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

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Term Occurence Count Dictionary
viral hepatitis 1 infectiousdiseases
amikacin 1 infectiousdiseasesdrugs
meningitis 3 infectiousdiseases
ofloxacin 2 infectiousdiseasesdrugs
piperacillin 2 infectiousdiseasesdrugs
Ceftazidime 1 infectiousdiseasesdrugs
candidemia 4 infectiousdiseases
fluconazole 4 infectiousdiseasesdrugs
invasive aspergillosis 1 infectiousdiseases
norfloxacin 1 infectiousdiseasesdrugs
Voriconazole 1 infectiousdiseasesdrugs
ceftriaxone 1 infectiousdiseasesdrugs
Opportunistic infection 2 infectiousdiseases
nitrofurantoin 1 infectiousdiseasesdrugs
cefotaxime 1 infectiousdiseasesdrugs
ciprofloxacin 2 infectiousdiseasesdrugs
septic shock 7 infectiousdiseases
vancomycin 4 infectiousdiseasesdrugs
aspergillosis 1 infectiousdiseases
hospital-acquired infection 1 infectiousdiseases
aztreonam 1 infectiousdiseasesdrugs
pneumonia 27 infectiousdiseases
tuberculosis 2 infectiousdiseases
abscess 5 infectiousdiseases
infectious disease 1 infectiousdiseases
meropenem 2 infectiousdiseasesdrugs
candidiasis 1 infectiousdiseases

Graph of close proximity drug and disease terms (within 200 characters).

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Select Drug Character Offset Drug Term Instance
Ceftazidime 41183 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,
Voriconazole 55731 amphotericin B provide wide-spectrum options for patients that may be at risk of non-Candida infections. Voriconazole (and most recently, isavuconazole) remain the drug of choice for invasive aspergillosis, although limitations
amikacin 41332 least two active drugs) including colistin/polymixin B, tigecycline, aminoglycosides1 (gentamycin, amikacin ), IV fosfomycin, high-dose prolonged infusion carbapenems. For uncomplicated UTI, consider monotherapy
aztreonam 52776 studies[[140]-[142]]. New compounds targeting carbapenem-resistant strains, including MBLs (e.g., cefiderocol, aztreonam -avibactam) are currently under investigation[[143]]. Regarding Pseudomonas spp., the novel beta-lactam/beta-lactamase
cefotaxime 14284 possible, especially among hospitalized patients[[11]]. Third generation cephalosporins (e.g., ceftriaxone, cefotaxime , or the antipseudomonal cephalosporin ceftazidime) or beta-lactam/beta-lactamase inhibitor combinations
ceftriaxone 14271 also possible, especially among hospitalized patients[[11]]. Third generation cephalosporins (e.g., ceftriaxone , cefotaxime, or the antipseudomonal cephalosporin ceftazidime) or beta-lactam/beta-lactamase inhibitor
ciprofloxacin 14520 piperacillin/tazobactam (active also against Enterococcus spp.) are frequently used to treat SBP[[11]]. Although ciprofloxacin represents a potential option for SBP treatment, rates of resistances associated to quinolone use remains
ciprofloxacin 15963 beta-lactam/beta-lactamase inhibitor combination, or a carbapenem) with or without a quinolone such as ciprofloxacin [[11]]. If risk factors for MRSA are documented (e.g., MRSA colonization or previous infection), treatment
fluconazole 24614 patients’ reduced tolerance, and altered drug pharmacokinetics caused by advanced liver disease.Although fluconazole is still widely used due to its favorable pharmacokinetics and tolerability, a shift to non-albicans
fluconazole 24749 due to its favorable pharmacokinetics and tolerability, a shift to non-albicans strains showing lower fluconazole susceptibility has been reported[[57]]. Echinocandins are currently recommended as first line treatment
fluconazole 24933 recommended as first line treatment in critically ill patients and in case of reduced susceptibility to fluconazole [[58]]. Despite evidence of resistance has emerged especially in C. glabrata, overall resistance rates
fluconazole 54084 12%, with non-albicans Candida accounting for 55% of the infections; of these, half were caused by fluconazole -resistant C. parapsilosis[[150]]. One-year patient survival rates were significantly reduced among patients
meropenem 16408 a broad-spectrum antibiotic active against Gram-negative bacilli (e.g., piperacillin/tazobactam or meropenem ) with an anti-MRSA drug (e.g., vancomycin, daptomicin) is recommended[[11]].OutcomeAlthough the diagnosis
meropenem 52168 ceftazidime-avibactam has demonstrated promising activity against CRKP in preliminary studies[[136]-[138]], and meropenem -vaborbactam has recently been approved for the treatment of complicated urinary tract infections caused
nitrofurantoin 15526 combinations[[11]]. In uncomplicated, non-bacteremic infections, oral options such as cotrimoxazole or nitrofurantoin can be used, according to the pathogen’s susceptibility. The use of quinolones, however, should be
norfloxacin 14703 associated to quinolone use remains high at various centers and among patients receiving long-term norfloxacin prophylaxis[[37]]. Tigecycline presents good intra-abdominal penetration and is active against Enterococci
ofloxacin 14524 piperacillin/tazobactam (active also against Enterococcus spp.) are frequently used to treat SBP[[11]]. Although cipr ofloxacin represents a potential option for SBP treatment, rates of resistances associated to quinolone use remains
ofloxacin 15967 beta-lactam/beta-lactamase inhibitor combination, or a carbapenem) with or without a quinolone such as cipr ofloxacin [[11]]. If risk factors for MRSA are documented (e.g., MRSA colonization or previous infection), treatment
piperacillin 14407 antipseudomonal cephalosporin ceftazidime) or beta-lactam/beta-lactamase inhibitor combinations such as piperacillin /tazobactam (active also against Enterococcus spp.) are frequently used to treat SBP[[11]]. Although
piperacillin 16381 infections, the association of a broad-spectrum antibiotic active against Gram-negative bacilli (e.g., piperacillin /tazobactam or meropenem) with an anti-MRSA drug (e.g., vancomycin, daptomicin) is recommended[[11]].OutcomeAlthough
vancomycin 16088 risk factors for MRSA are documented (e.g., MRSA colonization or previous infection), treatment with vancomycin or linezolid can be considered. SSTI, most frequently cellulitis, can be caused by both Gram-negative
vancomycin 16449 against Gram-negative bacilli (e.g., piperacillin/tazobactam or meropenem) with an anti-MRSA drug (e.g., vancomycin , daptomicin) is recommended[[11]].OutcomeAlthough the diagnosis and treatment of infections have improved
vancomycin 44545 consider the local epidemiology as a key parameter to implement the infection control practices.Although vancomycin remains the mainstay for treatment of MRSA, various limitations have been associated with its use, including
vancomycin 44876 increased renal toxicity compared to other available options[[88],[107],[108]]. Valid alternatives to vancomycin include linezolid, especially in the treatment of MRSA-related pneumonia, and daptomycin (Table 4)[[108]-[111]].
Select Disease Character Offset Disease Term Instance
Opportunistic infection 26522 diagnose. Furthermore, LC itself may be a cause of low-grade fever in up to 20% of patients[[63]]. Opportunistic infection s can also occur and their recognition may be less immediate, or require longer times to obtain culture
Opportunistic infection 31706 post-transplant bacterial infections, an accurate screening of donors is recommended (Table 3)[[76],[77]]. Opportunistic infection s (e.g., herpesvirus infections, nocaridosis, tuberculosis, etc.) are considered more common between
abscess 5878 (65)18[20]200325; n = 135UTI (31), SBP (26), pneumonia (25)NR9[25]200222; n = 70BSI (16), CVC-BSI (9), liver abscess (3)GPB (67)29[24]200232; n = 507SBP (24), UTI (19), pneumonia (14), CVC-BSI (8)GPB (47)22[17]200134;
abscess 6883 to other solid organ transplants, are more complex and may presents complications such as abdominal abscess , bile leaks, and hepatic artery stenosis[[13]]. Bacterial infections account for up to 70% of all infections
abscess 11497 overall incidence of bacteremia, urinary tract infections, pneumonia, meningitis, tuberculosis, and liver abscess appeared increased more than tenfold in LC, and mortality rates of each episode were 3 to 10 times higher
abscess 36375 BSI also warrants the investigation of deep-seated infections (e.g., endocarditis, intra-abdominal abscess es, etc.) and, when possible, prompt source control measures such as removal of vascular catheters and
abscess 37616 infections, accounting for up to 50% of early bacterial infections following LT, and include intraabdominal abscess es, peritonitis, and cholangitis[[84]-[86]]. IAI can be polymicrobial and are mainly caused by Enterococci,
aspergillosis 55818 infections. Voriconazole (and most recently, isavuconazole) remain the drug of choice for invasive aspergillosis , although limitations in its use in LTR and patients with compromised liver function are represented
candidemia 21026 culture-positive infections documented Candida spp. in 19 (10%) cases. Of these, 58% were SFP and 42% candidemia . Only 47% of fungal infections were diagnosed and treated with antifungal agents, while the remaining
candidemia 21912 with inappropriate empirical therapy[[28]]. Bassetti et al[[51]] previously analyzed 169 episodes of candidemia and 72 intra-abdominal candidiasis in cirrhotic patients, showing high rates of ICU admission (50%),
candidemia 22170 occurrence of septic shock (35%). Thirty-day mortality was 35.3% and was independently associated with candidemia (OR = 2.2, 95%CI: 1.2-4.5), septic shock (OR = 3.2, 95%CI: 1.7-6), and absence of adequate antifungal
candidemia 53787 most common cause of invasive fungal infections in LTR is Candida spp. Candida infections, including candidemia , abdominal infections, and biliary infections, are mostly nosocomial and occur early after LT[[149]].
candidiasis 21946 therapy[[28]]. Bassetti et al[[51]] previously analyzed 169 episodes of candidemia and 72 intra-abdominal candidiasis in cirrhotic patients, showing high rates of ICU admission (50%), non-albicans Candida infections (46%),
hospital-acquired infection 18182 aureus, MRSA) in the LC group[[43]]. In a study showing mortality rates of 37% among LC patients with hospital-acquired infection s, sepsis was an independent factor for hospital death (P = 0.005; 95%CI: 1.7-21.4)[[18]]. Another study
infectious disease 61438 involvement of multidisciplinary teams, including transplant surgeons, hepatologists, specialists in infectious disease s and infection control, microbiologists, and pharmacologists[[175]-[180]]
invasive aspergillosis 55809 non-Candida infections. Voriconazole (and most recently, isavuconazole) remain the drug of choice for invasive aspergillosis , although limitations in its use in LTR and patients with compromised liver function are represented
meningitis 11154 tissue infections (SSTI) (Table 1)[[18],[20]].Few reports have also documented high rates of bacterial meningitis among patients with cirrhosis compared to those without liver disease, including pneumococcal infections[[31]].
meningitis 11369 infections[[31]]. Increased creatinine serum levels were associated with mortality in cirrhotic patients with meningitis [[32]]. The overall incidence of bacteremia, urinary tract infections, pneumonia, meningitis, tuberculosis,
meningitis 11461 patients with meningitis[[32]]. The overall incidence of bacteremia, urinary tract infections, pneumonia, meningitis , tuberculosis, and liver abscess appeared increased more than tenfold in LC, and mortality rates of
pneumonia 4949 (e.g., urinary and central venous catheters, CVC) pose patients at risk of nosocomial infections such as pneumonia , CVC-related bacteremia, and urinary tract infections. Furthermore, the use of immunosuppressive agents
pneumonia 5502 (16), UTI (11)GNB (53)25[28]201761; n = 852Only BSI included; primary (60), abdominal (33), UTI (7), pneumonia (6)GNB (60)23[22]201538; n = 401Pneumonia (22), UTI (21), SBP (19)E. coli (72)31[23]201251; n = 207UTI
pneumonia 5678 (19)E. coli (72)31[23]201251; n = 207UTI (52), SBP (23), BSI (21)GPB (56)24[19]201033; n = 150UTI (37), pneumonia (22), BSI (13)GNB (62)37[18]200745; n = 233UTI (43), pneumonia (25), SBP (16)GNB (65)18[20]200325; n
pneumonia 5741 (21)GPB (56)24[19]201033; n = 150UTI (37), pneumonia (22), BSI (13)GNB (62)37[18]200745; n = 233UTI (43), pneumonia (25), SBP (16)GNB (65)18[20]200325; n = 135UTI (31), SBP (26), pneumonia (25)NR9[25]200222; n = 70BSI
pneumonia 5814 (62)37[18]200745; n = 233UTI (43), pneumonia (25), SBP (16)GNB (65)18[20]200325; n = 135UTI (31), SBP (26), pneumonia (25)NR9[25]200222; n = 70BSI (16), CVC-BSI (9), liver abscess (3)GPB (67)29[24]200232; n = 507SBP (24),
pneumonia 5938 (25)NR9[25]200222; n = 70BSI (16), CVC-BSI (9), liver abscess (3)GPB (67)29[24]200232; n = 507SBP (24), UTI (19), pneumonia (14), CVC-BSI (8)GPB (47)22[17]200134; n = 361UTI (41), SBP (23), BSI (21), pneumonia (17)E. coli (25)15[8]199439;
pneumonia 6024 (24), UTI (19), pneumonia (14), CVC-BSI (8)GPB (47)22[17]200134; n = 361UTI (41), SBP (23), BSI (21), pneumonia (17)E. coli (25)15[8]199439; n = 132SBP (44), UTI (26), pneumonia (16)GNB (65), E. coli (62)29[27]199347;
pneumonia 6090 361UTI (41), SBP (23), BSI (21), pneumonia (17)E. coli (25)15[8]199439; n = 132SBP (44), UTI (26), pneumonia (16)GNB (65), E. coli (62)29[27]199347; n = 170SBP (31), UTI (25), pneumonia (21)GNB (72)17[26]NR: Not
pneumonia 6167 132SBP (44), UTI (26), pneumonia (16)GNB (65), E. coli (62)29[27]199347; n = 170SBP (31), UTI (25), pneumonia (21)GNB (72)17[26]NR: Not reported; BSI: Bloodstream infections; SBP: Spontaneous bacterial peritonitis;
pneumonia 11022 25%[[8]]. Besides SBP, other frequent infections in cirrhotic patients include urinary tract infections, pneumonia , and skin and soft tissue infections (SSTI) (Table 1)[[18],[20]].Few reports have also documented high
pneumonia 11450 cirrhotic patients with meningitis[[32]]. The overall incidence of bacteremia, urinary tract infections, pneumonia , meningitis, tuberculosis, and liver abscess appeared increased more than tenfold in LC, and mortality
pneumonia 13048 SBP[[38],[39]]. Other microbiological tests include sputum and/or bronchoalveolar lavage cultures if pneumonia is suspected, stool cultures (including assays for Clostridium difficile diagnosis) in case of GI symptoms,
pneumonia 15728 however, should be limited due to their high potential for antimicrobial resistance selection.Nosocomial pneumonia represents a frequent life-threatening infection in LC. Antimicrobial options include a beta-lactam
pneumonia 27735 infections of 27% and 19%, respectively, mainly caused by ESBL-producing E. coli and carbapenem-resistant K. pneumonia e[[65],[66]]. MDRO accounted for nearly one-third of BSI in cirrhotic patients in a European multicenter
pneumonia 30923 surgical site infections[[74],[75]]. A prospective study including LTR with BSI identified CVC-BSI (31%), pneumonia (24%), and abdominal and/or biliary infections (14%) as most common sources of bacteremia. Diabetes
pneumonia 31867 nocaridosis, tuberculosis, etc.) are considered more common between 1 and 6 mo post-transplant, although pneumonia and intra-abdominal infections can still occur during this period. Risk factors that may favor bacterial
pneumonia 35492 BSI-associated mortality[[80]]. Potential sources of BSI include intra-abdominal infections (IAI), CVC-BSI, pneumonia , and, less frequently, urinary tract infections. Need for re-operation, prolonged use of indwelling
pneumonia 35736 graft rejection represent predisposing factors for BSI[[79]]. Gram-negative bacilli such as E. coli, K. pneumonia e, and P. aeruginosa are often the most commonly isolated pathogens, although enterococci, viridans streptococci,
pneumonia 36047 cultures from CVC and peripheral vein represent the gold standard for the diagnosis of BSI and CVC-BSI. If pneumonia or urinary tract infections are suspected, additional cultures (e.g., sputum, bronchoalveolar lavage,
pneumonia 41912 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
pneumonia 41978 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
pneumonia 42020 pneumonia (ceftaroline), community-acquired and hospital-acquired pneumonia excluding ventilator-associated pneumonia (ceftobiprole). MDR: Multidrug resistant; BLBLI: Beta-lactam/beta-lactamase inhibitor combination; BSI:
pneumonia 42949 Extended-spectrum-beta-lactamase Enterobacteriaceae.Methicillin-resistant S. aureus:S. aureus is an important cause of BSI, pneumonia , wound infections and IAI in LTR, especially within the first 3 post-transplant months[[88]]. Isolation
pneumonia 44950 options[[88],[107],[108]]. Valid alternatives to vancomycin include linezolid, especially in the treatment of MRSA-related pneumonia , and daptomycin (Table 4)[[108]-[111]]. Furthermore, novel anti-MRSA options have recently become available
pneumonia 46792 from Gram-positive to Gram-negative bacteria infections in the last decade[[71],[81]]. E. coli, K. pneumonia e, and P. aeruginosa currently represent commonly isolated bacteria in BSI after LT[[81],[92]]. Rates
pneumonia 47755 reached 43% in the United States and up to 52% in China[[92],[123]]. MDR P. aeruginosa causing nosocomial pneumonia in LTR has been reported between 50% and 65%[[124]].Rates of extended-spectrum beta-lactamases (ESBL)-producing
pneumonia 48797 for carbapenem-resistance Enterobacteriaceae is not yet established[[127]]. Carbapenem-resistant K. pneumonia e (CRKP), in particular, has emerged as a major threat for immunocompromised and hospitalized patients
septic shock 10168 were more likely to develop ascites, hepatic encephalopathy, hyponatremia, hepatorenal syndrome, or septic shock compared to noninfected ones. Furthermore, SBP can lead to severe renal failure, which is also associated
septic shock 12485 sepsis and multiorgan failure among cirrhotic patients, prompt identification of symptoms and signs of septic shock and assessment of organ function is paramount[[37]]. The diagnostic workup should also aim at identifying
septic shock 14000 rates of antimicrobial resistance, the site of infection, and patients’ clinical presentation (e.g., septic shock ).Patients with SBP usually have infections caused by enteric pathogens, such as Enterobacteriaceae and
septic shock 16898 the increase of endotoxins levels and cytokines can induce systemic inflammatory responses leading to septic shock , multiorgan dysfunction, and death[[29]].A systematic review including 178 studies showed better outcomes
septic shock 18460 cirrhotic compared to non-cirrhotic patients (42% vs 24% respectively, P < 0.001) and among those with septic shock (30% vs 49%, P < 0.05)[[43]]. Based on these data, a novel prognostic stage in the course of cirrhosis
septic shock 22081 showing high rates of ICU admission (50%), non-albicans Candida infections (46%), and occurrence of septic shock (35%). Thirty-day mortality was 35.3% and was independently associated with candidemia (OR = 2.2, 95%CI:
septic shock 22209 Thirty-day mortality was 35.3% and was independently associated with candidemia (OR = 2.2, 95%CI: 1.2-4.5), septic shock (OR = 3.2, 95%CI: 1.7-6), and absence of adequate antifungal treatment (OR = 0.4, 95%CI: 0.3-0.9)[[51]].These
tuberculosis 11473 meningitis[[32]]. The overall incidence of bacteremia, urinary tract infections, pneumonia, meningitis, tuberculosis , and liver abscess appeared increased more than tenfold in LC, and mortality rates of each episode were
tuberculosis 31775 recommended (Table 3)[[76],[77]]. Opportunistic infections (e.g., herpesvirus infections, nocaridosis, tuberculosis , etc.) are considered more common between 1 and 6 mo post-transplant, although pneumonia and intra-abdominal
viral hepatitis 4674 comorbidities associated with liver disease, including obesity, alcohol consumption, malnutrition, viral hepatitis and/or HIV infection predisposes to bacterial and fungal infections[[10]]. Frequent and prolonged hospitalizations

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