Response-Guided Therapy With Cefotaxime, Ceftriaxone, or Ciprofloxacin for Spontaneous Bacterial Peritonitis: A Randomized Trial: A Validation Study of 2021 AASLD Practice Guidance for SBP.

INTRODUCTION: For the treatment of spontaneous bacterial peritonitis (SBP), cefotaxime, ceftriaxone, and ciprofloxacin were used as first-line agents. However, considering the increasing rate of antibiotic resistance, it is unclear which of these drugs can be initially recommended. This study aimed to compare the current efficacy of the 3 antibiotics, namely cefotaxime, ceftriaxone, and ciprofloxacin, for the treatment of SBP in patients with cirrhosis with ascites, when guided by therapeutic responses. METHODS: This study was a multicenter, prospective, randomized controlled trial. The inclusion criteria were 16- to 75-year-old patients with liver cirrhosis with ascites, having polymorphonuclear cell count of >250/mm 3 . We performed a follow-up paracentesis at 48 hours to decide continuing or changing the assigned antibiotics and then assessed the resolution rates at 120 and 168 hours of treatment. RESULTS: A total of 261 patients with cirrhosis who developed SBP were enrolled. Most of the patients were diagnosed as those with SBP within 48 hours of admission. The resolution rates at 120 hours, which is the primary endpoint, were 67.8%, 77.0%, and 73.6% in the cefotaxime, ceftriaxone, and ciprofloxacin groups, respectively ( P = 0.388), by intension-to-treat analysis. The 1-month mortality was similar among the groups ( P = 0.770). The model for end-stage liver disease score and the SBP resolution were significant factors for survival. CONCLUSION: The efficacy of empirical antibiotics, such as cefotaxime, ceftriaxone, and ciprofloxacin, against SBP was not significantly different. In addition, these antibiotics administered based on response-guided therapy were still efficacious as initial treatment for SBP, especially in those with community-acquired infections.

Daily Norfloxacin vs. Weekly Ciprofloxacin to Prevent Spontaneous Bacterial Peritonitis: A Randomized Controlled Trial.

OBJECTIVES: For the prevention of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites, norfloxacin 400 mg per day is recommended as a standard regimen. This study aims to investigate whether ciprofloxacin once weekly administration is not inferior to norfloxacin once daily administration for the prevention of SBP. METHODS: This is an investigator-initiated open-label randomized controlled trial conducted at seven tertiary hospitals in South Korea. Liver cirrhosis patients with ascites were screened, and enrolled in this randomized controlled trial if ascitic protein ≤1.5 g/dL or the presence of history of SBP. Ascitic polymorphonucleated cell count needed to be <250/mm3. Patients were randomly assigned into norfloxacin daily or ciprofloxacin weekly group, and followed-up for 12 months. Primary endpoint was the prevention of SBP. RESULTS: One hundred twenty-four patients met enrollment criteria and were assigned into each group by 1:1 ratio (62:62). Seven patients in the norfloxacin group and five patients in the ciprofloxacin group were lost to follow-up. SBP developed in four patients (4/55) and in three patients (3/57) in each group, respectively (7.3% vs. 5.3%, P = 0.712). The transplant-free survival rates at 1 year were comparable between the groups (72.7% vs. 73.7%, P = 0.970). Incidence of infectious complication, hepatorenal syndrome, hepatic encephalopathy, and variceal bleeding rates were not significantly different (all P = ns). The factors related to survival were models representing underlying liver function. CONCLUSION: Once weekly ciprofloxacin was as effective as daily norfloxacin for the prevention of SBP in cirrhotic patients with ascites.

The combination of transcatheter arterial chemoembolization and sorafenib is well tolerated and effective in Asian patients with hepatocellular carcinoma: final results of the START trial.

This phase II, investigator-initiated, prospective single-arm multinational study (ClinicalTrials.gov registration NCT00990860) evaluated sorafenib in combination with doxorubicin-based transarterial chemoembolization (TACE) in patients with intermediate-stage, unresectable hepatocellular carcinoma (HCC). Patients with histologically or clinically diagnosed HCC received TACE with interrupted dosing of sorafenib (sorafenib discontinued for 3 days before and 4-7 days after TACE). TACE/sorafenib cycles were repeated every 6-8 weeks. Primary and secondary objectives were, respectively: to evaluate the safety and tolerability of TACE combined with sorafenib, and also their efficacy. The full analysis set comprised 192 patients (mean age 56.1 years). Most were male (87.0%), Eastern Cooperative Oncology Group (ECOG) score 0 (81.8%), Child-Pugh A (91.8%) and Barcelona Clinic Liver Cancer (BCLC) stage B (81.5%); 81.2% had chronic hepatitis B. Combined TACE/sorafenib was well tolerated, with only 8.1% of patients discontinuing owing to adverse events (AEs). The most common grade ≥3 AEs were palmar-plantar erythrodysesthesia syndrome (15.1%) and decreased platelet count (10.9%). Serious AEs (SAEs) occurred in 52 patients during the study; however, only four were considered related to sorafenib. A mean of 2.7 TACE cycles were administered and 52.6% of patients achieved complete response in target lesions; 16.8% achieved partial response, and 5.8% had progression of disease as their best response, evaluated by modified RECIST. Median progression-free survival and time to progression were 384 and 415 days, respectively, and the estimated 3-year overall survival was 86.1%. This study suggests that the combination of TACE and sorafenib is well tolerated and efficacious; the interrupted sorafenib dosing schedule may have contributed to a considerably lower AE profile than observed in other combination trials.

Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma.

BACKGROUND: Sorafenib currently sets the new standard for advanced hepatocellular carcinoma (HCC). It has been suggested that Asian patients with HCC have increased susceptibility to hand-foot skin reaction (HFSR) related to sorafenib therapy. The authors investigated the association between sorafenib-induced HFSR and genetic polymorphisms in Korean patients with HCC. METHODS: For this prospective cohort study, the authors enrolled 59 consecutive patients with intermediate stage HCC from 5 centers in Korea. All patients received sorafenib 400 mg twice daily in combination with transarterial chemoembolization (TACE). Genotyping was performed on a total of 49 single nucleotide polymorphisms (SNPs) in 8 candidate genes (minor allelic frequency ≥5%). Serum levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) were measured using enzyme-linked immunosorbent assays before therapy and 1 month after therapy. RESULTS: During a median treatment period of 18 months, 55 patients (93%) developed sorafenib-induced HFSR, including grade 1 reactions in 15 patients, grade 2 reactions in 27 patients, and grade 3 reaction in 13 patients. The SNPs TNF-α -308GG, VEGF -94GG, VEGF 1991CC, VEGF IVS3-28CC, and uridine diphosphate glucuronosyltransferase 1 family-polypeptide A9 (UGT1A9) IVS1-37431AA were associated significantly with the development of high-grade (grade 2 or 3) HFSR in univariate analysis (P < .05). In multivariate analysis, the SNPs VEGF 1991CC (odds ratio, 45.7), TNF-α -308GG (odds ratio, 44.1), and UGT1A9 IVS1-37431AA (odds ratio, 18.7) were identified as independent risk factors for the development of high-grade HFSR (P = .01, P = .02, and P = .02, respectively). He serum TNF-α level measured 1 month after sorafenib therapy was correlated significantly with the development of high-grade HFSR (odds ratio, 3.56; P = .026). CONCLUSIONS: Differences in the incidence of HFSR may have been caused by ethnic differences in genetic polymorphisms of the TNF-α, VEGF, and UGT1A9 genes, especially in relation to the expression of serum TNF-α after sorafenib therapy.

Interim analysis of START: Study in Asia of the combination of TACE (transcatheter arterial chemoembolization) with sorafenib in patients with hepatocellular carcinoma trial.

Transarterial chemoembolization (TACE) represents a first-line noncurative therapy for hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, has been shown to be effective and safe monotherapy in patients with advanced HCC and the current study reports the interim results of a prospective Phase II, open label, trial investigating the safety and efficacy of the combination of sorafenib and conventional TACE in patients from the Asia-Pacific region with intermediate HCC. Patients with histologically or clinically diagnosed HCC were treated with conventional TACE followed by sorafenib 4 to 7 days later. TACE was performed by selective transarterial chemotherapy in the vessels feeding the tumor with an emulsion of lipiodol (5-20 ml) and doxorubicin (30-60 mg) followed by embolization with absorbable particles (gel foam). TACE/sorafenib cycles were repeated every 6-8 weeks. Primary objectives were to evaluate the safety and tolerability, in addition to the efficacy of TACE combined with sorafenib for HCC. A total of 147 patients were included in the intention-to-treat analysis and received at least one dose of sorafenib. Gastrointestinal AEs were reported by 62.6% of patients while 57.8% reported skin AEs although most were mild to moderate. The mean number of cycles undertaken was 2.1 and 63.3% of patients achieved either partial response or stable disease. Clinically, the disease control rate was 91.2% while the overall response rate was calculated as 52.4%. Our study shows that concurrent sorafenib and TACE therapy is safe and effective with no unexpected side effects.

A prospective nationwide study of drug-induced liver injury in Korea.

OBJECTIVES: To address a growing concern about drug-induced liver injury (DILI), a nationwide study was performed to investigate the significance of DILI in Korea. METHODS: From May 2005 to May 2007, cases of DILI (alanine transferase > 3 × upper normal limit or total bilirubin > 2 × upper normal limit) from 17 referral university hospitals were prospectively enrolled. Adjudication by the seven review boards was considered for the confirmation of causality and the Roussel Uclaf Causality Assessment Method (RUCAM) scale was used. RESULTS: A total of 371 cases were diagnosed with DILI. The extrapolated incidence of hospitalization at university hospital in Korea was 12/100,000 persons/year. The causes included "herbal medications" (102, 27.5%), "prescription or non-prescription medications" (101, 27.3%), "health foods or dietary supplements" (51, 13.7%), "medicinal herbs or plants" (35, 9.4%), "folk remedies" (32, 8.6%), "combined" (30, 8.2%), "herbal preparations" (12, 3.2%), and others (8, 2.2%). Nine cases were linked to acetaminophen. The frequencies of hepatocellular, mixed, and cholestatic types were 76.3, 14.8, and 8.9%, respectively. A total of 234 cases met the criteria for Hy's law. Five patients died or underwent transplantation. Twenty-five cases (21 herbs and 4 medications) did not meet the time-to-onset criteria of the RUCAM. CONCLUSIONS: DILI appears to be a highly relevant health problem in Korea. "Herbal medications" are the principal cause of DILI. A more objective and reproducible causality assessment tool is strongly desired as the RUCAM scale frequently undercounts the cases caused by herbs owing to a lack of previous information and incompatible time criteria.

The effect of probiotics and mucoprotective agents on PPI-based triple therapy for eradication of Helicobacter pylori.

BACKGROUND/AIMS: Recent studies have found that probiotics have anti-Helicobacter pylori (HP) properties. We evaluated the additive effects of (i) Saccharomyces boulardii combined with proton pump inhibitor (PPI)-based triple therapy and (ii) S. boulardii and a mucoprotective agent (DA-9601) coupled with PPI-based triple therapy for HP eradication. METHODS: We recruited 991 HP infected patients and randomized them into one of three groups, (A) PPI-based 7-day triple therapy, (B) the same triple therapy plus S. boulardii for 4 weeks, and (C) the same 7-day triple therapy plus S. boulardii and mucoprotective agent for 4 weeks. All patients in the three groups were tested via (13)C-urea breath test 4 weeks after the completion of the therapy. RESULTS: According to the results of an intention-to-treat analysis, HP eradication rates for the groups A, B, and C were 71.6% (237/331), 80.0% (264/330), and 82.1% (271/330), respectively (p = .003). According to the results of a per protocol analysis, the eradication rates were 80.0% (237/296), 85.4% (264/309) and, 84.9% (271/319), respectively (p = .144). The frequency of side effects in group B (48/330) and C (30/330) was lower than that in group A (63/331) (p < .05). CONCLUSION: This study suggests that supplementation with S. boulardii could be effective for improving HP eradication rates by reducing side effects thus helping completion of eradication therapy. However, there were no significant effects on HP eradication rates associated with the addition of mucoprotective agents to probiotics and triple therapy.

Deleterious effects of silymarin on the expression of genes controlling endothelial nitric oxide synthase activity in carbon tetrachloride-treated rat livers.

AIMS: Defects in intrahepatic nitric oxide (NO) are attributed to reduced blood flow due to portal hypertension caused by diminished endothelial NO synthase (eNOS) activity. The aim of this study is to identify the therapeutic effects of silymarin on eNOS/NO-related enzymes and hepatic enzymes in carbon tetrachloride (CCl4)-induced cirrhotic rats. MAIN METHODS: CCl4 treated for 12 weeks was discontinued and then administrated with silymarin daily for 4 weeks. Collagen concentrations were determined by measuring hydroxyproline content. Serum was assayed for hepatic enzymes like alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities. NOS activities were measured by oxyhemoglobin oxidation assay, and levels of enzyme expression and phosphorylation were detected by Western-blot analyses. KEY FINDINGS: Silymarin treatment restored the values for collagen content and ALT and ALP activities when compared to the values with spontaneous resolution following discontinuation of CCl4. CCl4 treatment highly increased eNOS expression and NOS activity in livers, but the phosphorylation was markedly decreased. Silymarin decreased significantly eNOS expression and activity. Expression and/or phosphorylation of enzymes activating eNOS were unchanged (Akt and AMPK) or decreased (PKA) by silymarin. Especially, the expression of caveolin-1, an inhibitor of eNOS was unchanged by CCl4, but its phosphorylation was significantly increased. However, silymarin markedly increased caveolin-1 expression but decreased its phosphorylation to expression. SIGNIFICANCE: These results suggest that chronic silymarin treatment can improve cirrhosis-induced liver enzyme activities and fibrosis, but may aggravate the hemodynamic eNOS activity, particularly by decreasing eNOS expression and increasing caveolin-1 expression.

Factors affecting the technical difficulty of colonoscopy.

BACKGROUND/AIMS: Colonoscopy is a standard diagnostic tool for screening and surveillance of diseases affecting the colon. Colonoscopy may be painful for patients and difficult for the endoscopist. The aim of this study was to identify the factors affecting the technical difficulty of a colonoscopic examination and to predict potential difficult patients who will undergo colonoscopy. METHODOLOGY: A total of 646 outpatients were consecutively included in this study. Patient's age and gender, body mass index (BMI), prior surgical history, and the duration and symptoms of irritable bowel syndrome (IBS) were recorded before the procedure. The quality of bowel preparation, the difficulty of examination reported by the colonoscopist, the degree of patient pain, the degree of pain as reported by an observer, cecal intubation time andcolonoscopic findings were assessed after the procedure. RESULTS: We evaluated the difficulty of colonoscopy by cecal intubation time. Advanced age (>50 years), female gender, low BMI (< or = 23 Kg/m2), poor bowel preparation, prior surgical history, patient pain and the presence of IBS were associated with prolonged cecal intubation time. A multivariate logistic regression analysis demonstrated that advanced age, female gender, low BMI, poor bowel preparation and patient pain were independent factors related to prolonged cecal intubation time. CONCLUSIONS: In patients with advanced age, female gender and low BMI, information that colonoscopy may be difficult and painful should be provided. If a colonoscopy is not absolutely indicated, barium enema or CT colonography may be performed as alternative diagnostic modalities.

[The survey for the actual condition of drug medication and development of health care cost associated with toxic liver injury in Korean: a multicenter study for the detection and the development of nationwide reporting system of toxic liver injury].

BACKGROUNDS AND AIMS: In Korea, interests in health and health care costs have been increased along with the increase of mean survival rate and income level. The aim of this study is to investigate the actual condition of drug medication and burden of health care cost. METHODS: A total of 1,434 subjects in four tertiary medical centers were enrolled in this study. The questionnaires were obtained between March 2005 and September 2005. Based on this information, the actual condition of drug medication and health care cost were analyzed. RESULTS: The mean age of the subjects was 55.0+/-11.4 years (16-87 years). The male and female ratio was 1.74:1. The subjects with drug medication except for doctor's prescription are presently 26.6% and were 40.9% in the past. Traditional medicine (39.6%) and health food (29.9%) are more frequently used than herbal medicine (5.8%) and medical supplies (4.2%) now. In the past, herbal medicine (14.6%) was more frequently used compared with the present. The side effects of drug medication were developed in 90 subjects (7.5%). The total mean health care costs were 895,000 Won/year, the herbal medicine, 834,000 Won/year, the health food, 950,000 Won/year, and the traditional medicine, 324,000 Won/year. CONCLUSIONS: In this study, the subjects with other drug medications without doctor's prescription were as high as ever. The frequency of the use of the herbal medicine was decreased. However, the frequency for the use of the health food and traditional medicine have relatively increased. The side effects and additional large amounts of health care costs were occurred.

The effect of probiotics on Helicobacter pylori eradication.

BACKGROUND/AIMS: Conflicting results have been reported on the effect of a variety of probiotic strains on Helicobacter pylori (HP) eradication. In this study, we evaluated the outcome of a probiotic strain composed of bacillus subtilis and Streptococcus faecium on HP eradication. METHODOLOGY: We recruited 352 HP infected patients who were randomized into a triple-plus-probiotics group or a triple-only group; the participants received 1 week of PPI-based triple therapy with or without probiotics supplements. For the triple-plus-probiotics group, probiotics was continued for 8 weeks. All patients in the two groups were evaluated for 4 weeks after completion of therapy. RESULTS: Using the intention to treat analysis, evaluation of the triple-plus-probiotics group showed a higher eradication rate than the triple-only group (83.5% vs. 73.3%, p=0.027). Diarrhea and overall side effects were more common in the triple-only group (p<0.05). CONCLUSIONS: Supplementation with probiotic strains, composed of Bacillus subtilis and Streptococcus faecium, were shown to improve drug compliance, reduce side effects and enhance the intention-to-treat eradication rate of HP.

Effect of high-dose aspirin on Helicobacter pylori eradication.

We conducted a pilot study aimed at comparing the efficacy of the standard OAC (omeprazole-amoxicillin-clarithromycin) regimen with a combination of the OAC regimen and aspirin (OACA). Follow-up endoscopic findings showed that the previous ulcers were completely healed in all subjects. The eradication rates (per protocol) were 80.3% (49/61) in the OAC group and 86.7% (52/60) in the OACA group. The eradication rate was not significantly different between the two groups. The most common adverse event was a bad taste, and the overall adverse events were similar in the two groups. The combination of the OAC regimen and aspirin was not significantly superior to the standard OAC regimen, but it was well tolerated in a group of patients with peptic ulcer disease. Its potential for clinical use to augment the efficacy of H. pylori eradication may warrant further investigation.

Protective effects of bovine colostrum on non-steroidal anti-inflammatory drug induced intestinal damage in rats.

The aim of this study was to examine whether bovine colostrum was able to prevent the NSAID induced small intestinal damage in animals. The animal model population of the study consisted of 4 groups: control group, diclofenac group, diclofenac with 10% low fat milk group and diclofenac with 5% colostrum group. The animals with milk or colostrum were fed with 10% low fat milk or 5% colostral solution for 5 days before the administration of diclofenac. Gut injuries were induced by administration of a single dose of diclofenac (100 mg/kg orally). Epithelial permeability values (24 hour urinary excretion of 51Cr-ethylenediaminetetraacetic acid [51Cr-EDTA]), enteric aerobic bacterial counts, serum biochemical profiles and pathologic findings of distal ileum were measured. Diclofenac caused a marked increase in the intestinal permeability, enteric bacterial numbers and intestinal villous damage, and enteric protein and albumin loss. Combined administration of bovine colostrum reduced the increase in intestinal permeability, enteric bacterial overgrowth, protein losing enteropathy and mucosal villous damage of the small intestine induced by diclofenac. Bovine colostrum may have a beneficial effect in prevention of NSAID induced small intestinal injuries.