REVIEW URRENT C OPINION

Bacterial biliary tract infections in liver transplant recipients Christian van Delden

Purpose of review The purpose of this study is to provide an overview of bacterial biliary tract infections in liver transplant recipients with a focus on pathogenesis and conservative treatment strategies. Recent findings The development of interventional endoscopic and radiologic interventions has improved the outcome of conservative treatments for bile tract strictures and bilomas. However, recent data show an important rise of infections with multidrug-resistant (MDR) pathogens in liver transplant recipients. Summary Both recurrent cholangitis and infected bilomas are bacterial biliary tract infections in liver transplant recipients responsible for significant morbidity and graft loss, which require a multidisciplinary approach. Risk factors for biliary tract strictures and bilomas formation have recently been identified. With the improved outcome of a conservative management including prolonged and/or recurrent antibiotic treatments, the risk of selecting resistant pathogens is increased. There is an urgent need to develop new strategies to reduce the risk of secondary infections by MDR isolates in liver transplant recipients. Keywords liver transplantation, multidrug resistant, recurrent cholangitis bilomas

INTRODUCTION Bacterial, and especially intra-abdominal infections, remain a serious and frequent complication following liver transplantation, with a reported incidence of up to 80% depending on the series [1–3]. Biliary tract infections (BTIs) are particularly frequent during the first year posttransplantation being responsible for up to 38% of all bacterial infections [2] (Table 1 [2,4–6]). A recent study including 501 Finnish adult liver transplant recipients has highlighted the importance of BTI even later after liver transplant, with an incidence still increasing up to 21.8 per 1000 person-years between 1 to 5 years postliver transplant and decreasing to 2.5 per 1000 person-years only 11–15 years postliver transplant [4]. Most of these late BTIs were ascending cholangitis. Given its high frequency as a the primary site of bacterial infection, it is not surprising that BTI is responsible for up to 30% of bacteremia episodes occurring in liver transplant recipients [7]. However, in a study including 117 bacteremia episodes occurring in 62 out of 181 liver transplant recipients, BTI was not identified as a direct risk factor for blood stream infections [8]. Postliver

transplant BTIs can be classified in either recurrent cholangitis or infected bilomas.

RECURRENT CHOLANGITIS Risk factors for recurrent cholangitis include ascending infections associated with primary sclerosing cholangitis and the Roux-en-T-type of biliary anastomosis (hepatico-jejunostomy) [4]. Another significant risk factor for recurrent cholangitis are biliary strictures that are classified as anastomotic strictures and nonanastomotic strictures (NAS) [9,10 ]. NAS are either secondary to hepatic artery thrombosis or of the ‘ischemic-type biliary lesions’, involving &

Service of Transplantation, Department of Surgery, University Hospitals Geneva, Geneva, Switzerland Correspondence to Christian van Delden, Service des Maladies Infectieuses, De´partement des Spe´cialite´s de Me´decine, Hoˆpitaux Universitaires de Gene`ve, 4 rue Gabrielle-Perret-Gentil, CH1211 Geneva 14 Switzerland. Tel: +41 22 372 32 07; e-mail: [email protected] hcuge.ch Curr Opin Organ Transplant 2014, 19:223–228 DOI:10.1097/MOT.0000000000000083

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Table 1. Reported incidence of bacterial biliary tract infections in liver transplant recipients Type of infection

Incidence (%)

Biliary tract

8.8

Cholangitis

10

Biliary tract Biloma

References [2] [4]

3.5

[5]

11.5

[6]

fibrosis following biliary epithelium injury. Whereas NAS are usually multiple, and located in the intrahepatic ducts and/or proximally to the anastomosis on the donor duct, anastomotic strictures are single lesions localized at the anastomosis. Old-donor age, marginal grafts, prolonged ischemia time, partial liver transplant or living-donor liver transplant, as well as donation after cardiac death, have been associated with an increased risk of stricture formation [10 ]. Due to immunosuppression, signs and symptoms of cholangitis following liver transplant are frequently subtler than in the nontransplant population, especially in the presence of high doses of steroids given to treat a concomitant and/or suspected allograft rejection. Therefore, fever, unexplained systemic inflammation (elevated C-reactive protein, leukocytosis), abdominal pain and cholestatic pattern liver function tests in a liver transplant recipient should lead to a work-up including blood cultures and an abdominal Doppler ultrasound to detect biliary obstruction and evaluate the hepatic vasculature [11 ]. Magnetic resonance cholangiography (MRC) or endoscopic retrograde cholangiography (ERC) might be used in a second step to detect biliary strictures. Bactobilia occurs frequently after liver transplant as highlighted by cultures of bile fluid obtained by ERC from 66 liver transplant recipients, of whom 73% were positive as compared with only 16% of cultures from nonliver transplant controls [12]. In this study, Gram-positive bacteria predominated (48%), followed by Gram-negative (39%) and fungi (9%). Microbiology data specifically for cholangitis in liver transplant recipients are scarce. Even if cholangitis predominate in most studies investigating infectious complications in liver transplant recipients, the microbiology data provided frequently originates from various infectious sites, also including intra-abdominal abscesses, blood-stream infections, pneumonia and urinary tract infections [1,2,4,5]. In one study, Enterococcus sp. predominated during the first 6 months posttransplantation, whereas biliary tract related Escherichia coli was the major causative organism after 6 months [1]. &

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As a general observation, it appears that Grampositive organisms including Enterococcus sp. and Staphylococcus sp. are more frequent in the first months after transplantation. However, as a result of the recurrent exposure to antibiotics, not only Gram-negative pathogens, including Enterobacteriaceae (E. coli, Klebsiella pneumonia and so on), but also nonfermenters such as Pseudomonas aeruginosa become more frequent in recurrent episodes of cholangitis after 6 months. Several studies have recently described an alarming rise of infections with multidrug-resistant (MDR) pathogens in liver transplant recipients [13 –15 ]. These include extended-spectrum beta-lactamase (ESBL) and carbapenemase producing Gram-negative bacteria (E. coli, K. pneumonia, P. aeruginosa and Acinetobacter baumannii), as well as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus sp. (VRE) [16–19,20 ,21,22]. Most of these episodes were blood stream infections with some being of biliary origin. In a Chinese report including 190 bacteremic episodes in 475 liver transplant recipients, the incidence of MDR isolates reached 56% [17], whereas a recent Italian study reported an incidence of 41% [22]. Recurrent cholangitis has not been described so far as a risk factor for infections with MDR isolates. It is however likely that the frequent exposure to antibiotics of liver transplant recipients with recurrent cholangitis increases their risk of acquiring MDR isolates over time. In the presence of recurrent cholangitis, biliary strictures must be searched for, and corrected by percutaneous balloon dilatation, plastic endoprosthesis or surgical correction. The management of both anastomotic and nonanastomotic strictures requires a multidisciplinary approach recently reviewed elsewhere [10 ,11 ]. Lengthening the Roux-en-Y limb to eliminate bile reflux and stasis might be helpful to prevent recurrent cholangitis [23]. Whereas the success rate is high in anastomotic strictures, NAS still leads to graft failure in a significant number of cases [8,24]. &&

&&

&

&

&

INFECTED BILOMAS Infected bilomas are infected intrahepatic or parahepatic bilious collections [25]. Such biliary tract complications described in case reports and limited case series in 7–31% of liver transplant recipients have been frequently associated with hepatic artery thrombosis [26–30]. In a retrospective case–control study, infected bilomas were found in 57 out of 493 (11.5%) liver transplant recipients [6,31] (Table 1); 95% occurred during the first 12 months postliver transplant, with a median time to diagnosis of Volume 19  Number 3  June 2014

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9 weeks postliver transplant [31]. Intrahepatic collections were more frequent (67%), and the number of bilomas was 1.8 per patient, with up to four collections per patient. Their size varied from 1 to 11 cm. Cumulative mortality was significantly increased in liver transplant recipients with bilomas as compared with controls [odds ratio (OR) 2.4], with a 1-year mortality increase from 6 to 12% and a 3-year mortality from 11 to 21% [31]. The pathogenesis of biloma formation involves both ischemic necrosis subsequent to hepatic artery thrombosis (frequently complicating hepatic artery stenosis), and ischemic-type bile duct lesions in the absence of hepatic artery thrombosis [6,32,33]. Insufficient blood supply by the hepatic artery results in bile duct damage and subsequent leakage of bile leading to formation of a bilious collection. Such collections, if not infected at onset, are prone to become infected in the presence of factors favouring ascending infections such as Roux-en-Y-type biliary anastomosis, prolonged T-tube drainage, as well as during bacteremia from distant sites [6,34,35]. Parahepatic biloma are mostly associated with anastomotic bile duct leaks. Risk factors for biloma formation identified in several series included operative factors, cytomegalovirus donor–recipient status, early rejection, advanced donor age and female to male donation [27,33,36,37]. However, in a more recent case–control study [6], neither intraoperative or perioperative factors (cold ischemia time and T-tube use), nor frequency of rejection or type of immunosuppression were associated with an increased risk of bilomas formation. In multivariate analysis, the strongest risk factor was hepatic artery thrombosis with an OR of 90.9, followed by hepatic artery stenosis (OR 13.1), and Roux-en-Y-type biliary anastomosis (OR 5.8). The use of ursodeoxycholic acid was protective (OR 0.1). Strikingly, T-tube placement was associated with the isolation of coagulase-negative staphylococci (OR 9.6), suggesting that cutaneous pathogens colonizing these T-tubes gain access to the biliary tract via such tubes. Pretransplantation renal disease (OR 12.5) and infections with either Gram-negative microorganisms (OR 9.1) or Candida species (OR 4.9) have been identified as independent predictors for death in liver transplant recipients with bilomas [31]. Bilomas presented with fever (44%), abdominal pain (40%) and persistently abnormal liver enzyme levels (77%) [3,31]. However, 35% were asymptomatic and identified during work-up for unexplained abnormal liver function tests. Biphasic contrast-enhanced computed tomography (CT) remains the imaging test of choice [31]. Culture of fluid obtained by percutaneous aspiration is

essential to distinguish infected bilomas from sterile collections. Blood cultures were positive in only 16% at the time of biloma detection [6]. In contrast to liver abscesses in the nonliver transplant population, Gram-positive bacteria were the most frequent pathogens isolated from initial percutaneous aspirates of 57 bilomas [6,31]. Enterococci (37%) predominated, followed by coagulasenegative staphylococci (26%) and Candida spp. (26%). Gram-negative bacteria (Enterobacteriaceae and P. aeruginosa) were cultured in only 16%. Such predominance of Gram-positive microorganisms was also reported by others [28]. In 95% of latter cultures from percutaneous drainage catheters, multiple superinfecting pathogens were isolated. Although Gram-positive organisms remained frequent in these latter cultures, the incidence of Gram-negative bacteria increased, with Enterobacteriaceae reaching 35% and P. aeruginosa reaching 20%. Candida spp. were cultured in 79% of cases. The frequency of MDR (ESBL, VRE and fluconazoleresistant Candida glabrata) isolates increased in latter cultures, likely resulting from prolonged antibiotic exposure, with VRE increasing from 48 to 83% [6,31]. Because of their significant associated mortality, the classic approach of bilomas has been early retransplantation [3,27,38]. More recently, nonsurgical management of bilomas, including percutaneous drainage and prolonged antibiotic therapies, has been reported with some success [26,30,31,33,39]. This is particularly true for extrahepatic bilomas without evidence for ischemic cholangitis and biliary necrosis [31]. Percutaneous needle aspiration and culture of biloma fluid is essential to determine the optimal antibiotic therapy that should be tailored to each case and given for prolonged duration (4–6 weeks). Given the danger of superinfection with MDR isolates, it is essential to minimize the selection pressure by adapting the initial empiric therapy to culture results and using narrow spectrum antibiotics when possible. The best approach of drainage depends whether the collection is in communication with the biliary tree on cholangiography. Endoscopic stenting is indicated in the presence of communication, whereas percutaneous drainage should be obtained in its absence. In a series of 34 bilomas managed initially nonsurgically, resolution without the need for retransplantation was observed in 68% [31]. In a multivariate analysis, favourable outcome depended on the absence of hepatic artery thrombosis (OR 7.7), absence of enterococci (OR 7.7) and absence of Candida species (OR 9.1) [31]. If graft function is conserved, and the infection adequately controlled by drainage and antibiotic therapy, an initial nonsurgical

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management can be tempted. Second step-delayed retransplantation in the case of failure of an initial conservative attempt, might not be associated with a worse outcome than early retransplantation [31].

ANTIBIOTIC THERAPIES FOR BILIARY INFECTIONS IN LIVER TRANSPLANT RECIPIENTS The choice of antibiotic therapy should always be guided by culture results (blood cultures, aspiration or drainage fluid), with the attempt to avoid broadspectrum antibiotics whenever possible. The choice should take into account biliary drug concentrations, side effects and potential interactions with concomitant immunosuppressive therapies. Initial empiric therapies should be adapted to Gram-staining and culture results. However, cultures from drainage fluid might secondarily yield microorganisms that colonize the drainage tubing and do not necessarily establish their pathogenic role inside biliary collections. If new pathogens are cultured from drainage fluid, antibiotic therapies should only be adapted if the clinical situation worsens, or if a new transcutaneous aspiration of biliary fluid corroborates their presence directly in the biliary collection. Traditionally, ceftriaxone has been widely used for biliary infections because of the very high bile concentrations of this drug [40,41] (Table 2). However, ceftriaxone does not cover enterococci and has been associated with the selection of ESBL-producing Enterobacteriaceae. Treatment strategies for MDR Gram-negative pathogens in solid organ transplant recipient have been recently

&&

reviewed [13 ]. If required for ESBL Enterobacteriaceae or P. aeruginosa infections, carbapenem (imipenem, meropenem and ertapenem) antibiotics generally achieve good bile concentrations; however, ertapenem does not cover P. aeruginosa [42–44]. For carbapenemase-producing Enterobacteriaceae, tigecycline reaches adequate bile levels [45]. However, tigecycline reaches poor blood levels and should not be used in monotherapy in the presence of bacteremia [13 ]. For VRE or vancomycin-resistant Staphylococcus infections, both daptomycin and linezolid can be used [14 ,15 ,46,47] (Table 2). In the case of recurrent cholangitis, reducing the bacterial intestinal and bile burden might be an appealing strategy. Several approaches have been tempted to prevent infections after liver transplantation including selective digestive decontamination (SDD), the use of pre- and probiotics, as well as granulocyte colony-stimulating factors [48–51]. SDD in liver transplant recipients is controversial with strong supporters on both sides [52,53]. Whether SDD could reduce the incidence of recurrent cholangitis has been insufficiently investigated. Rifaximin has recently been shown to reduce the incidence of hepatic encephalopathy and suggested to be beneficial in inflammatory bowel disease and Clostridium infections [54–56]. This minimally absorbed oral antibiotic reaches high stool concentrations and covers most intestinal pathogens. It could theoretically be beneficial in reducing the bacterial burden in the intestinal tract. However, enterococci and Enterobacteriaceae rapidly develop resistance potentially hindering its benefit, and so far, this indication has not been clinically validated. &&

&&

&&

Table 2. Suggested antibiotic treatments for bacterial biliary tract infections in liver transplant recipients Pathogen Enterobacteriaceae [13 ] &&

P. aeruginosa [13 ] &&

A. baumannii [13 ] &&

Resistance phenotype

Suggested antibiotic

Non-ESBL producing

Ceftriaxone

ESBL producing

Carbapenema

Carbapenemase producingb

Tigecycline, colistin, aminoglycoside

Susceptible

Ceftazidimea (or another anti-Pseudomonas beta-lactam)

b

MDR

Ceftazidimea (or another anti-Pseudomonas beta-lactam) a aminoglycoside/ciprofloxacin

Susceptible

Ceftazidimea, carbapenema, ciprofloxacin

b

S. aureus [14 ] &&

Enterococcus [15 ] &&

MDR

Carbapenema, colistin, tigecycline

MSSA

Oxacillin, flucloxacillin

MRSA

Vancomycin, daptomycin, linezolid

Penicillin-susceptible

Amoxicillin

Penicillin-resistantb

Vancomycin, daptomycin, linezolid

VREb

Daptomycin, linezolid

MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant Enterococcus sp. a Consider prolonged or continuous infusion. b To be based on the individual susceptibility.

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To prevent recurrent cholangitis without selecting resistant pathogens, some centres use intermittent antibiotic regimens given at high doses twice per week. Such therapies should always be tailored individually and based on pathogens isolated during infectious episodes.

ANTIBIOTIC PROPHYLAXIS TO PREVENT INFECTIONS DURING BILIARY TRACT ENDOSCOPIC PROCEDURES ERC has been shown to promote infections of the biliary tree and the pancreas with potential severe sepsis [57]. Many centres therefore give prophylactic antibiotics before ERC. The benefice of routine prophylaxis has however been questioned recently by a review of 11 484 ERC procedures performed over a period of 11 years showing a low rate of infection, except in liver transplant recipients who remained at an increased risk of infection despite antibiotics [58]. Percutaneous transhepatic biliary cholangiography and drain placement are associated with risks of cholangitis and sepsis exceeding 20% [59,60]. This risk has been reduced to less than 2% by the use of prophylactic antibiotics [61]. Different regimens have been recommended as primary prophylaxis for biliary tract endoscopic procedures, including ceftriaxone as well as metronidazole or piperacillin-tazobactam [61,62]. However, piperacillin-tazobactam might not always reach bactericidal levels in bile and has been associated with failures to prevent cholangitis [63,64]. Because of breakthrough bacteremia with both these regimens, we have opted since 2010 for a combination associating ceftriaxone and amoxicillin. This combination, combining high bile concentrations and coverage for both enterococci and susceptible Gram-negative pathogens, has given excellent protection. In the case of known colonization by ESBL-producing pathogens or penicillin-resistant enterococci, carbapenems or vancomycin should be used.

CONCLUSION Biliary infections are frequent after liver transplantation and are associated with significant morbidity and graft loss. Both recurrent cholangitis and infected bilomas are challenging infections that deserve a multidisciplinary approach. Clinical signs and symptoms might be lessened by concomitant immunosuppressive therapies. Bilomas require drainage, whereas both anastomotic and nonanastomotic strictures should be corrected to prevent bile stasis and ascending infections in the case of recurrent cholangitis. Gram-positive pathogens predominate initially. Antibiotics should be used

parsimoniously and tailored to isolated pathogens, in order to minimize the risk of selecting resistant isolates. Both Gram-positive and negative multidrug-resistant isolates have been reported with increasing frequency, further hampering outcome. New strategies to prevent selection of resistance during prolonged and/or recurrent antibiotic therapies in liver transplant recipients are urgently needed. Acknowledgements C.V.D. is supported by grants from the Swiss National Science Foundation (32473B_140929 and 33CS30_148512) and the Roche Organ Transplant Research Foundation (146670301). Conflicts of interest C.V.D. reports speaker honoraria, grant support, travel support and consultancy fees from Astellas, Gilead, Pfizer, MSD, Basilea and Sanofi. None of them represents a direct conflict of interest regarding this manuscript.

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Volume 19  Number 3  June 2014

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Bacterial biliary tract infections in liver transplant recipients.

The purpose of this study is to provide an overview of bacterial biliary tract infections in liver transplant recipients with a focus on pathogenesis ...
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