Bacterial infections in cirrhosis: A critical review and practical guidance

Table 1 State of immune dysfunction in patients with cirrhosis

Natural barriers	Fragile, thin and/or edematous skin
	Alteration of GI motility and mucosal permeability
	Alteration of GI bacterial flora, bacterial overgrowth
	↑ GI mucosal ulcerations
Hepatic RES activity	Portosystemic shunting
	Kupffer cells - ↓ number, impaired function
Cellular defense mechanisms	RES - ↓ activation, ↓ chemotaxis, ↓ phagocytosis, ↓ production of pro-inflammatory cytokines (IL-1, IL-6, IL-18, TNF-α)
	PMN - ↓ lifespan, ↓ intracellular killing activity, ↓ phagocytosis, ↓ chemotaxis
Serum factors	↓ Complement levels (C3, C4, CH50)
	↓ Opsonic activity
	↓ Protein C activity
Iatrogenic and treatment-related factors	↑ Invasive procedure and catheters
	Frequent hospitalization
	Immunosuppressive agents (autoimmune hepatitis, post-transplantation)
	Interferon therapy (viral hepatitis)
	Proton pump inhibitors
Other compelling factors	Malnutrition
	Alcohol drinking

Adapted from Bunchorntavakul C, Chavalitdhamrong D. World J Hepatol 2012; 4: 158-168. RES: Reticuloendothelial system; GI: Gastrointestinal; IL: Interleukins; TNF: Tumor necrosis factors; PMN: Polymorphonuclear cells.

Table 2 Types of infection and suggested empirical antibiotic therapy in patients with cirrhosis

Types of infection	Common responsible bacteria	Suggested empirical antibiotic
SBP, spontaneous bacteremia, SBE	Enterobacteriaceae	1st line: Cefotaxime or ceftriaxone or BL-BI IV
	S. pneumoniae	Options: Ciprofloxacin PO for uncomplicated SBP1; carbapenems IV for nosocomial
	S. viridans	infections in areas with a high prevalence of ESBL
		BL-BI may prefer in those with suspicious for enterococcal infection2
Pneumonia	Enterococci	Community-acquired: ceftriaxone or BL-BI IV + macrolide or levofloxacin IV/PO
	S. pneumoniae	Nosocomial and health care-associated infections: Meropenem or cetazidime IV +
	H. infuenzae	ciprofloxacin IV (IV vancomycin or linezolid should be added in patients with risk
	M. pneumoniae	factors for MRSA3)
	Legionella spp.
	Enterobacteriaceae
	P. aeruginosa
	S. aureus
Urinary tract infection	Enterobacteriaceae	1st line: Ceftriaxone or BL-BI IV in patients with sepsis. Ciprofloxacin or
	E. faecalis	cotrimoxazole PO in uncomplicated infections
	E. faecium	Options: In areas with a high prevalence of ESBL, IV carbapenems for nosocomial infections and sepsis (+ IV glycopeptides for severe sepsis); and nitrofurantoin PO for uncomplicated cases
Skin and soft tissue infections	S. aureus	Community-acquired: Ceftriaxone + cloxacillin IV or BL-BI IV
	S. pyogenes	Nosocomial: Meropenem or cetazidime IV + glycopeptides IV
	Enterobacteriaceae
	P. aeruginosa
	Vibrio vulnificus
	Aeromonas spp.
Meningitis	S. pneumoniae	Community-acquired: Cefotaxime or ceftriaxone IV + vancomycin IV
	Enterobacteriaceae	Ampicillin IV should be added if L. monocytogenes is suspected4
	L. monocytogenes	Nosocomial: Meropenem + vancomycin IV
	N. meningitidis

Adapted from Fernandez J, Gustot T. J Hepatol 2012; 56 (Suppl 1): S1-12.

¹Quinolones should not be used in patients submitted to long-term norfloxacin prophylaxis or in geographical areas with a high prevalence of quinolone-resistant Enterobacteriaceae;

²Risk factors for Enterococci: Quinolone prophylaxis, hospital-acquired infection;

³Risk factors for MRSA: Ventilator-associated pneumonia, previous antibiotic therapy, nasal MRSA carriage;

⁴Risk factors for L monocytogenes: Hemochromatosis, detection of gram-positive bacilli/coccobacilli in cerebrospinal fluid. BL-BI: Beta-lactam/beta-lactamase inhibitors (e.g., amoxicillin/clavulanic acid, ampicillin/sulbactam, and piperacillin/tazobactam); MRSA: Methicillin-resistant Staphylococcus aureus; ESBL: Extended spectrum beta-lactamases; SBP: Spontaneous bacterial peritonitis; SBE: Spontaneous bacterial empyema; IV: Intravenous; S. pneumoniae: Streptococcus pneumoniae; S. viridans: Streptococcus viridans; H. infuenzae: Haemophilus influenzae; M. pneumoniae: Mycoplasma pneumoniae; P. aeruginosa: Pseudomonas aeruginosa; S. aureus: Staphylococcus aureus; E. faecalis: Enterococcus faecalis; E. faecium: Enterococcus faecium; S. pyogenes: Streptococcus pyogenes; L. monocytogenes: Listeria monocytogenes; N. meningitidis: Neisseria meningitidis.

Table 3 Common manifestations and risk factors of bacterial pathogens in patients with cirrhosis

Pathogens	Common clinical syndrome	Risk factors	Remarks
Aeromonas spp. (A. hydrophila, A. sobria, A. aquariorum)[120-126]	SBP, bacteremia, SSTI, enterocolitis	Contaminated food and water	Increased incidence
		Diabetes	High mortality (20%-60%), especially when
		Most reports were from East Asia	presence of hypotension on admission
Campylobacter spp.[127,128]	Bacteremia, SBP	Alcoholic	Increased incidence
			High mortality (10% in bacteremia)
Clostridium spp. (C. perfringens, C. bifermentans, C. septicum)[4,129,130]	SSTI	Diabetes	Increased incidence
			Very high mortality (54%-65%)
Clostridium difficile[108,131-133]	ATB-associated diarrhea and colitis	Broad-spectrum ATB	Increased incidence
		Hospitalization	Higher mortality (14%) when compare to non-cirrhotics
		PPIs	Increased cost and length of hospital stay
Enterococcus spp. (E. faecium, E. faecalis, E. galinarum)[134-136]	SBP, bacteremia, UTI, endocarditis, biliary tract infection	Healthcare-associated infection	Increased incidence
		Quinolone prophylaxis	High mortality (30% in bacteremia; 60% in SBP)
			Increased incidence of VRE colonization and infection in liver transplant setting
Listeria monocytogenes[137,138]	SBP, bacteremia, meningitis	Hemochromatosis	Increased incidence
Mycobacterium TB[2,139,140]	Pulmonary TB, TB peritonitis, TB lymphadenitis, disseminated TB	Alcoholic	Increased incidence, especially extrapulmonary forms (>
		Developing countries	50% of TB peritonitis cases in the United States had
		Exposed to TB case	underlying cirrhosis)
			High mortality (22%-48%)
			Increased risk for multi-drug resistant TB
			Increased risk for anti-TB-induced hepatotoxicity
Pasteurella multocida[141-143]	SBP, bacteremia septic arthritis, meningitis	Presence of ascites (TB peritonitis)	Increased incidence
		Domestic animal (cats or dogs) bites or scratches	High mortality (10%-40% in bacteremia)
Staphylococcus aureus[45,144,145]	SSTI, UTI, SBP, bacteremia, endocarditis	Alcoholic	Increased incidence of MRSA carriage and infection
		Invasive procedures	High mortality (30% in bacteremia)
		Hospitalization	Removal of the eradicable focus was associated with
			decreased mortality
Streptococcus bovis[146,147]	Bacteremia, SBP meningitis, endocarditis, septic arthritis	Quinolone prophylaxis	Increased incidence
		Colonic lesion(s): Adenoma or	High mortality (up to 40% in bacteremia with
		adenocarcinoma (presence in	advanced cirrhosis)
		18%-40% of cases)	Colonic lesion(s) was present in 18%-40% of cases
		Alcoholic
Streptococcus group B[148-150]	SSTI, bacteremia, SBP, meningitis, pneumonia	Post endoscopic sclerotherapy and banding ligation	Increased incidence
			High mortality (10%-25% in SBP and bacteremia;
			45% in meningitis)
Streptococcus pneumoniae[89-92]	Pneumonia, SBP bacteremia, SSTI, meningitis	Alcoholic	Increased incidence of invasive pneumococcal disease
		Post-splenectomy	High mortality (10%-20%)
		Not vaccinated
Vibrio spp. (V. vulnificus, non-o1 V. cholera, V. parahemolyticus)[151-153]	SSTI, bacteremia, gastroenteritis, diarrhea, SBP	Hemochromatosis	Increased incidence
		Exposed to seawater and undercooked seafoods	Very high mortality (50%-60% in bacteremia; 24% in SSTI)
		Most reports were from East Asia
Yersinia spp. (Y. enterocolitica, Y. pseudotuberculosis)[154,155]	Bacteremia, SBP, hepatosplenic abscesses	Hemochromatosis	Increased incidence (in hemochromatosis)
		Exposed to animals and	High mortality (50% in bacteremia)
		contaminated foods

SBP: Spontaneous bacterial peritonitis; SSTI: Skin and soft tissue infection; UTI: Urinary tract infection; ATB: Antibiotics; PPIs: Proton-pump inhibitors; TB: Tuberculosis; MRSA: Methicillin-resistant Staphylococcus aureus; A. hydrophila: Aeromonas hydrophila; A. sobria: Aeromonas sobria; A. aquariorum: Aeromonas aquariorum; C. perfringens: Clostridium perfringens; C. bifermentans: Clostridium bifermentans; C. septicum: Clostridium septicum; E. faecium: Enterococcus faecium; E. faecalis: Enterococcus faecalis; E. galinarum: Enterococcus galinarum; Mycobacterium TB: Mycobacterium tuberculosis; V. vulnificus: Vibrio vulnificus; V. cholera: Vibrio cholera; V. parahemolyticus: Vibrio parahemolyticus; Y. enterocolitica: Yersinia enterocolitica; Y. pseudotuberculosis: Yersinia pseudotuberculosis; VRE: Vancomycin-resistant Enterococci.

Table 4 Vaccinations and other preventive measures for bacterial infections in patients with cirrhosis

Avoidance
Raw/uncooked foods, especially seafood
Close contact to at-risk animals or sick people
Wound exposure to flood or seawater
Vaccination[87]
Influenza	Recommended yearly for all patients with chronic liver disease
Pneumococcal (polysaccharide)	Recommended for all cirrhotic patient
	Booster dose after 3-5 yr
Hepatitis A	Recommended for all non-immune, cirrhotic patient, 2 injections 6-12 mo apart
	Anti-HAV should be checked 1-2 mo after the second dose
Hepatitis B	Recommended for all cirrhotic patient without serological markers of HBV (e.g., negative HBsAg, anti-HBs, and anti-HBc antibodies)
	3 injections (at month 0, 1 and 6)
	Anti-HBs should be checked 1-2 mo after the last dose
	Patients with advanced cirrhosis should receive 1 dose of 40 μg/mL (Recombivax HB) administered on a 3-dose schedule or 2 doses of 20 μg/mL (Engerix-B) administered simultaneously on a 4-dose schedule at 0, 1, 2 and 6 mo
Other vaccines, e.g., Td, Tdap, MMR, varicella	Recommendations are as same as general adult population
Prophylactic antibiotics
Secondary prophylaxis for SBP[32,41]	Recommended for all cirrhotic patients who recovered from SBP
	Norfloxacin 400 mg PO daily
	Alternatives: TMP/SMX 1 double-strength tablet or ciprofloxacin 500 mg PO daily
Primary prophylaxis in GI bleeding[32,41]	Recommended for all cirrhotic patients with GI hemorrhage
	Norfloxacin 400 mg PO twice daily or ceftriaxone 1 g IV daily for 7 d
	IV ceftriaxone is preferred, in patients with advanced cirrhosis as defined by the presence of at least two of the following: Ascites, severe malnutrition, encephalopathy or bilirubin > 3 mg/dL
Primary prophylaxis in patients with low ascitic fluid protein[32,41]	Recommended for cirrhotic patients with ascitic fluid protein < 1.5 g/dL and at least one of the following is present: Serum creatinine > 1.2 mg/dL, blood urea nitrogen > 25 mg/dL, serum sodium < 130 mEq/L or Child-Pugh > 9 points with bilirubin > 3 mg/dL
Prophylaxis before undergoing endoscopic and surgical procedures	Prophylactic antiobiotics are recommended for the moderate-high risk invasive endoscopic or surgical procedures (choice of antibiotics should be individualized)
	Prophylactic antibiotics are not routinely recommended for diagnostic endoscopy, elective variceal band ligation or sclerotherapy, and abdominal paracentesis

HBV: Hepatitis B virus; SBP: Spontaneous bacterial peritonitis; Td: Tetanus-Diphtheria; Tdap: Tetanus-Diphtheria-Pertussis; MMR: Measles/Mumps/Rubella; GI: Gastrointestinal; TMP/SMX: Trimethoprim/sulfamethoxazole; PO: Per oral; IV: Intravenous.

Table 5 Studies demonstrated risk of bacterial infections in cirrhotic patients receiving proton pump inhibitors

Ref.	Design	n	Results
Campbell et al[116]	Case-control	116	NS for SBP (OR = 1.05; 95%CI: 0.43-2.57)
Bajaj et al[108]	Case-control	83230	PPI use were significantly higher in those with CDAD (74% vs 31%, P = 0.0001)
Bajaj et al[112]	Retrospective, propensity-matched	1268	↑ Serious infections (HR = 1.66; 95%CI: 1.31-2.12)
de Vos et al[119]	Case-control	102	PPI were more frequently used in SBP patients than in controls, but did not influence prognosis of SBP
Min et al[113]	Retrospective cohort	1554	↑ SBP (HR = 1.39; 95%CI: 1.057-1.843)
Mandorfer et al[117]	Retrospective	607	PPI neither predisposes to SBP (HR = 1.38; 95%CI: 0.63-3.01) or other infections (HR = 1.71; 95%CI: 0.85-3.44)
Terg et al[118]	Prospective	770	PPI therapy was not associated with a higher risk of SBP and other infections
Merli et al[114]	Cross-sectional	400	↑ Bacterial infections (OR = 2; 95%CI: 1.2-3.2)
O'Leary et al[115]	Prospective	188	↑ Infections: CDAD and SBP (OR = 2.94; 95%CI: 1.39-6.20)

NS: Not significance; SBP: Spontaneous bacterial peritonitis; PPI: Proton pump inhibitor; CDAD: Clostridium difficile associate disease.