Management of bacterial and fungal infections in end stage liver disease and liver transplantation: Current options and future directions

Table 1 Main studies reporting the characteristics and mortality rates associated with infections in patients with liver cirrhosis

Year	Prevalence of infections (%); patient n	Main infection sites (%)	Most common pathogens (%)	Mortality rates (%)	Ref.
2018	NR; n = 312	Only BSI included; primary (32), SBP (16), UTI (11)	GNB (53)	25	[28]
2017	61; n = 852	Only BSI included; primary (60), abdominal (33), UTI (7), pneumonia (6)	GNB (60)	23	[22]
2015	38; n = 401	Pneumonia (22), UTI (21), SBP (19)	E. coli (72)	31	[23]
2012	51; n = 207	UTI (52), SBP (23), BSI (21)	GPB (56)	24	[19]
2010	33; n = 150	UTI (37), pneumonia (22), BSI (13)	GNB (62)	37	[18]
2007	45; n = 233	UTI (43), pneumonia (25), SBP (16)	GNB (65)	18	[20]
2003	25; n = 135	UTI (31), SBP (26), pneumonia (25)	NR	9	[25]
2002	22; n = 70	BSI (16), CVC-BSI (9), liver abscess (3)	GPB (67)	29	[24]
2002	32; n = 507	SBP (24), UTI (19), pneumonia (14), CVC-BSI (8)	GPB (47)	22	[17]
2001	34; n = 361	UTI (41), SBP (23), BSI (21), pneumonia (17)	E. coli (25)	15	[8]
1994	39; n = 132	SBP (44), UTI (26), pneumonia (16)	GNB (65), E. coli (62)	29	[27]
1993	47; n = 170	SBP (31), UTI (25), pneumonia (21)	GNB (72)	17	[26]

NR: Not reported; BSI: Bloodstream infections; SBP: Spontaneous bacterial peritonitis; UTI: Urinary tract infections; CVC: Central venous catheter; GNB: Gram-negative bacteria; GPB: Gram-positive bacteria.

Table 2 Management of fungal infections in patients with liver cirrhosis

Type	Characteristics	Management	Ref.
SFP, fungemia, disseminated fungal infection (mainly Candida spp.)	Delayed diagnosis and therapy. Lack of clinical signs and suspicion. Frequent concomitant SBP. High mortality.	Suspect if peritonitis is not improved after 48 h of empirical antibiotic treatment. Perform fungal cultures (ascites and blood).	[44,45,52,53]
Antifungal prophylaxis	Factors influencing mortality less known. Mortality higher than SBP due to delayed diagnosis.	Indicated for SBP (high risk, previous episode, GI bleeding). No clear indication for fungal infections. Consider in: ICU patients without improvement > 48 h, high prevalence (> 5%) regions, risk factors (corticosteroids, prolonged microbial use, CVC, TPN, high APACHE score, dialysis).	[48,54]
Antifungal treatment	Recommendations for fungal infections in LC.	Prompt initiation. Echinocandins as first-line treatment (e.g., fungemia, nosocomial SFP or critically ill with CA-SFP). Fluconazole indicated if less severe infections. De-escalation if patient is stable and sensitivity tests available.	[52-54]

SFP: Spontaneous fungal peritonitis; SBP: Spontaneous bacterial peritonitis; GI: Gastrointestinal; CVC: Central venous catheter; TPN: Total parenteral nutrition; APACHE: Acute Physiology and Chronic Health Evaluation; LC: Liver cirrhosis; CA: Community-acquired.

Table 3 Management of infections in liver transplant recipients

Population/ infection	Risk factor and type of infection	Management	Ref.
Liver transplant candidates/all infections	Donor-derived. Active/latent infections. Vaccine-preventable infection.	Donor screening. Careful patient history and physical examination. Identification of infections requiring therapy. Immunization.	[160-165]
Liver transplant recipients/bacterial	Nosocomial infections (ICU, invasive devices). Recurrent infections (anatomical defects). Immunosuppression.	Peri-transplant antibiotic prophylaxis (< 48 h). Prompt diagnostic workup (uncommon presentations, opportunisms). Source control when needed.	[76,83,160]
Liver transplant candidates and recipients/MDRO	Colonization (MRSA, VRE, CRE) linked to increased risk of infections. Risk of transmission between patients and across wards.	Surveillance cultures (CRE, VRE, MRSA) and decolonization (MRSA). Infection control (hand hygiene, isolation, contact precautions).	[102,112,164]

LT: Liver transplantation; ICU: Intensive care unit; MDRO: Multidrug-resistant organisms; MRSA: Methicillin-resistant Staphylococcus aureus; VRE: Vancomycin-resistant enterococci; CRE: Carbapenem-resistant Enterobacteriaceae.

Table 4 Treatment options for multidrug resistant organisms in liver transplant recipients

Pathogens	Recommendation	Antimicrobial regimens	Ref.
MDR Gram-positives
MRSA	Nasal decolonization with mupirocin. Daptomycin highly bactericidal in BSI; non effective in pulmonary infections. Linezolid and tigecycline bacteriostatic.	Vancomycin1/linezolid OR Daptomycin OR Tigecycline OR Novel anti-MRSA cephalosporins (ceftaroline, ceftobiprole)2.	[107-111]
VRE	Daptomycin highly bactericidal in BSI; non effective in pulmonary infections. Linezolid and tigecycline bacteriostatic.	Linezolid OR Daptomycin OR Tigecycline.	[113,121,122]
MDR Gram-negatives
ESBL-producing Enterobacteriaceae	Conflicting data on carbapenem superiority vs BLBLI. Meropenem recommended for high inoculum infections and unstable patients.	Carbapenems OR Piperacillin/tazobactam.	[175-177]
Carbapenem-resistant Enterobacteriaceae	Test antimicrobial susceptibility (also on colonizing strains). Some evidence of better outcomes with combination therapy vs monotherapy. New molecules promising but scarce data in LT.	Ceftazidime/avibactam, OR Combination regimen (at least two active drugs) including colistin/polymixin B, tigecycline, aminoglycosides1 (gentamycin, amikacin), IV fosfomycin, high-dose prolonged infusion carbapenems. For uncomplicated UTI, consider monotherapy (aminoglycosides, fosfomycin).	[127,137,138,175,178]
MDR P. aeruginosa	Test antimicrobial susceptibility. New molecules promising but scarce data in LT.	Combination regimen (at least two active drugs) including colistin, an anti-pseudomonal beta-lactam (if susceptible), aminoglycosides1, fosfomycin OR Ceftolozane/tazobactam, ceftazidime/avibactam	[175,179,180]

¹Therapeutic drug monitoring recommended;

²Approved for skin and soft tissue infections and community-acquired pneumonia (ceftaroline), community-acquired and hospital-acquired pneumonia excluding ventilator-associated pneumonia (ceftobiprole). MDR: Multidrug resistant; BLBLI: Beta-lactam/beta-lactamase inhibitor combination; BSI: Bloodstream infections; LT: Liver transplantation; MDRO: Multidrug-resistant organisms; MRSA: Methicillin-resistant Staphylococcus aureus; VRE: Vancomycin-resistant enterococci; CRE: Carbapenem-resistant Enterobacteriaceae.