Key words : Fluoroquinolones, Liver recipient, Multidrug resistant bacteria, Postoperative infection, Spontaneous bacterial peritonitis

Introduction

Infections and intra- and perioperative complications are responsible for ~60% of graft losses and deaths during the first year after liver transplant.¹ The risk of infection is influenced by the posttransplant period, the immunosuppressive treatment, and the patient’s exposure to certain pathogens.^2–4 Most infections occurring during the first month after transplant are mainly health care associated and are related to surgical technique and postoperative care.⁵ The Spanish Network of Infection in Transplantation has reported an incidence of 11.52 infections per 1000 transplant-days in the first month after liver transplant in our setting.⁶

Bacterial infections, which are the most common after liver transplant, mainly affect the abdomen, bloodstream, urinary tract, and lungs.^2-4,7,8 Infections due to multidrug resistant (MDR) bacteria have increased in recent years.^3,4,9,10 These infections require changes in the usual antibiotic treatment and can affect patient morbidity and mortality,^5,11-13 making them a concern worldwide. Hence, risk factors for the development of these infections have been investigated, including both pretransplant factors (eg, previous colonization by MDR or frequent antibiotic use) and posttransplant factors (eg, invasive devices, lengthy hospitalization, surgical complications, antibiotic exposure, and transfusions).^2,5,11,12

Bacterial infections are an important clinical problem in patients with cirrhosis,^14,15 and many liver transplant candidates receive antibiotics, which can increase the risk of infection by MDR bacteria.^15,16 Spontaneous bacterial peritonitis (SBP) is associated with substantial mortality,^17-19 a significant decrease in survival,²⁰ and high recurrence rates.²¹ For this reason, norfloxacin is recommended as primary prophylaxis in patients with severe liver disease and low protein ascites, and as a secondary prophylaxis after a first episode of SBP.^15,18,22-24 This practice has increased the risk of colonization or infection by MDR bacteria in liver transplant candidates.^4,16,25-27

The etiology of SBP has been investigated in cirrhotic patients and liver transplant recipients to determine whether the classic antibiotic treatments, such as third-generation cephalosporins, are still adequate.²⁸ Nonetheless, there are no studies, to our knowledge, specifically assessing prophylactic norfloxacin as a risk factor for MDR bacterial infection after liver transplant. In this study, we examined prophylactic norfloxacin for SBP as a risk factor for the development of MDR bacterial infection in liver transplant recipients in the immediate postoperative period. We also explored the association of other variables with the development of these infections and the impact of MDR infections on short-term mortality.

Materials and Methods

Study design
A prospective observational cohort study was designed in which we included all consecutive adult patients (>18 years of age) undergoing liver transplant at 2 tertiary university hospitals in a major European city (hospital 1 and hospital 2), from January 2015 to December 2016. Recipients who died within 48 hours after transplant were excluded. The study was approved by the Ethics Committees for Clinical Research of both hospitals (PR[AG]191/2015). Informed consent was obtained from all participants.

Data collection
We collected demographic, clinical, and microbio-logical data from donors and recipients. The clinical data included pretransplant characteristics and perioperative and postoperative information. We only took into consideration points for the analytical parameters of the Model for End-Stage Liver Disease (MELD) and not the points given for hepatocellular carcinoma (HCC) or other situations considered as an exception to MELD, which receive extra points to gain priority for transplant.⁷

Screening for colonization by MDR bacteria before liver transplant is performed as part of the standard clinical practice in hospital 2, but not in hospital 1, where it is done based on clinical suspicion. The MDR bacterial colonization was labeled “unknown” if pretransplant screening had not been performed.

The standard perioperative antibiotic prophylaxis is amoxicillin-clavulanate for 48 hours in hospital 1 and teicoplanin, usually with aztreonam or ceftazidime, for 24 hours in hospital 2. The microbiological information included any sample related to postoperative infections. Three month patient survival and retransplant rates were recorded.

For each recipient, we recorded all postoperative infections occurring up to the time point when an MDR bacterial infection was observed or up to the end of the first month after transplant. Once an MDR bacterial infection was observed in a liver transplant recipient, no more infections were recorded for this patient. Postoperative infection data included the infection site, microbiological information, health care-associated versus community-acquired infection, antimicrobial treatment, resolution of the infection, and survival. Clinical and laboratory data related to the infection were also collected but only in patients with MDR bacterial infection.

Patients were classified into 2 groups based on exposure or not to prophylactic norfloxacin for at least 3 months before liver transplant (400 mg orally, once daily). No other antibiotic rather than norfloxacin was used as prophylaxis of SBP.

The primary objective of the study was to analyze prophylactic norfloxacin use as a risk factor for the development of MDR bacterial infection in the immediate postoperative period of liver transplant. Secondary objectives were to determine the overall incidence of bacterial infections in liver transplant recipients, to explore other potential risk factors of MDR bacterial infections, and to evaluate mortality at 90 days after transplant.

Definitions
Antibiotic treatment before transplant was defined as that administered to treat any kind of infection within 3 months before the transplant procedure, independent of prophylaxis with norfloxacin.

Infections were defined according to the Centers for Disease Control and Prevention (CDC) criteria.²⁹ For the study analysis, microorganisms isolated in a patient with no clinical signs of infection and febrile episodes in which no microorganism was isolated were not considered true infections. Postoperative infection was defined as an infection that developed within the first month after transplant.

Health care-associated infection (HAI) was defined according to CDC criteria as an infection with no evidence of being present or incubating at the time of admission to the acute care setting.29 In this study, HAIs were limited to infections that developed 48 hours after hospital admission or within 8 days after discharge.

The definition of MDR bacteria is as described previously.30 Resistance definition criteria for MDR pathogens were mainly as follows: vancomycin resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus (MRSA), β-lactamase and carbapenemase or extended-spectrum β-lactamase (ESBL) producing Enterobacterales and Acinetobacter baumanii, or Pseudomonas aeruginosa with acquired nonsusceptibility to at least 1 agent in 3 or more antimicrobial categories.

Death was related to postoperative infection when sepsis, shock, or multiorgan failure was the fundamental cause of death during admission or during readmission within 8 days after discharge.

Microbiological processing
Clinical samples related to postoperative infections were cultured in enriched and selective media, some of which were specific for resistant microorganisms. Identification of isolates was usually performed by mass spectrometry (VITEK MS, bioMérieux) and antimicrobial susceptibility by microdilution and diffusion with concentration gradient strips (VITEK2 and E-test, respectively, both from bioMérieux) following the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. Detection of resistance mechanisms was also performed according to EUCAST recommendations.³¹

Statistical analyses
Continuous variables are presented as median with interquartile range (IQR) and categorical variables as number (%). Baseline characteristics between patients with or without prophylactic norfloxacin were compared using Wilcoxon Mann Whitney test for quantitative variables or the chi-square test for qualitative variables (the Fisher exact test was used when chi-square was not appropriate). The association between postoperative MDR bacterial infection and previous use of prophylactic norfloxacin was also calculated by means of the chi-square test.

The association between MDR bacterial infection and prophylactic norfloxacin was also calculated by means of logistic regression to control for potential confounders. To further assess the independence of the association, a multivariate logistic regression was conducted, which included all variables significantly associated with norfloxacin in the bivariate analysis. To limit the number of variables in the final model, a forward stepwise method was used. The stepwise selection was performed using the model’s Akaike Information Criterion. Results are expressed as the odds ratio (OR) and 95% CI.

Finally, other potential risk factors for MDR bacterial infections were explored. First, the association of each exposure with development of MDR bacterial infection was assessed by bivariate analysis. A multivariate logistic regression analysis was then performed that included the variables that were significantly associated. The number of variables in the model was also limited with the same method.

The threshold of statistical significance was P ? .05. For statistical analyses, we used “R” version 3.6.1 (2019-07-05, The R Foundation for Statistical Computing).

Results

Patient characteristics
During 2015 and 2016, 171 consecutive liver transplant recipients were identified; 1 patient died within the first 48 hours after transplant and 13 denied their consent. In total, 157 liver recipients were prospectively included: 60 from hospital 1 and 97 from hospital 2. No recipients were lost to follow-up. Among the study population, 54 (34.6%) were identified to be on norfloxacin prophylaxis for at least 3 months before liver transplant (norfloxacin group), with use as primary prophylaxis in 24 patients and as secondary prophylaxis in 30 patients.

Median age was 57.7 years (IQR 52.1-64.3), and 121 (77.1%) were men. Cirrhosis was the most frequent indication for transplant, and the most common causes of cirrhosis were alcohol use and chronic hepatitis C infection. Multidrug-resistant bacterial colonization before transplant was investigated in 91 recipients (58%) and was positive in 10 (6.4%), all from hospital 2. Teicoplanin was the most commonly used perioperative antibiotic prophylaxis (98 recipients, 62.4%) and was usually given with aztreonam (80 recipients, 51%) or with an antipseudomonal cephalosporin, and the second most frequent perioperative antibiotic prophylaxis was amoxicillin-clavulanate. The main induction immunosuppressive therapy was basiliximab + methylprednisolone + mycophenolate, with later introduction of tacrolimus around day 5 after the transplant procedure (52.9%).

Among study patients, 69 patients (43.9%) had HCC, which presented more frequently in the group without norfloxacin (59.8% vs 14.8%; P < .001). Median MELD score prior to transplant was 14 (IQR 10-22) and significantly higher (20 vs 11; P < .001) in the norfloxacin group. In addition, patients in the norfloxacin group presented with more complications due to advanced cirrhosis during the year before transplant, including ascitic decompensation (88.9% vs 25.5%; P < .001), hepatic encephalopathy (63% vs. 27.5%; P < .001), upper gastrointestinal bleeding (25.9% vs 5.9%; P < .001), and hepatorenal syndrome (37% vs 7.8%; P < .001). As seems obvious, these patients had more frequently a past history of SBP before transplant (57.4% vs 6.9%; P < .001).

Furthermore, patients in the norfloxacin group were also more likely to have needed vasoactive support in the intensive care unit 30 days before transplant (31.5% vs 8.8%; P < .001) and have received treatment other than norfloxacin prophylaxis as treatment for an infection within 3 months before the transplant procedure (61.1% vs 24.5%; P < .001). Patients in the norfloxacin group received more red blood cell transfusions (4 vs 2; P < .001) and were more frequently treated with antithymocyte globulin as immunosuppressive induction therapy (16.7% vs 1%; P < .001). Other recipient characteristics are summarized in Table 1.

Only 1 recipient required retransplant within 3 months, resulting from primary graft dysfunction. Three patients died over the 3-month follow-up: 1 due to multiorgan failure, 1 due to septic shock, and 1 due to cerebral embolism. Thus, overall survival was 98%. Although mortality was higher in the norfloxacin group, the difference was not statistically significant between the 2 groups (3.7% vs 1%; P = .27) and was not statistically significant between patients with or without MDR bacterial infection (0% vs 2.1%; P > .99).

Median age of the donors was 58 years (IQR 46.5-70.5), and the main causes of death in donors were stroke (65.3%) and trauma (20%).

Postoperative infections
Over the study period, 47 recipients developed 63 postoperative infections, at a median of 8 days (IQR, 3.5-13 days) from transplant to the first infection. All but 1 was health care-associated. Urinary tract infections were the most frequent, with 14 episodes (22.2%), followed by respiratory infections (11 episodes, 17.5%), abdominal infections (10 episodes, 15.8%), and bacteremia (9 episodes, 14.3%). In addition, 8 episodes (12.7%) of cytomegalovirus viremia occurred during the first month after transplant; for 7 of them, patients received antiviral treatment with either ganciclovir or valganciclovir.

Seventeen MDR bacterial infections were recorded: 6 in hospital 1 and 11 in hospital 2. The incidence of MDR bacterial infections was similar in the 2 hospitals (10% vs 11.3%, respectively; P > .99). The MDR bacterial infections occurred at a median of 11 days (IQR, 5 17 days) since transplant. All but 1 MDR bacteria (one Enterobacter cloacae AmpC), were resistant to fluoroquinolones. In all cases, the infection was health care associated, and 3-month survival was 100%. Urinary tract infections were the most common, with 10 episodes (58.8%), followed by bacteremia with 3 episodes (17.6%). ESBL-producing Klebsiella pneumoniae was most often isolated, being present in 9 infections (52.9%). Four recipients with MDR bacterial infection had been colonized by MDR bacteria before transplant, and the antibiogram-colonizing bacterial strain matched the one causing the postoperative infection in all cases. The microorganisms isolated and other features of the MDR bacterial infections are summarized in Table 2.

One-month cumulative incidence of MDR bacterial infection was almost 5 times higher in the norfloxacin group (22.2% vs. 4.9%; relative risk = 5.6, 95% CI, 1.85-16.89; P = .001). The incidence of MDR bacterial infection did not differ between patients receiving norfloxacin as primary prophylaxis and patients receiving norfloxacin as secondary prophylaxis (20.8% vs 23.3%; P = .83). This remained significant after controlling (by means of general logistic models) for the use of pretransplant vasoactive support (OR = 3.68, 95% CI, 1.17 12.79; P = .03), MELD score (OR = 4.32, 95% CI, 1.46-14.58; P = .01), previous SBP (OR = 4.59, 95% CI, 1.31-17.31; P = .02), chronic renal impairment (OR = 4.98, 95% CI, 1.68-16.8; P = .005), the number of packed red blood cells (OR = 5.1, 95% CI, 1.75-17.02; P = .004), the use of antithymocyte globulin as induction (OR = 4.95, 95% CI, 1.63 16.92; P = .006), and HCC (OR = 4.03, 95% CI, 1.28-14.68; P = .02). After we controlled for antibiotic treatment prior to transplant, prophylactic norfloxacin did not reach statistical significance (OR = 3.09, 95% CI, 0.99-10.84; P = .06).

The variables selected by the forward stepwise method were antibiotic treatment prior to transplant and the use of vasoactive support prior to transplant. None of the variables included in the model was statistically significant. The association with norfloxacin also did not reach statistical significance (OR = 2.77, 95% CI, 0.85-9.93; P = .09).

Exploratory analysis of other potential risk factors for multidrug-resistant bacterial infections
Prophylactic use of norfloxacin was significantly higher in recipients who developed MDR bacterial infection than in those who did not. Additionally, a greater proportion of recipients with MDR bacterial infection had received antibiotic treatment in the 3 months before transplant (Table 3).

Recipients with MDR bacterial infection had worse liver function with higher pretransplant MELD scores and had cirrhotic decompensations more frequently. In addition, MDR bacterial infection was statistically associated with patients admitted to the intensive care unit within 30 days and those who required vasoactive support, mechanical ventilation, or renal replacement therapy in the month before transplant. Conversely, the presence of HCC was statistically less frequent in recipients with MDR bacterial infection (Table 3).

On multivariate analysis, prophylactic norfloxacin (OR = 2.77, 95% CI, 0.85 9.93; P = .1), prior antibiotic treatment (OR = 4.43, 95% CI, 1-23.2; P = .06), and the use of vasoactive support prior to transplant (OR = 2.66, 95% CI, 0.76 9.91; P = .13) were the risk factors selected for the final model.

Discussion

The results of the study support that prophylactic norfloxacin, used for SBP, is an important risk factor for MDR bacterial infection in the first month after liver transplant.

Norfloxacin prophylaxis is widely recommended for SBP, and its use has been supported by systematic reviews.^{15,18,23,24,32,33} However, since its introduction, the incidences of MDR bacterial colonization and infection have increased in cirrhotic patients, leading to changes in the antibiotic schemes for treating infection in this population.^15,16,34 Presently, the role of prophylactic norfloxacin in the development of MDR bacterial infections and its suitability continue to be discussed.³⁵

Colonization by MDR bacteria is a proven risk factor for infection by these microorganisms in both liver transplant candidates and recipients.^36-39 Our data support this notion, but the association was not independent, perhaps because both pretransplant norfloxacin and antibiotic treatment are the truly associated variables. Infections and colonization by MDR bacteria in cirrhotic patients are related to decompensation and lower transplant-free survival.³⁹ In liver transplant recipients, MDR bacteria are associated with poor outcomes, such as lengthy intensive care unit stays and decreased survival.³⁸ Nonetheless, to the best of our knowledge, there are no studies specifically assessing the use of prophylactic norfloxacin as a risk factor for MDR bacterial infections in the immediate posttransplant period.

In a Spanish prospective multicenter study, selective intestinal decontamination with norfloxacin had no protective effect in the prevention of early bacterial infections after liver transplant. Furthermore, patients who received norfloxacin had a statistically higher incidence of respiratory tract infections and a higher, but not significant, incidence of intra-abdominal infections than patients who did not receive this drug. The presence of MDR bacteria was not evaluated in the study, but the authors reported a higher percentage of infections due to nonfermenting gram-negative bacilli in recipients who received norfloxacin prior to transplant.⁴⁰ A randomized, double blind, placebo-controlled study conducted in The Netherlands in 2002 showed similar results: early infection after liver transplant was not prevented in patients who received norfloxacin as selective decontamination before transplant. In addition, these authors reported a higher rate of infections due to gram-positive cocci in the intervention group.⁴¹

Some studies in liver transplant recipients have focused on prophylactic norfloxacin use in relation to preoperative colonization by MDR bacteria. Bert and colleagues found that norfloxacin prophylaxis was significantly associated with fecal carriage of ESBL-producing Enterobacterales on univariate analysis, but it was not an independent predictor in the final logistic regression model.⁴² The same group subsequently published a retrospective study that analyzed the risk factors and impact of perioperative prophylaxis on the risk of posttransplant infection caused by ESBL producing Enterobacterales in previously colonized patients. Independent predictors of MDR infection were Klebsiella pneumoniae, MELD score over 25, preoperative SBP prophylaxis, and therapeutic antibiotic treatment during the previous month before transplant. Authors suggested to rationalize carbapenem prescription as perioperative antibiotic prophylaxis based on a clinical risk score of ESBL prevalence.⁴³ Our study was conducted not only in colonized patients, as has been previously commented, but 4 recipients with MDR bacterial infection had been colonized by the same MDR bacteria prior to transplant. In contrast, investigation of MDR bacterial colonization was not performed as a screening protocol. Knowing the colonization status before transplant could be useful to guide perioperative antibiotic prophylaxis, and norfloxacin prophylaxis perhaps could be reconsidered in liver transplant candidates.

Other proposed antibiotics for oral decontami-nation in solid-organ transplant recipients, like colistin plus neomycin, did not show reduction in MDR bacterial infections due to Enterobacterales.⁴⁴

On the other hand, in 2012, Sun and colleagues published a study investigating the impact of rifaximin use for hepatic encephalopathy on the risk of early infection after liver transplant. The authors reported that rifaximin seemed to have a protective effect in patients with more severe liver disease (MELD >30), without increasing the risk of MDR bacterial infection.⁴⁵ Unlike norfloxacin, rifaximin is poorly absorbed, and this feature may partially explain why its use was not associated with MDR bacterial infection, even if rifaximin, like norfloxacin, is usually given to patients with more severe liver disease. Although rifaximin seems to be an optimal choice for SBP prophylaxis, norfloxacin continues being the first-line recommendation, although no more data on liver transplant recipients are available.⁴⁶

In our study, therapeutic antibiotic treatment in the 3 months within transplant was also an important risk factor for MDR bacterial infections. Prior antibiotic therapy has been shown to be significantly more frequent in solid-organ transplant recipients, including liver recipients, with posto-perative MDR bacterial infection.^47,48

A higher MELD score related to more severe liver disease before transplant was significantly associated with recipients who developed MDR bacterial infections, although it was not an independent factor. Variables relating clinical decompensations or complications, which are due to advanced cirrhosis, were significantly associated with the use of prophylactic norfloxacin, although there were also no independent factors. These findings agree with the results of previous studies^36,37,48,49 and with findings showing how advanced liver disease is related to infectious complications prior to transplant.^25,38

Prophylactic norfloxacin was associated with MDR bacterial infection, supporting the study hypothesis. However, it was not independently associated. This is probably due to the strong association between norfloxacin prophylaxis and other variables (such as vasoactive support and prior antibiotic treatment), which in turn are strongly associated with development of MDR bacterial infections. This leads to covariance in the multivariate models, which limits their applicability. Norfloxacin remained significant after controlling for most of the variables associated with its use.

Our study is limited by the relatively small number of MDR bacterial infections. Larger studies might include greater numbers of MDR bacterial infections and confirm the independence of norfloxacin association. However, observational studies based on larger cohorts might face the same issue: association between norfloxacin and other exposures. Therefore, randomized controlled trials are warranted.

Among the strengths of the study, prospective evaluation of consecutive patients reduced the probability of missing MDR bacterial infection. In addition, the samples were from different centers with a similar frequency of MDR bacterial infections.

Conclusions

Our results suggest that prophylactic norfloxacin is associated with MDR bacterial infection in the early posttransplant period. Regardless of the indepen-dence of the association, in patients with postoperative infections who have received norfloxacin, clinicians should be aware of patient risk of MDR bacterial infections, especially during the first month after liver transplant.

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