1 Introduction
Liver transplantation (LT) has become an effective treatment for pediatric patients with end-stage liver diseases. Despite advances in perioperative management, surgical techniques, postoperative medical care, infectious control, and immunosuppressive therapy, bacterial infections remain a significant cause of morbidity and mortality among LT recipients.[1] [1,2]
Multidrug-resistant organisms, particularly multidrug-resistant gram-negative bacilli (MDR-GNB), have emerged as predominant pathogens among LT recipients.[1,3] [3,4] [1,5,6]
Incidence of bacterial infections has been reported to be 40% to 80% following pediatric LT.[7–11] pediatric population are scarce. This retrospective study aimed to evaluate the incidence of early postoperative bacterial infections caused by MDR-GNB and to identify associated factors among pediatric LT recipients.
2 Patients and methods
We performed a retrospective study of all pediatric patients aged 1 month to 18 years who underwent LT at Faculty of Medicine Ramathibodi Hospital, a tertiary care university-based hospital in Bangkok, Thailand between 2010 and 2019. A total of 123 pediatric LT recipients were included in the study period. Patients’ information was reviewed from electronic medical records. The following information was recorded; age, gender, underlying diseases, pediatric end-stage liver disease (PELD) or model for end-stage liver disease (MELD) score, history of abdominal surgery, antibiotic exposure within 3 months before LT, on-going infection at the time of LT, history of infected biloma, operation time, cold ischemic time, operative complications, length of hospital stay, length of ICU stay, biliary complications, acute rejection, cytomegalovirus (CMV) and Epstein-Barr virus reactivation after LT, sites of infections, history of re-operation, and death. The incidence of bacterial infection or GNB infection were measured within 3 months after LT. The study was approved by the Institutional Review Board, Faculty of Medicine Ramathibodi Hospital, Bangkok, Thailand (COA. No. MURA2018/1044).
2.1 Immunosuppressive regimens
Postoperative immunosuppressive drugs comprised of a calcineurin inhibitor (tacrolimus), corticosteroid, and mycophenolate mofetil. If rejection occurred, the dosage of calcineurin inhibitor was increased, with or without administration of pulse methylprednisolone therapy.
2.2 Antimicrobial prophylaxis regimen
Intravenous ampicillin/sulbactam (200 mg/kg/d of ampicillin) and ceftriaxone (50 mg/kg/d) were used as standard preoperative antibiotic prophylaxis. Six patients received antibiotics other than routine preoperative antibiotics (piperacillin/tazobactam in 4 patients, ceftriaxone and metronidazole in 2 patients). Antibiotics were started at the beginning of surgery and continued for 7 days postoperation. Oral neomycin (10 mg/kg/dose) was given on the day before transplantation. For Pneumocystis jirovecii prophylaxis, trimethoprim-sulfamethoxazole was given orally 3 days/week for 6 months after surgery or until corticosteroids were discontinued. None of the patients received antifungal prophylaxis. For cytomegalovirus prevention strategies, pre-emptive therapy was used as the primary approach in all cases, including D+/R– patients. Weekly monitoring for plasma CMV viral load for 12 weeks after LT was implemented in all patients. During the study period, a viral load of more than 1000 copies/mL was used as a cut-off value for initiation of ganciclovir.
2.3 Microbiological monitoring
All patients were admitted in ICU following the transplant procedure. Surveillance bacterial cultures were taken from tracheal aspirate and rectal swab at the time of ICU admission. Abdominal drain fluid cultures, blood cultures, and urine cultures were performed twice a week during the first postoperative week. Afterwards, abdominal drain fluid cultures were performed once a week until all drains were removed. While patients were admitted, blood, urine, tracheal or bronchoalveolar lavage specimens were collected if clinically indicated.
2.4 Diagnosis of infection
Based on clinical manifestations and microbiological results, all infectious complications were categorized into one of the following; surgical site infections (including intra-abdominal and hepatobiliary tract), bloodstream (including catheter-related infections), pneumonia, and urinary tract infection (UTI). Intra-abdominal infection was defined as a positive culture from intra-abdominal fluid, peritoneal fluid, or bile. UTI was diagnosed by the presence of clinical signs and symptoms of UTI with a positive urine culture (≥104 cfu/mL or > 105 cfu/mL if urine was collected by a catheter or mid-stream urine, respectively). Proven bacterial infections were defined as the presence of pathogens from a normally sterile sample. Isolation of organisms from non-sterile samples in the absence of clinical symptoms of infection was considered as colonization. Diagnosis of bacterial infections was defined and categorized according to the criteria of the Centers for Diseases Control and Prevention.[12,13]
Bacterial cultures were performed by standard microbiological procedures. Antimicrobial susceptibility was interpreted based on the Clinical and Laboratory Standards Institute guidelines. Drug resistance was defined based on the European Society of Clinical Microbiology and Infectious Diseases 2012.[14] Enterobacteriaceae (CRE) was defined as strains of Enterobacteriaceae resistant to at least 1 carbapenem.
2.5 Statistical Analysis
STATA version 16 (StataCorp, College Station, TX) was used to perform all statistical analyses. Continuous variables were expressed as median and interquartile range (IQR) in non-normally distributed data. Comparison between groups was performed by Student test or Mann–Whitney U test. Categorical variables were expressed with frequencies and percentages, and comparison was performed by Pearson Chi-square or Fisher exact test. Kaplan–Meier survival analysis was used to identify the incidence of MDR infection after LT. Univariate and multivariate analyses were done with Cox proportional hazard modeling to identify associated factors for MDR-GNB infection and CRE-infection after LT. All the variables with a P- value < .05 in univariate analysis were used in multivariate analysis.
3 Results
3.1 Patients’ demographic and clinical characteristics
Over the study period, 123 pediatric patients underwent LT between January 2010 and December 2019. We excluded recipients who had incomplete data record (n = 4), and death during operation (n = 1). Thus, 118 patients were analyzed in the study. Fifty-two patients (44%) were male with a median age of 1.7 years (IQR 1.1_ 2.8 years). The majority of patients underwent living-donor LT (LDLT) (95.8%). The median PELD/MELD score before LT was 19 (IQR; 16–23). The most common underlying disease was biliary atresia (78.8%) with 62 patients (52.5%) having had Kasai procedure (hepatoportoenterostomy) before LT. Demographic and clinical characteristics of patients are shown in Table 1 .
Table 1 -
Demographic and clinical characteristics of patients (N = 118).
Clinical characteristics
N (%)
Male sex
52 (44)
Age (yr); median (IQR)
1.7 (1.1–2.8)
Underlying diseases
Biliary atresia
93 (78.8)
Acute liver failure
7 (5.9)
Allagile syndrome
4 (3.4)
Other causes of cirrhosis
14 (11.8)
PELD score; median (IQR)
19 (16–23)
Previous abdominal surgery before LT
62 (52.5)
Donor
Living Donor
113 (95.8)
Cadaveric Donor
5 (4.2)
Antibiotic exposure within 3 mo before LT
63 (53.4)
Operation time (h); median (IQR)
11.1 (10.1–12.5)
Cold ischemic time (min); median (IQR)
72 (52–92)
Intraoperative complications
Massive bleeding∗
84 (84)
Bowel injury
6 (6)
Adrenal gland injury
3 (3)
Vascular injury
5 (5)
Biliary injury
2 (2)
Hospital stay; median (IQR)
48 (34–65)
<1 mo
20
1–3 mo
80
>3 mo
18
Length of ICU stay (d); median (IQR)
8 (6–14)
Duration of endotracheal intubation (d); median (IQR)
3 (2–7)
Duration of urinary catheter (d); median (IQR)
5 (3–6)
Duration of central venous catheter (d); median (IQR)
12 (8–17)
Duration of abdominal drain (d); median (IQR)
27 (20–37)
Early postoperative complications
Bile leak
27 (33)
Hepatic artery stenosis/thrombosis
18 (21.9)
Hepatic vein stenosis/thrombosis
18 (21.9)
Portal vein stenosis/thrombosis
19 (23.2)
Sites of infection
Intra-abdominal infection
46 (46.4)
Bloodstream infection
23 (23.2)
Urinary tract infection
11 (11.1)
Pneumonia
16 (16.2)
CMV reactivation
37 (31.4)
EBV reactivation
5 (4.2)
Acute graft rejection
21 (17.8)
Postoperative surgical intervention (ie, liver biopsy, abdominal drain insertion, PTBD insertion, dilate hepatic vein)
35 (29.6)
Re-operation
58 (49.1)
Death
8 (6.7)
CMV = cytomegalovirus, EBV = Epstein Barr virus, ETT = endotracheal intubation, LT = liver transplantation, PELD = pediatric end-stage liver disease, PTBD = percutaneous trans-hepatic biliary drainage.
∗ Massive bleeding is defined as rate of blood loss >150 mL/min or Blood loss >1.5 mL/kg/min in 20 min or replacement of 50% of total blood volume within 3 h.
3.2 Bacterial infections after LT
Among 118 LT recipients, 64 (53.7%) patients developed 96 episodes of a culture-proven bacterial infection within 3 months after LT. The median time to bacterial infections was 7 days after LT (IQR; 3–19). From Kaplan–Meier analysis, 50% of patients developed at least 1 episode of a bacterial infection within 47 days (Fig. 1 ). The most common site of infection was intra-abdomen (47.9%), followed by bloodstream infection (23.9%), pneumonia (16.7%), and urinary tract infection (11.5%). Thirty-five patients (54.7%) developed a single site infection, while the remaining experienced multiple sites of infection. Interestingly, of the 96 episodes, 93 GNB isolates were responsible for these infections. The most frequent GNB isolates were Escherichia coli, Klebsiella spp., and Pseudomonas aeruginosa (Supplement Table 1, https://links.lww.com/MD/F193
Figure 1: Kaplan–Meier curve of pediatric liver transplant recipients with bacterial infection.
3.3 Incidence of MDR-GNB infection after LT
Among 93 GNB isolates, a total of 58 MDR-GNB isolates (62.4%) were identified from 42 patients, with the predominance of Enterobacteriaceae (44 isolates, 75.9%). Thirteen patients had more than 1 episode of MDR-GNB infection (2 episodes in 10 patients and 3 episodes in 3 patients). The median time to the diagnosis of MDR-GNB infection following LT was 9 days (IQR; 5–33). From Kaplan–Meier analysis, the incidence rate of MDR-GNB infection was 6 per 1000 patient-days, and 25% of the patients developed at least 1 episode of MDR-GNB infection within 25 days postoperation (Fig. 2 ). The majority of MDR-GNB was extended-spectrum beta-lactamases-producing Enterobacteriaceae (34 isolates, 58.6%), followed by other MDR-GNB (14 isolates, 24.1%), and CRE (10 isolates, 17.2%). The details of MDR-GNB are shown in Table 2 .
Figure 2: Kaplan–Meier curve of pediatric liver transplant recipients with multidrug-resistant gram-negative bacilli infection.
Table 2 -
The details of multi-drug resistant gram-negative bacilli isolates from 42 patients.
Species
Total number of isolates (N)
ESBL-producing organisms
Escherichia coli
16
Klebsiella pneumoniae
13
Enterobacter cloacae
3
Klebsiella oxytoca
1
Enterobacter aerogenes
1
MDR-GNB
Pseudomonas aeruginosa MDR
6
Acinetobacter baumannii MDR
2
Stenotrophomonas maltophilia MDR
4
Elizabethkingkia meningosepticum MDR
2
Carbapenem resistant Enterobacteriaceae (CRE)
Escherichia coli
2
Klebsiella pneumoniae
6
Enterobacter cloacae
2
ESBL = extended spectrum beta-lactamase, MDR-GNB = multidrug-resistant gram-negative bacilli.
3.4 Factors associated with MDR-GNB infection after LT
In univariate analysis, variables significantly associated with MDR-GNB infection were exposure to third-generation cephalosporins within 3 months before LT, operation time, length of ICU stay, re-operation, postoperative bile leakage, and CMV reactivation/infection. In multivariate analysis, exposure to third-generation cephalosporins within 3 months before LT (hazard ratio [HR] 2.20, confidence interval [CI] 95% 1.13–4.30, P = .021), operation time (HR 1.20 [CI 95% 1.05–1.38], P = .008), and length of ICU stay (HR 1.03 [CI 95% 1.00–1.06], P = .049), remained independent risk factors associated with MDR-GNB infection after LT (Table 3 ). Regarding infections caused by CRE, the only independent associated factor was PELD score of more than 21 (HR 11.48 [CI 95% 1.37–-96.18], P = .024) (Table 4 ).
Table 3 -
Univariate and multivariate analyses of associated factors of multidrug-resistant gram-negative bacteria infection.
Univariate analysis
Multivariate analysis
Factors
HR (95% CI)
P -value
HR (95% CI)
P -value
Sex, male
1.16 (0.63–2.13)
.642
Exposure to third-generation cephalosporins within 3 mo before LT
2.40 (1.30–4.43)
.005∗
2.20 (1.13–4.30)
.021∗
Operation time (h)
1.22 (1.07–1.40)
.003∗
1.20 (1.05–1.38)
.008∗
Cold ischemic time
1.00 (0.99–1.00)
.888
Length of ICU stay (d)
1.04 (1.02–1.06)
<.001∗
1.03 (1.00–1.06)
.049∗
Re-operation
2.13 (1.14–3.98)
.017∗
1.27 (0.60–2.66)
.532
Postoperative surgical intervention
1.74 (0.94–3.23)
Bile leakage
2.10 (1.11–4.01)
.023∗
1.20 (0.60–2.45)
.600
CMV reactivation
3.64 (1.60–8.32)
.002∗
0.98 (0.33–2.92)
.974
EBV reactivation
1.18 (0.29–4.90)
.816
Acute graft rejection
0.74 (0.31–1.75)
.491
CMV = cytomegalovirus, EBV = Epstein-Barr virus, HR = hazard ratio, ICU = intensive care unit, LT = liver transplantation.
∗ Statistically significant by Cox proportional hazard modelling.
Table 4 -
Univariate and multivariate analyses of associated factors of carbapenem-resistant
Enterobacteriaceae infection.
Univariate
Multivariate
Factors
HR (95% CI)
P -value
HR (95% CI)
0- value
PELD score ≥22
13.49 (1.62–112.08)
.016∗
11.48 (1.37–96.18)
.024∗
Exposure to third-generation cephalosporins within 3 months before LT
1.03 (1.00–1.06)
.045∗
1.02 (0.99–1.06)
.182
HR = hazard ratio, LT = liver transplantation, PELD = pediatric end-stage liver disease.
∗ Statistically significant by Cox proportional hazard modelling.
3.5 Impact of MDR-GNB infection on mortality
Eight patients died within the first 3 months after LT, representing the overall mortality rate of 6.8%. However, only 2 patients died due to uncontrolled intra-abdominal infection and sepsis. There was no significant difference in the 3-month mortality between recipients with a history of MDR-GNB infection and non-MDR- GNB infection (HR 3.09 [CI 95% 0.74–12.95], P = .122). In univariate analysis, the 3-month mortality rate was significantly higher in patients with a history of CRE infection. However, no significant difference was found in after adjustment with a length of ICU stay, graft rejection, and re-operation.
4 Discussion
Bacterial infections remain a significant complication following pediatric LT. Gram-negative bacilli, particularly MDR strains, have emerged as predominant organisms among adult LT recipients. In this study, we retrospectively reviewed 118 pediatric LT recipients and noted a high rate of MDR-GNB infection. The identified risk factors for MDR-GNB infection in this study were exposure to third-generation cephalosporins within 3 months before LT, operation time, and length of ICU stay. To the best of our knowledge, this is the first study to identify the incidence and associated factors of MDR-GNB infection among pediatric LT recipients.
The incidence of bacterial infections following pediatric LT has varied among transplant centers, ranging from 46% to 79%. [7–10,15] [7–11]
MDR-GNB have emerged as predominant pathogens and become a significant cause of morbidity and mortality following LT.[16] [16–19] [20] Enterobacteriaceae, P aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia . We found that Enterobacteriaceae were the predominant pathogens (75.9%, 44 in 58 isolates), similar to other studies.[9,21–23]
In multivariate analysis, independent risk factors associated with MDR-GNB infection were exposure to third-generation cephalosporins within 3 months before LT, operation time, and length of ICU stay. Children with end-stage liver diseases are likely to be hospitalized repeatedly and inevitably exposed to antibiotics. Exposure to broad-spectrum antibiotics has been recognized as a significant risk factor for MDR-GNB acquisition, particularly extended-spectrum beta-lactamases-producing organisms.[16,19,24]
Operative factors predispose to MDR-GNB infection among LT candidates in previous studies.[19,25] pediatric LT operation, particularly LDLT in small children, is a technically complicated than adult LT with whole LT. Previous abdominal surgery, Kasai operation, and abdominal infection cause the operation more difficult and taking longer operation time. Therefore, abdominal infection in pediatric LT recipients is often higher than adult LT.[26,27] [25]
ICU stay is generally associated with mechanical ventilation, vascular access, and retaining of catheters. Thus, critically ill patients are vulnerable to infections, particularly nosocomial infections, which are often caused by drug-resistant organisms. The previous study among LDLT recipients showed that longer ICU stay was an independent factor for postoperative bacterial infections.[23]
Interestingly, the rate of CRE among MDR-GNB infection is considerably high in this study (17.2%). We found that a high PELD score at the time of transplantation was an independent factor associated with CRE infection following pediatric LT. This finding agreed with previous studies in adult recipients, which demonstrated that a high pre-LT MELD score was associated with post-LT CRE infection.[28,29] [30] [31] pediatric LT recipients.
This study has certain limitations. First, the nature of retrospective, single-center study might limit the generalization of the results. Second, pre-LT colonization was not identified in all patients. Therefore, we were unable to access the association between pre-transplant colonization with MDR-GNB and post-LT MDR-GNB infection.
In conclusion, we highlighted the high rate of bacterial infections caused by MDR-GNB following pediatric LT. To the best of our knowledge, this is the first study to show the incidence and associated factors of MDR-GNB infection following pediatric LT. Pre-LT exposure to third-generation cephalosporins, prolonged operation time, and length of ICU stay was associated with increased risk of MDR-GNB infection. Additionally, high PELD score before LT is a significant risk factor for CRE infection. Our findings emphasized that antimicrobial stewardship program is crucial in order to prevent and reduce antimicrobial resistance. Besides, pre-LT screening for stool carriage of drug-resistant organisms and strict surveillance for the emergence of MDR-GNB infection in at-risk patients after LT should be implemented. Furthermore, the awareness of the prevalence and resistant pattern is essential for guideline development to minimize the risk of MDR-GNB infection in this group of patients.
Acknowledgment
The authors thank Pawin Numthavaj, MD, PhD, from Department of Clinical Epidemiology and Biostatistics for statistic consultation.
Author contributions
Conceptualization: Chanita Phichaphop, Sophida Boonsathorn, Nopporn Apiwattanakul.
Data curation: Chanita Phichaphop.
Investigation: Chanita Phichaphop.
Methodology: Chanita Phichaphop, Sophida Boonsathorn, Nopporn Apiwattanakul.
Resources: Suporn Treepongkaruna, Chollasak Thirapattaraphan.
Supervision: Sophida Boonsathorn, Nopporn Apiwattanakul, Chonnamet Techasaensiri, Chatmanee Lertudomphonwanit, Suporn Treepongkaruna.
Validation: Sophida Boonsathorn.
Visualization: Sophida Boonsathorn.
Writing – original draft: Chanita Phichaphop.
Writing – review & editing: Sophida Boonsathorn.
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