Prophylactic antibiotics confer no advantage in elective endoscopic treatment for cirrhotic patients with gastroesophageal variceal bleeding history

Abstract

BACKGROUND

The necessity of routine preoperative antibiotic prophylaxis (AP) for elective endoscopic treatment of gastroesophageal varices (GEV) remains controversial.

AIM

To evaluate whether preoperative AP is beneficial in elective endoscopic treatment for patients with previous bleeding history of GEV.

METHODS

In this retrospective case-control study, cirrhotic patients with a previous history of GEV bleeding who were readmitted for elective endoscopic treatment were enrolled. Patients who received no preoperative antibiotics were assigned to the antibiotic-free (AF) group, while those who received preoperative cephalosporin infusion before endoscopic intervention were assigned to the AP group. The use of antibiotics was determined by physician experience. Postoperative bacterial infection, 3-month rebleeding rate, and other clinical outcomes were compared between the two groups.

RESULTS

A total of 442 patients (220 in the AF group, and 222 in the AP group) were included in the final analysis. The incidence of post-operative bacterial infection was 18.6% in the AF group and 17.6% in the AP group (P > 0.05). Three-month rebleeding rates were 5.9% and 7.2% in the AF group and AP group (P > 0.05), respectively. Stratified analyses using the Sarin classification of GEV, endoscopic modality, Child-Pugh grade, and cirrhosis etiology demonstrated no significant difference in postoperative bacterial infection rate between the AF and AP groups.

CONCLUSION

Preoperative AP does not confer benefits in elective endoscopic treatment for patients with a previous history of GEV bleeding.

Key Words: Gastroesophageal variceal bleeding; Prophylactic antibiotics; Secondary prophylaxis; Bacterial infection; Rebleeding

Core Tip: The necessity of routine preoperative antibiotic prophylaxis (AP) for elective endoscopic treatment of gastroesophageal varices in cirrhotic patients remains controversial. In this retrospective case-control trial, similar rates of postoperative bacterial infection and 3-month rebleeding were found between patients who received AP and those who did not, indicating that preoperative AP does not confer additional benefit in elective endoscopic treatment for cirrhotic patients with a previous history of gastroesophageal variceal bleeding.

INTRODUCTION

Gastroesophageal varices (GEV) due to portal hypertension are common in patients with cirrhosis, particularly in those at the decompensated stage[1]. Massive hemorrhage resulting from variceal rupture constitutes a medical emergency and requires prompt endoscopic intervention[2]. As portal hypertension persists in cirrhosis, GEV will inevitably recur[3]. Combined endoscopic therapy and pharmacologic treatment have been shown to reduce rebleeding and mortality rates in elective endoscopic treatment for patients with a previous history of GEV bleeding[4,5]. Consequently, regular endoscopic surveillance and prophylactic intervention are recommended after an initial episode of acute variceal bleeding[6].

The incidence of bacterial infection among hospitalized patients with cirrhosis exceeds 30% and increases to approximately 45% during episodes of variceal hemorrhage, largely due to impairment of the intestinal mucosal barrier[7]. Moreover, the presence of infection further exacerbates portal hypertension[8]. A meta-analysis demonstrated that antibiotic therapy reduces bacterial infection and rebleeding rate in patients with GEV, and decreases mortality and length of hospital stay[9]. Accordingly, current guidelines for the management of GEV recommend antimicrobial prophylaxis during acute bleeding episodes, which should be continued for several days[10]. However, there is no consensus regarding the use of prophylactic antibiotics for elective endoscopic treatment of GEV.

In clinical practice, we have observed that many patients with cirrhosis undergoing elective endoscopic treatment of GEV do not develop post-operative bacterial infection, even in the absence of preoperative antibiotic prophylaxis (AP). In contrast, postoperative infection is occasionally observed in patients who receive prophylactic antibiotics. Based on these observations, we hypothesize that preoperative AP may have no advantages in patients undergoing elective endoscopic therapy for secondary prophylaxis of GEV bleeding. To test this hypothesis, the current retrospective case-control study was conducted.

MATERIALS AND METHODS

Patient selection

This bi-center retrospective study was conducted at the Second Affiliated Hospital of Zhejiang University School of Medicine and the Affiliated Jinhua Hospital, School of Medicine, Zhejiang University. The study protocol was approved by the Ethical Review Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (No. 2026-0728). The trial was conducted in accordance with the ethical principles of the Declarations of Helsinki and Istanbul, and was registered at ClinicalTrials.gov (Identification number: NCT07616466). Informed consent was waived due to the retrospective study design.

Cirrhotic patients with a history of GEV bleeding who were readmitted for elective endoscopic treatment were screened for eligibility. The exclusion criteria were as follows: (1) Age < 18 years or ≥ 81 years; (2) Allergy to cephalosporin; (3) Agranulocytosis (neutrophil count < 0.5 × 10⁹/L); (4) Massive ascites; and (5) Signs of bacterial infection. Patients were withdrawn from analysis if they were transferred to another department for additional interventions after endoscopy. If the patients did not return for a follow-up visit and telephone calls were not answered, they were also withdrawn from the final analysis.

Study design

This retrospective time- and Child-Pugh class-matched case-control study was conducted following the recruitment of cirrhotic patients from January 1, 2024, to December 31, 2025. On the day of endoscopy, no preoperative antibiotics were administered in the AF group, whereas patients in the AP group received 2.0 g ceftriaxone intravenously prior to endoscopic therapy. The assignment of patients into the AF and AP groups was dependent on institutional policy regarding antibiotics, and physician experience. The endoscopic intervention strategy was determined based on portal venous characteristics observed on computed tomography (CT) portal venography and endoscopic findings. Treatment modalities included endoscopic cyanoacrylate injection (ECI) using tissue adhesive (1050044, Braun, Spain), endoscopic variceal ligation (EVL) using a ligator (MBL-U-10, Cook, United States), and endoscopic injection sclerotherapy (EIS) using lauromacrogol (Tianyu Pharmaceuticals, China). Procedures were performed using a therapeutic gastroscope (GIF-Q260J, Olympus, Japan). The choice of single or combined techniques was at the discretion of an experienced endoscopist with at least 5 years of clinical practice. All patients received a single intravenous dose of a proton pump inhibitor prior to endoscopy, followed by continued administration every 12 hours during hospitalization. A liquid diet was initiated on the second postoperative day if no contraindications were present.

Primary outcome

The primary outcome was post-operative bacterial infection, defined as one of the following conditions: (1) Spontaneous bacterial peritonitis: Ascitic fluid polymorphonuclear cell count > 250/mm³ with a positive ascitic culture, or polymorphonuclear cell count > 500/mm³ when ascitic culture is negative; (2) Pulmonary infection: Confirmed by the presence of pneumonic patches or pleural effusion on pulmonary CT; (3) Urinary tract infection: Abnormal urinary sediment (> 15 leukocytes/ highpower field) with a positive urine culture; (4) Bacteremia: Presence of a positive blood culture without definite infectious focus; and (5) Possible infection: Unexplained fever > 37.5 °C lasting for more than 6 hours, combined with increased inflammatory index (white blood cell > 15000/mm³, neutrophil percentage > 70%, or C-reactive protein > 10 mg/L), but with negative blood cultures[11].

Secondary outcomes

Three-month rebleeding: Rebleeding was defined as the presence of overt hemorrhage, including hematemesis, hematochezia, or melena, due to varices within 3 months following the endoscopic intervention.

Post-operative hospitalization duration: Patients were discharged when they tolerated a liquid diet and reported no discomfort. The duration between endoscopic intervention and discharge was recorded.

Statistical analysis

Depending on the normality of data, continuous variables are presented as mean ± SD or median (interquartile range), and were compared using the Student's t-test or Mann-Whitney U test. Categorical variables are reported as n (%) and were compared using the χ² test or Fisher’s exact test. All statistical analyses were performed using SPSS software, version 20.0 (IBM Corp, Armonk, NY, United States).

RESULTS

Included patients

Between January 1, 2024, and December 31, 2025, a total of 503 patients receiving elective endoscopic therapy for secondary prophylaxis of GEV bleeding in our two centers were screened. Twenty-three patients were excluded based on predefined criteria, and 480 patients were initially included. Following the endoscopic intervention, four patients were referred to the Department of Surgical for liver transplantation or resection of newly diagnosed malignant tumors, and five patients were transferred to the Department of Interventional Radiology for transjugular intrahepatic portosystemic shunt or splenic embolization. In addition, twenty-nine patients were lost to follow-up. These 38 patients were defined as withdrawal, and 442 patients (AF:AP = 220:222) were included in the final analysis. Figure 1 outlines the detailed reasons for exclusion and withdrawal.

Figure 1 Participant flowchart. AF: Antibiotic-free; AP: Antibiotic prophylaxis.

Clinical characteristics and endoscopic strategies

Table 1 summarizes the baseline demographic and clinical characteristics. No significant differences were observed between the two groups in terms of demographics, baseline characteristics, or types of varices. The value of hepatic venous pressure gradient was available in only a proportion of the participants (AF: 167, AP: 178), and a comparison was made between these 345 patients in the two groups. Table 2 lists the endoscopic treatment modalities. In the AF group, ECI was performed in 138 patients, EVL in 116 patients, and EIS in 20 patients. In the AP group, ECI, EVL, and EIS were performed in 137, 118, and 17 patients, respectively. No significant differences were observed between the two groups regarding endoscopic modality.

Table 1 Baseline characteristics of enrolled patients, n (%) or median (interquartile range) or mean ± SD.

Characteristics	AF (n = 220)	AP (n = 222)	P value
Male	164 (74.5)	154 (69.4)	0.226
Age (≥ 60 years)	105 (47.7)	121 (54.5)	0.154
Etiology of cirrhosis
Hepatitis B	100 (45.5)	97 (43.7)	0.710
Alcohol	65 (29.5)	62 (27.9)	0.707
Autoimmune	16 (7.3)	14 (6.3)	0.686
Schistosomiasis	7 (3.2)	11 (5.0)	0.346
Wilson’s disease1	2 (0.9)	4 (1.8)	0.685
MASLD	10 (4.5)	12 (5.4)	0.678
Hepatitis C1	3 (1.4)	1 (0.5)	0.371
Cryptogenic cirrhosis	17 (7.7)	21 (9.5)	0.516
Type of GEV
EV	201 (91.4)	209 (94.1)	0.259
GV	205 (93.2)	198 (89.2)	0.139
GOV1	149 (67.7)	139 (62.6)	0.259
GOV2	23 (10.5)	30 (13.5)	0.322
GOV3	14 (6.4)	16 (7.2)	0.724
IGV1	17 (7.7)	13 (5.9)	0.434
IGV21	2 (0.9)	0 (0.0)	0.247
Child-Pugh class
A	141 (64.1)	139 (62.6)	0.747
B + C	79 (35.9)	83 (37.7)
HVPG (≥ 12 mmHg)2	86 (51.5)	101 (56.7)	0.329
Diabetes	65 (29.3)	58 (26.1)	0.423
Hypertension	53 (23.9)	58 (26.1)	0.622
Portal vein thrombosis	46 (20.7)	51 (23.0)	0.600
Ascites	141 (63.5)	150 (67.6)	0.441
BMI (kg/m2)	22.25 (20.53, 24.28)	22.09 (20.28, 24.52)	0.831
ALT (U/L)3	25.5 (19.0, 34.8)	27.0 (20.0, 36.3)	0.414
AST (U/L)3	34.0 (28.0, 45.8)	36.0 (30.0, 46.0)	0.205
Albumin (g/L)	37.9 ± 5.1	37.7 ± 4.9	0.593
Total bilirubin (μmol/L)3	20.5 (13.3, 27.8)	18.1 (14.3, 25.1)	0.754
PT (second)3	14.9 (14.0, 15.8)	14.7 (14.1, 15.8)	0.608
WBC count (109/L)3	3.0 (2.3, 4.2)	3.3 (2.4, 4.6)	0.134
Neutrophil count (109/L)3	1.8 (1.3, 2.6)	1.9 (1.4, 2.7)	0.623
Hemoglobin (g/dL)3	10.5 ± 2.4	10.7 ± 2.3	0.202
Platelet count (109/L)3	66.0 (43.0, 103.8)	69.0 (44.0, 123.8)	0.300

¹Fisher’s exact test was used.

²The value of hepatic venous pressure gradient was available in only a proportion of recruiters (antibiotic-free: 167, antibiotic prophylaxis: 178).

³Non-parametric Mann-Whitney U test was used.

AF: Antibiotic-free; AP: Antibiotic prophylaxis; GEV: Gastroesophageal varices; EV: Esophageal varices; GV: Gastric varices; GOV1: Gastroesophageal varices type 1; GOV2: Gastroesophageal varices type 2; GOV3: Gastroesophageal varices type 3; IGV1: Isolated gastric varices type 1; IGV2: Isolated gastric varices type 2; MASLD: Metabolic dysfunction-associated steatotic liver disease; HVPG: Hepatic venous pressure gradient; BMI: Body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; PT: Prothrombin time; WBC: White blood cell.

Table 2 Endoscopic methods used for secondary prophylaxis, n (%).

Methods	AF	AP	P value
ECI	138 (62.7)	137 (61.7)	0.826
EVL	116 (52.7)	118 (53.2)	0.929
EIS	20 (9.1)	17 (7.7)	0.586

AF: Antibiotic-free; AP: Antibiotic prophylaxis; EIS: Endoscopic injection sclerotherapy; EVL: Endoscopic variceal ligation; ECI: Endoscopic cyanoacrylate injection.

Postoperative clinical events

In the AF group, 41 patients (18.6%) developed postoperative bacterial infection. In the AP group, postoperative bacterial infection occurred in 39 patients (17.6%). No significant difference was observed between the AP and AF groups (OR = 0.93, 95%CI: 0.57-1.52, P = 0.770; Figure 2A). The most common type of infection was spontaneous bacterial peritonitis in both groups (6.8% in the AF group and 6.3% in the AP group). The average length of postoperative hospital stay did not differ significantly between the two groups (2.3 vs 2.2 days, P = 0.386; Figure 2B).

Figure 2 Postoperative clinical outcomes. A: Rates of postoperative infection in the antibiotic-free (AF) and antibiotic prophylaxis (AP) groups; B: Length of postoperative hospital stay in the AF and AP groups; C: Three-month rebleeding rates in the AF and AP groups. AF: Antibiotic-free; AP: Antibiotic prophylaxis.

Five patients experienced hematemesis and eight patients experienced melena in the AF group within 3 months after endoscopic therapy. In the AP group, ten patients developed hematemesis and six patients developed melena within 3 months after endoscopy. The overall 3-month rebleeding rates did not differ significantly between the two groups (OR = 1.24, 95%CI: 0.58-2.54, P = 0.582; Figure 2C).

Stratified analysis

In stratified analyses by type of varices, no significant differences in postoperative infection rates were observed between the AF group and AP group for either esophageal varices (17.9% vs 17.2%, P = 0.855) or gastric varices (18.6% vs 17.1%, P = 0.838). Further stratification of gastric varices according to the Sarin classification also revealed no significant differences between the AF and AP groups. When stratified by endoscopic modality, postoperative infection rates in the AF group were 17.4%, 24.1%, and 10.0% for ECI, EIS, and EVL, respectively, which were comparable to those in the AP group (19.7%, 21.2%, and 5.9%, respectively; P > 0.05 for all).

Patients were also stratified by liver reserve function into Child-Pugh class A and Child-Pugh class B/C. No significant difference in post-operative infection rates between the AF and AP groups were observed in patients with either preserved liver function (14.2% vs 15.8%, P = 0.700) or impaired liver function (26.6% vs 20.5%, P = 0.360).

Further stratification by etiology of cirrhosis showed that postoperative infection in the AF group occurred in 19.0% and 18.5% of patients with post-hepatitis B and alcoholic cirrhosis. Corresponding rates in the AP group were 18.6% and 19.4%, respectively (P > 0.05 for all; Table 3).

Table 3 Stratified analysis of postoperative bacteria infection risk, n (%).

Characteristics	Infection rate in AF	Infection rate in AP	P value
Type of GEV
EV	36 (17.9)	36 (17.2)	0.855
GV	41 (18.6)	38 (17.1)	0.838
GOV1	27 (18.1)	27 (19.4)	0.777
GOV2	5 (21.7)	5 (16.7)	0.640
GOV31	4 (28.6)	3 (18.8)	0.675
IGV11	4 (23.5)	3 (23.1)	1.000
IGV21	1 (50.0)	0 (0.0)	1.000
Endoscopic method
ECI	24 (17.4)	27 (19.7)	0.621
EVL	28 (24.1)	25 (21.2)	0.590
EIS1	2 (10.0)	1 (5.9)	1.000
Child-Pugh class
A	20 (14.2)	22 (15.8)	0.700
B + C	21 (26.6)	17 (20.5)	0.360
Etiology of cirrhosis
Hepatitis B	19 (19.0)	18 (18.6)	0.937
Alcohol	12 (18.5)	12 (19.4)	0.898
Autoimmune1	4 (25.0)	2 (14.3)	0.657
Schistosomiasis1	2 (28.6)	3 (27.3)	1.000
Wilson’s disease1	0 (0.0)	0 (0.0)	1.000
MASLD1	1 (9.1)	1 (8.3)	1.000
Hepatitis C1	1 (33.3)	0 (0.0)	1.000
Cryptogenic cirrhosis1	2 (11.8)	3 (14.3)	1.000

¹Fisher’s exact test was used.

AF: Antibiotic-free; AP: Antibiotic prophylaxis; GEV: Gastroesophageal varices; EV: Esophageal varices; GV: Gastric varices; GOV1: Gastroesophageal varices type 1; GOV2: Gastroesophageal varices type 2; GOV3: Gastroesophageal varices type 3; IGV1: Isolated gastric varices type 1; IGV2: Isolated gastric varices type 2; MASLD: Metabolic dysfunction-associated steatotic liver disease; EIS: Endoscopic injection sclerotherapy; EVL: Endoscopic variceal ligation; ECI: Endoscopic cyanoacrylate injection.

Postoperative inflammatory index

White blood cell count and neutrophil count after endoscopic therapy were increased compared with preprocedural values. However, no significant differences were observed between the two groups for post-operative white blood cell count (P = 0.241), neutrophil count (P = 0.684), neutrophil proportion (P = 0.229), or C-reactive protein level (P = 0.414; Table 4).

Table 4 Postoperative inflammatory indices, median (interquartile range) or n (%).

Variables	AF	AP	P value
WBC count (109/L)1	3.3 (2.7, 4.4)	3.5 (2.6, 4.7)	0.241
Neutrophil count (109/L)1	2.2 (1.7, 3.0)	2.3 (1.7, 3.3)	0.684
Neutrophil percent (%)1	68.4 (60.1, 75.1)	67.5 (57.0, 73.6)	0.229
C-reactive protein (> 10 mg/L)1	4.6 (1.8, 6.7)	4.5 (1.6, 6.4)	0.414

¹Non-parametric Mann–Whitney U test was used.

AF: Antibiotic-free; AP: Antibiotic prophylaxis; WBC: White blood cell.

DISCUSSION

Due to bacterial overgrowth, disruption of the intestinal mucosal barrier, bacterial translocation, and immune dysfunction, patients with cirrhosis are predisposed to infection[12]. In the context of endoscopic intervention for GEV, post-endoscopic bacteremia occurs less frequently during an elective procedure than during acute bleeding episodes[13]. However, a survey of elective endoscopic treatment for GEV reported that intraprocedural bleeding occurred in 7.5% patients, mimicking the status of acute bleeding[14]. In addition, mucosal injury at puncture sites when injecting tissue adhesive or sclerosing agent may further exacerbate bacterial translocation and increase the risk of post-operative infection[15].

Guidelines recommend routine use of antibiotics in acute bleeding of GEV. With regard to elective endoscopic intervention in GEV, AP may confer benefits, but must be balanced against adverse effects and antibiotic overuse. Substantial evidence has linked antibiotic exposure to two major complications: Clostridioides difficile-related colitis[16] and the emergence of multidrug-resistant bacteria[17]. The increasing incidence of these complications, along with other antibiotic-associated adverse events, such as diarrhea and hypersensitivity reactions, emphasizes the importance of strict, risk-stratified antibiotic use[18].

Elective endoscopic treatments for GEV include ligation, tissue adhesive obturation and sclerotherapy, among others[19]. A previous study demonstrated that using antibiotics prophylactically could reduce the incidence of fever and rebleeding in elective endoscopic tissue adhesive injection for gastric varices[15]. The present study focused on elective endoscopic therapy for secondary prophylaxis of GEV bleeding, and the results showed that prophylactic antibiotic use did not affect the overall incidence of postoperative infection rate, opposing the routine preoperative use of antibiotics.

Risk stratification has been proposed as an option to reduce unnecessary antimicrobial exposure in patients with cirrhosis. In acute variceal hemorrhage, cirrhotic patients of Child-Pugh class A have lower rates of bacterial infection and mortality than those of Child-Pugh class B/C in the absence of AP[20]. Another study reported that in elective endoscopic treatment of gastric varices with cyanoacrylate injection combined with lauromacrogol, viral hepatitis was an independent risk factor for major post-operative complications compared with other etiologies of cirrhosis[14]. However, in the present study, no superiority of preoperative antibiotic use was observed in patients with poor hepatic functional reserve or specific cirrhosis etiologies.

The rebleeding rate after emergent endoscopic treatment of gastric varices was reported to exceed 20%[21], whereas < 5% of patients undergoing elective cyanoacrylate injection experienced recurrent bleeding[14]. In this study, the overall rebleeding rate within 3 months after endoscopic therapy was 5.9%-7.2%, and preoperative antibiotic use had no obvious impact on rebleeding rate, indicating that AP confers no advantage in preventing hemorrhage after elective endoscopic intervention for GEV.

CONCLUSION

Prophylactic antibiotic use provides no benefit in elective endoscopic treatment for patients with a previous history of GEV bleeding, either in reducing postoperative infection rate during hospitalization or in preventing rebleeding within 3 months. Considering the potential selection bias introduced by the retrospective design of this study, further double-blind randomized controlled trials conducted in multiple centers are warranted.