standard for the empirical antibiotic treatment (see Tables 24.1 and 24.2) [40]. Amoxicillin–clavulanic acid and ciprofloxacin show similar results [41, 42]. However, quinolones are not yet recommended in patients receiving long-term norfloxacin prophylaxis and in geographical areas with high prevalence of quinolone-resistant bacteria. For nosocomial and HCA SBP, there is no clear recommendation at this time and the choice of empirical antibiotics depends on the local epidemiological patterns of resistance. If ESBL-producing Enterobacteriaceae are frequent, carbapenems or tigecycline could be a good choice for the treatment of nosocomial SBP. Another strategy is a step-by-step protocol consisting in a first-line antibiotic treatment, i.e., piperacillin–tazobactam, followed by an assessment of response (defined by a reduction of ascitic neutrophil count > 25 % at day 2 of antibiotics) and in case of nonresponse, by a shift to a broader antibiotic, i.e., carbapenems.
Table 24.1
Recommended empirical antibiotics for infected cirrhotic patients
Type of infection | Recommended empirical antibiotics | |
|---|---|---|
Community-acquired infections | Nosocomial infectionsa | |
SBP, SBE and spontaneous bacteremia | Cefotaxime or ceftriaxone or amoxicillin/clavulanic acid | Piperacillin/tazobactamb or Meropenemc ± glycopeptided |
Urinary infections | Uncomplicated: ciprofloxacin or cotrimoxazole If sepsis: cefotaxime or ceftriaxone or amoxicillin/clavulanic acid | Uncomplicated: nitrofurantoin or fosfomycin If sepsis: piperacillin/tazobactamb or meropenemc ± glycopeptided |
Pneumoniae | Amoxicillin/clavulanic acid or ceftriaxone + macrolide or levofloxacinor moxifloxacin | Piperacillin/tazobactamb or meropenem/ceftazidime + ciprofloxacin ± glycopeptided should be added in patients with risk factors for MRSAg |
Cellulitis | Amoxicillin/clavulanic acid or ceftriaxone + oxacillin | Meropenem/ceftazidimef + oxacillin or glycopeptidesd |
Table 24.2
Recommendations for the management of spontaneous bacterial peritonitis
Therapy |
After diagnosis of peritonitis has been made (> 250 neutrophils/mm3 in ascitic fluid), start with third-generation cephalosporins (i.e., cefotaxime 2 g/8–12 h IV or ceftriaxone 1 g/24 h IV) unless risk factors for multirresistant bacteria are presenta |
Infuse albumin (1.5 g/kg at diagnosis of the infection and 1 g/kg 48 h later) |
Maintain antibiotic therapy for at least 5 days or until disappearance of signs of infection. Patients should be evaluated daily to assess signs of infection. A follow-up paracentesis helps evaluate response to therapy |
After resolution of infection, start long-term oral norfloxacin 400 mg/day |
Prevention |
Patients with gastrointestinal hemorrhage: |
Norfloxacin 400 mg/12 h orally or per gastric tube for 7 days in patients with preserved liver function and not actively bleeding. |
Intravenous ceftriaxone 1g/day for 7 days in patients with advanced liver failure and/or actively bleeding. |
Patients with ascites with a previous episode of SBP |
Norfloxacin 400 mg/day indefinitely |
Evaluation for liver transplantation |
Patients with ascites and advanced liver diseaseb without a previous episode of SBP and low ascitic fluid protein concentration (< 15 g/liter): |
Norfloxacin 400 mg/day indefinitely |
Special Case: Secondary Peritonitis
Secondary peritonitis is infrequent (5–10 % of all peritonitis) but is associated with a very high mortality rate (66 %) [43]. Secondary peritonitis is suggested when at least two of the following parameters are present in ascites: glucose levels < 50 mg/dL, protein concentration > 10 g/dL, or LDH concentration > normal serum levels but these criteria only have a sensitivity of 67 %. In the case of gut perforation, ascitic amylase or bilirubin levels could be high. In the case of secondary peritonitis, the ascitic culture is frequently positive and polymicrobial. Abdominal computerized tomography (CT) without contrast to avoid renal impairment is diagnostic in 90 %. Prompt treatment with broad-spectrum antibiotics with anti-anaerobic activity (amoxicillin/clavulanic acid, piperacillin/tazobactam, or ceftazidime/metronidazole), and early decision for surgery are essential for the management of secondary peritonitis.
Other Infections
Pneumonia
Deterioration of consciousness secondary to hepatic encephalopathy and basal atelectasis due to tense ascites contributes to the high frequency of lung infections in cirrhosis. In cirrhotic patients with severe sepsis, lung infections are the more frequent infectious foci, suggesting that pneumonia is a severe infection in cirrhosis [44]. Indeed, community-acquired pneumonia (CAP) of cirrhotic patients is more frequently associated with septic shock and higher 1-month-mortality rates than those in the noncirrhotic population (14 vs. 7 %) [45]. The mortality of cirrhotic patients with community-acquired pneumococcal pneumonia requiring hospitalization increases to 34 % (sixfold higher than in the general population) despite adequate antibiotics [46]. The more severe form of lung infection is the acute respiratory distress syndrome (ARDS) defined by severe hypoxemia, bilateral lung infiltration, and the absence of left heart failure. The mortality of ARDS in general population is 65 %, and cirrhosis is independently associated with mortality with a very high odds ratio of 27 [47].
Diagnosis
In the case of pneumonia, patients may have cough, pleuritic chest pain, dyspnea, or sputum production but may be asymptomatic. A chest radiograph may show lobar consolidation, interstitial infiltrates, and/or cavitation. If there is a high-clinical suspicion of pneumonia with a negative chest radiograph, CT scan should be performed. Pneumococcal and legionella urinary antigen tests should also be performed.
Microbiology
Only 28 % of CAP are culture positive with 75 % of GPC and 25 % of GNB [1]. The proportion of GNB and polymicrobial cultures (GNB + GPC) increases in nosocomial infections. Isolated microorganisms are Streptococcus pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in order of frequency. P. aeruginosa and ESBL-producing Enterobacteriaceae are isolated in nosocomial and HCA pneumonia [3]. Cirrhosis seems also to be a predisposing condition of atypical infections such Legionella spp. [48].
Antibiotics
The recommendations for the empiric treatment for CAP do not differ from those of the general population (Table 24.1). As detailed previously, cirrhosis is considered as a major comorbidity, and thus some experts suggest the combination of antibiotics against typical and atypical bacteria [49]. The possibilities are a quinolone (moxifloxacin, levofloxacin) or the combination of a β-lactam (amoxicillin–clavulanate or third-generation cephalosporin) plus a macrolide. For nosocomial and HCA pneumonia, the use of empiric antibiotics should follow local recommendations.
Urinary Tract Infection
UTIs are frequent in cirrhotic patients and, as in the general population, more frequent in women and those with urinary catheters. UTIs are frequently asymptomatic in cirrhotic patients. The hospital mortality rate of UTIs is around 10 % and increases to 18 % in the case of multiresistant bacteria [3].
Diagnosis of UTI
UTI may be asymptomatic in cirrhotic patients or associated with dysuria, frequency, urgency, and suprapubic pain. In the case of pyelonephritis, patients frequently describe flank pain. If UTI is suspected, urinalysis and urine culture must be performed. The diagnosis is based on ≥ 10 urinary leukocytes/mm3 or positive urinary leukocyte esterase. If cirrhotic patients have persistent symptoms of uncomplicated UTI after 48 h of appropriate antibiotic therapy or symptoms of pyelonephritis, renal ultrasound or abdominal CT should be performed to detect a stone, papillary necrosis, obstruction, and/or abscess.
Microbiology
Eighty percent of UTIs in cirrhotic patients are culture positive with a large majority of GNB (76 %) in community-acquired UTIs. The proportion of GPC increases in nosocomial infections. E. coli is the most frequently isolated microorganism followed by Enterococcus faecalis, Klebsiella pneumonia, and Enterococcus faecium.
Antibiotics
Third-generation cephalosporins, amoxicillin–clavulanic acid, quinolones, or trimethoprim–sulfamethoxazole are the first choice for community-acquired UTIs (Table 24.1). For uncomplicated UTIs, oral antibiotics are recommended. Quinolones and trimethoprim–sulfamethoxazole are not recommended in patients receiving long-term norfloxacin prophylaxis and in geographical areas with high prevalence of quinolone-resistant bacteria. In nosocomial infections, nitrofurantoin is a good option in uncomplicated UTI. In some regions with a high prevalence of ESBL-producing bacteria, carbapenems should be used. In the case of severe sepsis or septic shock secondary to UTI, a glycopeptide must be added to anti-GNB antibiotic to cover E. faecium.
Skin and Soft Tissue Infection
SSTIs, in particular those of lower limb or abdominal wall, are not rare in cirrhotic patients with peripheral edema and/or ascites. SSTIs are observed in 2–11 % of cirrhotic patients [50, 51]. In a Spanish cohort, the mortality rate of SSTI was 4 % [52]. The mortality could increase to > 50 % in the case of GNB-related SSTIs [53].
Diagnosis of SSTI
The most common symptom of cellulitis is pain, tenderness, swelling, and redness in a distinct area of skin. For SSTI, ultrasound of the region is a useful tool for excluding occult abscess and to guide microbiological sampling and/or surgical drainage and for making the differential diagnosis with deep venous thrombosis. CT scan should be performed if necrotizing fascitis is suspected.
Microbiology
Skin cultures are positive in nearly 50 % of cases. GPC are isolated more frequently than GNB, but up to one third of cultures yielded GNB. Classically, the most commonly isolated GPC are S. aureus, Streptococcus pyogenes, and E. faecalis. GNB are represented by E. coli, P. aeruginosa, and Enterobacter cloacae.
Antibiotics
Amoxicillin–clavulanic acid or ceftriaxone and oxacillin, which cover Staphylococcus, are the first choice for community-acquired cellulitis (Table 24.1). These antibiotics are ineffective on Pseudomonas spp. In these cases, ceftazidime and oxacillin or piperacillin–tazobactam could be a better choice in those with a high risk of Pseudomonas spp.
Prevention of Organ Failure: The Use of Albumin
Spontaneous Bacterial Peritonititis
In patients with cirrhosis, an open-label unblinded randomized clinical trial (RCT) in patients with SBP (without shock) treated with cefotaxime showed that the intravenous (IV) administration of a 20 % albumin solution reduced the incidence of renal failure and decreased mortality rates from 29 to 10 % [54]. In this trial, albumin was given at an arbitrary dose of 1.5 g/kg body weight at the time of diagnosis, followed by 1 g/kg body weight on day 3 (Table 24.2). This effect was not observed in patients with low risk of mortality (total bilirubin < 4 mg/dL and creatinine < 1 mg/dL) [55]. A recent small unblinded RCT suggested that a 20 % albumin solution improved systemic hemodynamics better than a 6 % hydroxyethyl starch solution in SBP [56].
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