Methicillin-resistant Staphylococcus aureus bacteremia among liver transplant recipients: epidemiology and associated risk factors for morbidity and mortality.

Bacteremia due to Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), complicates the clinical course of liver transplantation and is associated with high morbidity and mortality. Intravascular catheters had been reported to be the most frequent source of MRSA bacteremia. Among bacteremic liver recipients, 26.3%-100% of S. aureus were MRSA. Previous studies identified pre-transplant and post-transplant acquired S. aureus carriage, greater severity of liver disease, hepatocellular carcinoma and infection with immuno-modulatory viruses as predictors of S. aureus bacteremia in liver recipients. MRSA bacteremia accompanied by pneumonia and abdominal infections was related to mortality. Vancomycin, as well as daptomycin, is a first-line antibiotic for MRSA bacteremia. The purpose of this review is to better understand the characteristics of MRSA bacteremia by summarizing the epidemiology and antimicrobial resistance of S. aureus, the primary source, and related risk factors for morbidity and mortality of MRSA bacteremia. We have also explored the diagnostic, therapeutic and preventive measures for MRSA bacteremia to improve the outcomes of liver recipients.

Introduction

Staphylococcus aureus harbors several virulence factors that increase its ability to adhere, colonize and invade tissues and sequentially increase the pathogenicity.1,2 Liver transplant recipients have a greater propensity to S. aureus colonization/infections than other solid organ transplant patients because of the complexity of the surgical procedure and the frequent use of intravascular catheters.3 S. aureus bacteremias represented 23.5% of all S. aureus infections and complicated the clinical course of liver transplantation (LT).4,5 Methicillin-resistant S. aureus (MRSA) bacteremias represented 42%–69% of all MRSA infections after LT and increased duration of hospitalization, costs, morbidity and mortality.3,4,6–8

The past 2 decades have seen continuous increase of LT practices in People’s Republic of China. Since January 1, 2015, organ donation from cardiac death donors has become the only legitimate source of organ transplantations in People’s Republic of China, and there were 10,965 patients undergoing LT from January 1, 2015 to December 31, 2017. In our transplant center from January 1, 1999, to December 31, 2017, 18 (6.5%) of 279 consecutive liver recipients underwent 18 episodes of S. aureus bacteremias, while 13 of 18 S. aureus were methicillin resistant. The incidence of S. aureus bacteremia was 28.3% (15/53) before March 18, 2005, and thereafter, the rate decreased to 1.3% (3/226) after various strategies being performed. Having witnessed the development of LT and postoperative MRSA, we would like to summarize the epidemiology and antimicrobial resistance of S. aureus, the primary source, and related risk factors for morbidity and mortality to better understand the characteristics of MRSA bacteremia in liver recipients. We have also attempted to explore the diagnostic, therapeutic and preventive measures for MRSA bacteremia to improve the outcomes of liver recipients.

Methods

Using the search terms “bloodstream infection”, “bacteremia”, “septicemia”, “infection”, “epidemiology”, “microbiology”, “Staphylococcus aureus”, “MRSA”, “risk factor”, “predictor”, “mortality”, “liver transplantation” and “solid organ transplantation”, we searched 4 electronic databases (PubMed, EMBASE, Cochrane library and World Health Organization database-Index Medicus for South East Asia) from the timeframe of 1988 through 2017 for relevant literature published. All searches were augmented by reviewing bibliographic references to confirm potentially relevant studies. During the literature search, no restriction was applied. However, the analysis of drug resistance and mortality rate did not apply to the studies where the sample sizes of patients with S. aureus/MRSA bacteremia were <5.

Relevant morbidity and mortality rates of S. aureus/MRSA bacteremia

S. aureus bacteremia has been reported to have an incidence range of 1%–23.5% and has been responsible for 24% of all bacteremias in patients with liver cirrhosis.9–13 The incidence of S. aureus bacteremia increased from 1.2% before LT to 9.6% after LT, which means S. aureus bacteremia is easier to occur in liver recipients than in liver cirrhotic patients.9

The morbidity of S. aureus bacteremia varied from 0.6% to 29% among liver recipients,5,9,14–36 and for MRSA bacteremia, it was 0.4%–27.4%.5,6,9,14,15,17,19,22,23,26,35,37–40 According to a study conducted at the Pittsburgh VA Medical Center, of 233 consecutive liver recipients, 3.8% underwent MRSA bacteremia during 1989–1993, 24.5% during 1993–1995, 30% during 1996–1998 and 11.3% during 1998–2003.37

The mortality rate in liver recipients with S. aureus bacteremia and MRSA bacteremia has been identified to be 20%–46%34,39,41 and 15%–60%,4,27,37,38 respectively. For those patients with MRSA bacteremia accompanied by pneumonia and abdominal infections, death rate was up to 86%.4 The mortality rates of S. aureus/MRSA bacteremia among liver recipients are illustrated in Table 1.

Table 1

Mortality rates of Staphylococcus aureus/MRSA bacteremia among liver recipients

Study/country	Study period	Mortality rates due to S. aureus/MRSA bacteremia
Singh et al4/USA	1990–1998	15% of liver recipients with MRSA bacteremia at 14 days after onset of bacteremia; 23% of liver recipients with MRSA bacteremia at 30 days after onset of bacteremia
Singh et al37/USA	1989–2003	27.8% of liver recipients with MRSA bacteremia at 30 days after onset of bacteremia
Singh et al41/USA	1995–2005	46.2% of liver recipients with S. aureus bacteremia at 1 year after onset of bacteremia
Bedini et al27/Italy	2000–2005	60% of liver recipients with MRSA bacteremia at 30 days after onset of bacteremia
Hashimoto et al5/Japan	1996–2004	20% of liver recipients with S. aureus bacteremia during the study period
Takatsuki et al38/Japan	1997–2007	50% of liver recipients with MRSA bacteremia
Zhou et al34/People’s Republic of China	2001–2014	45% of liver recipients with S. aureus bacteremia

Abbreviation: MRSA, methicillin-resistant S. aureus.

Previous studies revealed that S. aureus was responsible for 2.3%–46.3%5,9,14,15,18–20,27–32,35–37,42–49 of all pathogens causing bacteremia among liver recipients and MRSA was 1.6%–41.4%.5,9,14,15,18,19,27,35,36,44,45,49,50 In a case report, Doucette et al51 claimed that S. aureus accounted for half of four cases wherein donor-derived bacteremias were transmitted to liver recipients, despite appropriate antibiotic prophylaxis. The incidence rates of S. aureus/MRSA in all pathogens causing bacteremia among liver recipients are shown in Table 2.

Table 2

Incidence rates of Staphylococcus aureus/MRSA in all pathogens causing bacteremia among liver recipients

Study/country	Study period	Type of organisms	Incidence rates (proportion of S. aureus/MRSA in all pathogens causing bacteremia in liver recipients), %
Colonna et al32/USA	1984–1985	GNB+GPB	S. aureus: 9.1
George et al29/USA	1985–1987	GNB+GPB	S. aureus: 3.2
McClean et al30/Canada	1990–1992	GNB+GPB+fungi	S. aureus: 19.0
Wade et al20/England	1990–1993	GNB+GPB	S. aureus: 13.4
Falagas et al31/USA	Unknown	GNB+GPB	S. aureus: 14.5
Singh et al4/USA	1995–1998	GNB+GPB	S. aureus: 46.3; MRSA: 41.4
Torre-Cisneros et al15/Spain	1994–1999	GNB+GPB	S. aureus: 11.8; MRSA: 4.2
Singh et al37/USA	1989–2003	GNB+GPB	S. aureus: 41
Munoz-Price et al28/USA	1994–1999	GNB+GPB	S. aureus: 10.2
Bedini et al27/Italy	2000–2005	GPB	S. aureus: 11.9; MRSA: 11.9
Moreno et al21/Spain	2003–2005	GNB+GPB+fungi	S. aureus: 7.2
Kawecki et al9/Poland	2001–2004	GNB+GPB+fungi	S. aureus: 2.9; MRSA: 2.9
Hashimoto et al5/Japan	1996–2004	GNB+GPB+fungi	S. aureus: 19.2; MRSA: 15.4
Kim et al19/Korea	2005–2007	GNB+GPB+fungi	S. aureus: 7.5; MRSA: 7.5
Bert et al45/France	1997–2007	GNB+GPB+fungi	S. aureus: 19.8; MRSA: 9.9
Iida et al44/Japan	2006–2009	GNB+GPB	S. aureus: 16.2; MRSA: 7.7
Shi et al35/People’s Republic of China	2003–2006	GNB+GPB	S. aureus: 4; MRSA: 4
Lee et al18/USA	1997–2006	GNB+GPB	S. aureus: 15.1; MRSA: 5.8
Karapanagiotou et al47/Greece	2008–2010	GNB+GPB+fungi	S. aureus: 21.1
Sganga et al36/Italy	2008–2011	GNB+GPB	S. aureus: 2.3; MRSA: 2.3
Wan et al43/People’s Republic of China	2002–2012	GNB+GPB+fungi	S. aureus: 20.8
Yeşilkaya et al48/Turkey	2004–2012	GNB+GPB+fungi	S. aureus: 7.1
Kim et al46/Korea	2005–2011	GNB+GPB+fungi	S. aureus: 10.3
Bodro et al50/Spain	2007–2012	GNB+GPB+fungi	MRSA: 3.1
Doucette et al51/Canada	2009–2012	GNB+GPB	S. aureus: 50 of all donor-derived bacteremias
Ye et al42/People’s Republic of China	2003–2014	GNB+GPB+fungi	S. aureus: 15.1
Bodro et al49/Spain	2007–2013	GNB+GPB+fungi	S. aureus: 6.0; MRSA: 1.6
de Oliveira et al1/Brazil	Unknown	GPB	MRSA: 7.8
Berenger et al131/Canada	2003–2012	GNB+GPB+fungi	S. aureus: 10.7; MRSA: 4

Abbreviations: MRSA, methicillin-resistant S. aureus; GNB, Gram-negative bacilli; GPB, Gram-positive bacterium.

Principle sources of S. aureus/MRSA bacteremia

Intravascular catheters were confirmed as the most frequent source of S. aureus bacteremia in several studies.17,20,52,53 A patient’s colonized skin is also a usual source of S. aureus bacteremia after LT.54 Other studies reported that the principle sources of S. aureus bacteremia in liver recipients included primary infection (including either intravascular catheters or unknown source) (21.4%–57.7%), abdominal or biliary tract (7%–33.6%), lung (6%–55%), urogenital tract (1.3%–17%), gastrointestinal tract (52.8%), endocarditis (3.8%), surgical wounds (1.3%–33%) and donor transmission (1.2%).4,14,15,21,25,34,35,41,45,46,51,55–57

Risk factors for MRSA colonization/infection/bacteremia and for S. aureus/MRSA infection/bacteremia-related mortality

Liver recipients are at a high risk of MRSA colonization because of multiple hospital admissions, prolonged stay in hospital and recent broad-spectrum antimicrobial use.58 A number of risk factors for MRSA colonization have been recognized by previous studies, including the severity of patients, prior use of antimicrobial, preoperative use of fluoroquinolones, use of invasive medical devices, postoperative bleeding at the surgical site and prolonged stay in intensive care unit.24,59,60

MRSA colonization is generally seen as a factor strongly related to infection in post-LT.61–64 Other risk factors for MRSA infection after LT are listed as follows: alcoholic cirrhosis, decreased prothrombin ratio, presence of central lines, being intubated, immunosuppressed status, multiple admissions to the intensive care unit, retransplantation and prolonged hospitalization.4,23,24,40,58,61 Additionally, risk factors such as age 60 years or greater, preoperative use of antimicrobials, operation time (>16 hours) and perioperative dialysis and/or apheresis are also known to increase the risk of MRSA infection. However, postoperative use of fluoroquinolone was negatively associated with acquisition of MRSA.22,39,58

As mentioned in limited number of studies, pre-transplant and post-transplant acquired S. aureus carriage, greater severity of liver disease, hepatocellular carcinoma and infection with immunomodulatory viruses such as cytomegalovirus (CMV) increase the risk of S. aureus bacteremia in liver recipients.23,41,45,55

CMV does stimulate certain activities of the host immune system by upregulation of specific T- and B-cell alloimmune responses through innate immune mechanisms or stimulation of alloimmunity via cross-reactive viral antigens, but in aggregate the effects of the virus are immune suppressive.65 Potential mechanisms of CMV-induced immunosuppression included suppression of CD4 T-lymphocyte activation and proliferation, as well as inhibition of the expression of surface-soluble CD14 in alveolar macrophages.66,67 Table 3 provides an overview of risk factors for S. aureus/MRSA infection/bacteremia among liver recipients.

Table 3

Risk factors for Staphylococcus aureus/MRSA bacteremia among liver recipients

Study/country	Microbiology	Risk factors
Singh et al4/USA	MRSA infection including bacteremia	Cytomegalovirus seronegativity and primary cytomegalovirus infection
Desai et al61/England	MRSA infection including bacteremia	MRSA carriage
Bert et al24/France	S. aureus infection including bacteremia	MRSA carriage, MSSA carriage, alcoholic cirrhosis and decreased prothrombin ratio
Singh et al55/USA	S. aureus bacteremia	S. aureus carriage after transplantation
Singh et al41/USA	S. aureus bacteremia	Hepatocellular carcinoma
Hashimoto et al23/Japan	MRSA infection including bacteremia	Operation time (>16 hours) and postoperative colonization with MRSA
Hashimoto et al5/Japan	MRSA infection including bacteremia	Age (≥60 years); preoperative MRSA colonization, preoperative use of antimicrobials, operation time (>16 hours) and perioperative dialysis and/or apheresis predicted postoperative MRSA acquisition Postoperative use of fluoroquinolones was negatively associated with acquisition of MRSA
Russell et al40/USA	S. aureus infection including bacteremia	Candidates and recipients with MRSA colonization
Bert et al45/France	S. aureus bacteremia	Preoperative S. aureus nasal carriage
Florescu et al54/USA	MRSA infection including bacteremia	Recent surgical procedure prior to infection

Abbreviations: MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus.

The isolation of S. aureus, per se, was a risk factor for mortality in solid organ transplant recipients with bacteremia.15 In a single-center retrospective study of 2,959 solid organ transplant patients, Malinis et al16 suggested an association between pulmonary focus and S. aureus bacteremia-related mortality. On reviewing the literature it was found that data are scarce focusing on liver recipients with S. aureus bacteremia. Only one previous study conducted by Singh et al4 documented that MRSA bacteremia accompanied by pneumonia and abdominal infections was associated with mortality in liver recipients. Risk factors for associated mortality in liver recipients with S. aureus/MRSA infection/bacteremia are displayed in Table 4.

Table 4

Risk factors of mortality for liver recipients with Staphylococcus aureus/MRSA bacteremia

Study/country	Transplantation type	Microbiology	Risk factors for related mortality due to bacteremia
Singh et al4/USA	LT	MRSA	Accompanied by pneumonia and abdominal infections
Malinis et al16/USA	SOT including LT	S. aureus	Pulmonary focus

Abbreviations: MRSA, methicillin-resistant S. aureus; LT, liver transplantation; SOT, solid organ transplantation.

Antimicrobial resistance of S. aureus

Previous studies confirmed that, among bacteremic LT, 26.3%–100% of S. aureus were methicillin resistant.4,14,18,26,27,34,35,39,44–46,49 The resistance rates of MRSA to vancomycin, amikacin and ciprofloxacin were 0%, 50% and 53.5%, respectively.45 Ye et al42 analyzed the data from 19 episodes and concluded that 52.6% of S. aureus were resistant to levofloxacin, 26.3% to amikacin and 5.3% to vancomycin. One study conducted by Zhou et al34 reported that S. aureus was highly resistant to erythromycin and penicillin (resistance rates >90%). Table 5 illustrates the drug resistance rates of S. aureus/MRSA causing bacteremia among liver recipients.

Table 5

Drug resistance rates of Staphylococcus aureus/MRSA causing bacteremia among liver recipients

Study/country	Study period	Drug resistance rates
Singh et al4/USA	1990–1998	MRSA (26) responsible for 100% of all S. aureus (26)
Singh et al4/USA	1995–1998	MRSA (17) responsible for 90% of all S. aureus (19)
Bert et al33/France	1997–2002	21.4% (3/14) was heterogeneous glycopeptide-intermediate S. aureus
Bedini et al27/Italy	2000–2005	MRSA (5) responsible for 100% of all S. aureus (5)
Hashimoto et al5/Japan	1996–2004	MRSA (4) responsible for 80% of all S. aureus (5)
Saner et al26/Germany	2003–2006	MRSA (7) responsible for 70% of all S. aureus (10)
Bert et al45/France	1997–2007	MRSA (28) responsible for 56% of all S. aureus (21)14.3% (8/56) was resistant to gentamicin50% (28/56) was resistant to amikacin53.5% (30/56) was resistant to ciprofloxacin0% was resistant to vancomycin
Iida et al44/Japan	2006–2009	MRSA (9) responsible for 47.4% of all S. aureus (19)
Shi et al35/People’s Republic of China	2003–2006	MRSA (13) responsible for 100% of all S. aureus (13)
Lee et al18/USA	1997–2006	MRSA (8) responsible for 38.1% of all S. aureus (21)
Kim et al46/Korea	2005–2011	MRSA (13) responsible for 92.9% of all S. aureus (14)
Ye et al42/People’s Republic of China	2003–2014	10.5% (2/19) was resistant to rifampicin26.3% (5/19) was resistant to amikacin52.6% (10/19) was resistant to levofloxacin5.3% (1/19) was resistant to vancomycin0% was resistant to teicoplanin or linezolid
Bodro et al49/Spain	2007–2013	MRSA (5) responsible for 26.3% of all S. aureus (19)
Zhou et al34/People’s Republic of China	2001–2014	MRSA (16) responsible for 26.3% of all S. aureus (20)90% (18/20) was resistant to erythromycin70% (14/20) was resistant to clindamycin50% (10/20) was resistant to levofloxacin75% (15/20) was resistant to trimethoprim-sulfamethoxazole30% (6/20) was resistant to amikacin95% (19/20) was resistant to penicillin10% (2/20) was resistant to rifampicin80% (16/20) was resistant to oxacillin0% was resistant to vancomycin or teicoplanin or linezolid

Abbreviation: MRSA, methicillin-resistant S. aureus.

Reasons for the high rates and wide ranges of both S. aureus/MRSA bacteremia and its related mortality

The great number of S. aureus/MRSA bacteremia in LT population is probably explained by a global trend of epidemiology of microbiology, antibiotic prophylaxis such as quinolones for spontaneous bacterial peritonitis, prolonged use of central venous catheters, high immunosuppression required due to the immunity of the allograft and, most importantly, the poor general condition before LT.10,62,68 The high mortality rate in LT population could be partly explained by virulence of S. aureus strains and high frequency of drug resistance.4,69–71 Furthermore, bacteremia, per se, could also be a marker of other factors related to higher mortality, comprising poor graft function, surgical complications and prolonged intensive care unit stay.72

We noticed that there is a wide range of morbidity and mortality of bacteremia between centers, and this phenomenon might result from geographic differences in microbiological environments, along with various diagnostic criteria, severity of the illness, colonization pressure, the frequency of performing active surveillance cultures, immunosuppressive drugs and study designs. As for MRSA bacteremic LT patients, studies differed between the study periods, the follow-up duration, the intrinsic virulence of S. aureus strains or between centers performing the different prophylactic and therapeutic antimicrobial strategies, causing the diversity in outcomes.73,74 The death rate also varied significantly for different sources of bacteremia. Singh et al4 described that mortality was 67% for bacteremic liver recipients accompanied with pneumonia, 6% for those with abdominal infection and 0% for patients with catheter-related infection or wound and urogenital infections.

Diagnosis of MRSA colonization and infection

In the past, the isolation of pathogens by traditional cultures used to take 96 hours, whereas with new methods using the GeneOhm™ MRSA polymerase chain reaction test and GeneXpert MRSA/SA test, only 27.6 and 21.4 hours are required, respectively.75 Rapid molecular diagnostics within hours rather than days enable the prompt pre-emptive treatment of S. aureus carriers when appropriate.76,77

Molecular characterization allows clinicians to know if there is a resistance gene related to antimicrobials, such as mupirocin, or antiseptics such as chlorhexidine in MRSA isolates to propose a future intervention study.78,79 Thanks to advances in molecular methods, we are now able to evaluate MRSA isolates and to develop strategies to control and prevent colonization and infection (for example, chlorhexidine baths and treatment with nasal mupirocin). The methods include staphylococcal chromosome cassette mec by polymerase chain reaction, multilocus sequence typing, whole-genome sequencing, pulsed-field gel electrophoresis and Staphylococcus protein A typing.69,80,81 Staphylococcal chromosome cassette mec typing and pulsed-field gel electrophoresis are helpful for understanding the molecular epidemiology of MRSA with the latter one showing a greater discriminatory power, whereas Staphylococcus protein A typing is useful for both investigation of hospital outbreaks and studies of molecular evolution of MRSA preventive measures for MRSA bacteremia.1,81,82

The aforementioned results of high morbidity and mortality among liver recipients highlight the urgency to curtail the incidence of MRSA bacteremia. There are some measures to prevent MRSA bacteremia in liver recipients the same as those in nonimmunosuppressed hospitalized patients, including source control, preservation of kidney function, restriction of the use of invasive devices and equipment, removing all unnecessary catheters at the earliest possible time and minimizing postoperative length of stay in intensive care unit.

MRSA colonization before LT occurred in 5.1%–47.4% of the cases.23,55 Up to 87.5% of colonized patients developed MRSA infections, which contained bacteremia.4,24,39,61,78,83–85 Thus, we should keep a close eye on MRSA colonization. Preoperative and postoperative screening for MRSA nasal carriage is crucial, and control measures of eliminating nasal carriage of S. aureus should be taken. Furthermore, medical workers should take actions to prevent transmission of MRSA from patient to patient, such as hand washing with hydroalcoholic solutions.17,24,86,87 Intranasal mupirocin 2% ointment with or without a combination of chlorhexidine gluconate body wash could be used to eradicate both methicillin-susceptible S. aureus (MSSA) and MRSA in liver recipients with S. aureus carriage, but mupirocin resistance may exist.88–91

Catheter-related bacteremia caused by MRSA was preventable with appropriate prevention strategies.72 Strict adherence to the principles of intravascular catheter management established by CDC sharply reduced its incidence.92–94 Skin antisepsis with chlorhexidine gluconate or daily skin cleansing with 2% chlorhexidine gluconate can also control this type of bacteremia well.95 Other studies have reported the efficacy of antibiotic impregnated catheters.96

When serious MRSA infections occur, it is suggested to reduce or remove immunosuppressive agents to elevate host reactivity and to prevent the onset of MRSA bacteremia. Corticosteroids can block transcription of cytokine genes and nonspecific inhibition of T lymphocytes and macrophages. Maintenance treatment without prednisone, therefore, can decrease the development of MRSA bacteremia.

The treatment for donors with S. aureus colonization and/or infections and a surveillance of liver recipients of organs from donors with S. aureus bacteremia were also needed, since S. aureus may be transferred in the donated organs and appropriate prophylaxis did not eliminate the risk of transmission.51,97–99 However, the addition of vancomycin or teicoplanin should be reserved for confirmed MRSA sepsis rather than for decolonization therapy for MRSA carriers, because overuse of these glycopeptide antibiotics could be associated with other potential problems such as superinfection.100

Effects of infection control measures on reducing colonization/infection rates and mortality

The prevalence of newly detected MRSA colonization by active surveillance cultures declined from 8.0% to 5.4%.40 Russell et al40 found that the rate of health care-associated MRSA infection declined from 4.1 per 1,000 patient days during 2001–2003 to 1.2 per 1,000 patient days during 2004–2006, as a result of active surveillance cultures in all liver service units since 2002. Another previous study at a university hospital also reported that despite the number of MRSA-colonized patients went up during a 3-year period, the proportion of MRSA infection cases decreased from 50% to 6% after the successful use of active surveillance cultures, barrier precautions and decolonization therapy for carriers.87 The incidence of hospital-acquired MRSA cases significantly decreased after a successful hand hygiene promotion program in a district hospital in the UK.101 In London, researchers at St George’s hospital reported that reductions in MRSA rates were strongly associated with reducing the prescribing of cephalosporins and ciprofloxacin.102

One of the largest transplant centers reported an impact of an aggressive infection control strategy in liver recipients, which decreased the rate of S. aureus bacteremia from 26% to 4%, including positive screening for nasal and rectal colonization, effective isolation strategies and decolonization with intranasal mupirocin therapy.55 Various strategies could lead to a decline in the proportion of MRSA bacteremia.37 According to Hashimoto et al,5 following infection control policies and standard perioperative prophylaxis aimed at decreasing either the risk of MRSA colonization or infection, only 2.1% (5/242) of liver recipients developed S. aureus bacteremia and of these 242 patients, only 1 (0.4%) (1/242) died of bacteremia.

Clinical management of S. aureus bacteremia

Choosing empirical antibiotic therapy while awaiting for the results of blood cultures must take into account susceptibility changes of S. aureus causing bacteremia and the high frequency of MRSA. Currently, glycopeptides (vancomycin, teicoplanin), linezolid, daptomycin, quinupristin-dalfopristin and, more recently, tigecycline are several treatment options for MRSA infection.103–105 The standard treatment for MRSA is glycopeptide, which has been widely used, but its current administration to treat MRSA infections has been in great debate because it has a modest effect despite showing in vitro sensitivity.106 Takatsuki et al38 had introduced their successful experience of salvage therapy with linezolid after teicoplanin failure for systemic severe MRSA infection, while others107 demonstrated that none of them was proven to work as good as vancomycin against MRSA.

Vancomycin and daptomycin are the only two FDA-approved agents for the treatment of MRSA bacteremia in the US. Therefore, a recent review still recommended them as the first-line antibiotic therapy for MRSA bacteremia.108 As far as concentrations of vancomycin were concerned, trough monitoring was recommended to achieve target concentrations of 15–20 μg/mL.109 It is important to note that vancomycin is less effective for the treatment of MSSA bacteremia and endocarditis when compared with β-lactam agents.110,111 Patients receiving empirical vancomycin who are found to have catheter-related bacteremia due to MSSA should be switched to cefazolin.112

MRSA treated with vancomycin is associated with reduced vancomycin susceptibility and treatment failure.113 The prevalence of heteroresistant vancomycin-intermediate S. aureus is also increasing; antibiotics with in vitro activity against it comprised linezolid, daptomycin, ceftaroline, tigecycline and quinupristin/dalfopristin.114 However, drug resistance of S. aureus to these antibiotics is described.115 Furthermore, according to the black box warning by FDA, tigecycline, which can increase the risk of death, should be reserved only for situations in which alternative treatments are not suitable.108

Telavancin is a novel lipoglycopeptide antibiotic with potential activity against MRSA. It was successful in treating MRSA bacteremia in some case reports.116–118 Nonetheless, in a study involving 73 patients with bacteremic pneumonia, telavancin was not related to a significant difference in cure rate when compared with vancomycin.119

It is notable that combination therapy for MRSA bacteremia appeared no more effective and was even more harmful than vancomycin monotherapy. Adding gentamicin, rifampin or both to vancomycin offers no meaningful benefit and may confer harm for treating MRSA bacteremia.120,121 The addition of a β-lactam antibiotic to vancomycin or daptomycin for treating MRSA bacteremia has unproven benefit.122 The mortality on day 30 was 41% among those who received combination therapy compared with 7% (1/14) among those who received vancomycin monotherapy in liver recipients with MRSA bacteremia.4

As far as duration of antibiotic use is concerned, when organs are utilized from donors with S. aureus bacteremia, recipients should receive a relatively long (2–4 weeks) antibiotic course.51,123 Based on published guidelines and observational studies, MRSA bacteremia should be administrated intravenous (IV) antibiotic therapy of ≥14 days for uncomplicated bacteremia or ≥28 days for complicated bacteremia.88,108,112 Transplant patients with S. aureus catheter-related bacteremia should receive 4–6 weeks of antimicrobial therapy.112 For adults with infective endocarditis, IV vancomycin or daptomycin 6 mg/kg/dose IV once daily for 6 weeks is recommended.109

Infectious disease consultation is nowadays a great concern. It is likely that the reduction in all-cause mortality in patients with S. aureus bacteremia is via improved quality measures of management, including removal of infectious foci, repeat blood culture, echocardiography, appropriate antibiotic therapy and administration of prolonged treatment of complicated infections.124,125 A large multicenter cohort study suggested that in the non-transplant population with S. aureus bacteremia, infectious disease consultation is associated with better adherence to quality measures, reduced in-hospital mortality and earlier discharge.126 In a single-center retrospective study, Malinis et al16 reported that infectious disease consultation, as one of contributing factors in reducing mortality, was obtained in 65 of 70 (93%) solid organ transplant patients.

Source control by eliminating and/or debriding primary sites of bacteremia was recommended and additional blood cultures 2–4 days after initial positive cultures were needed, especially when vancomycin treatment failed and MRSA bacteremia was persistent.109 Within the liver, Kupffer cells are optimally positioned within the vasculature to encounter circulating bacteria, which are critical for their clearance from the bloodstream during steady state and during sepsis.127–129 Kupffer cells contribute to neutrophil recruitment and their dysfunction is a risk factor for post-LT bacteremia.130 It can be explained by Kupffer cell dysfunction if any case of otherwise unexplained persistent MRSA bacteremia occurs in a post-LT patient, despite having been treated with an appropriate anti-microbial agent.

Prolonged therapy and early evaluation for valve replacement surgery are recommended if prosthetic valve infective endocarditis is confirmed.109 In addition, all liver recipients with S. aureus bacteremia should be evaluated with echocardiography, preferably by transesophageal echocardiography unless the patient meets criteria for being at low risk.16,108

Future research

Given the considerable morbidity and mortality in liver recipients with MRSA bacteremia, considerably more work will need to be done to explore more intensive prophylactic measures and effective treatments.

Data are lacking with regard to the risk factors for the development of MRSA bacteremia, particularly its associated mortality, after LT. In addition, most of the literature studies provided just a general comment about preventive measures and did not specifically focus on LT with MRSA bacteremia. The safety and outcomes linked with donor-transmitted MRSA infections are controversial.4,14,51 Chlorhexidine resistance has not been frequently described in MRSA isolates. However, the efficacy of mupirocin prophylaxis on MRSA infection in LT is debatable.17,38 Evidence from well-controlled studies, therefore, is needed to better confirm the risk factors for MRSA bacteremia and its related mortality, and to better confirm the efficacy of mupirocin in this population thus to form specifically preventive strategies.

Treatment data specific to liver recipients with S. aureus bacteremia are also limited. Since inadequate empirical therapy has been identified as a significant risk factor for bacteremia-related mortality, more funding and clinical trials are urgently needed to explore therapeutic options for MRSA. Data were also particularly scarce regarding the proportion of liver recipients with S. aureus bacteremia who received infectious disease consultation. A future challenge will be to ensure that this patient population benefit from this expert advice and improved care.

Recommendation for prevention and management of S. aureus/MRSA colonization/infection/bacteremia

The incidence of S. aureus bacteremia decreased from 28.3% to 1.3% in our liver recipients when appropriate measures were taken. Our recommendations for management of S. aureus colonization and infection for now are as follows: 1) removing the risk factors for S. aureus/MRSA colonization/infection/bacteremia such as reducing broad-spectrum antibiotics for prophylaxis and using invasive medical devices and central lines, and minimizing postoperative length of stay in the intensive care unit and hospital; 2) improving surgical techniques and reducing intraoperative bleeding and transfusions; 3) using molecular methods to diagnose MRSA colonization and infection; 4) controlling source by eliminating and/or debriding primary sites of bacteremia; 5) preventing transmission of MRSA from patient to patient such as strict hand hygiene measures and effective isolation strategies; 6) treating donors with S. aureus colonization and/or infections; 7) preoperative and postoperative screening and decolonization therapy for S. aureus/MRSA carriers in liver recipients; and 8) using vancomycin and daptomycin as the first-line antibiotic therapy for MRSA bacteremia.