Norfloxacin vs Ceftriaxone in the Prophylaxis of Infections in Patients With Advanced Cirrhosis and Hemorrhage
2006; Elsevier BV; Volume: 131; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2006.07.010
ISSN1528-0012
AutoresJavier Fernández, L Ruíz del Arbol, Cristina Gómez, Rosa Durández, R. Serradilla, Carlos Guarner, Ramón Planas, Vicente Arroyo, Miguel Navasa,
Tópico(s)Organ Transplantation Techniques and Outcomes
ResumoBackground & Aims: Oral norfloxacin is the standard of therapy in the prophylaxis of bacterial infections in cirrhotic patients with gastrointestinal hemorrhage. However, during the last years, the epidemiology of bacterial infections in cirrhosis has changed, with a higher incidence of infections caused by quinolone-resistant bacteria. This randomized controlled trial was aimed to compare oral norfloxacin vs intravenous ceftriaxone in the prophylaxis of bacterial infection in cirrhotic patients with gastrointestinal bleeding. Methods: One hundred eleven patients with advanced cirrhosis (at least 2 of the following: ascites, severe malnutrition, encephalopathy, or bilirubin >3 mg/dL) and gastrointestinal hemorrhage were randomly treated with oral norfloxacin (400 mg twice daily; n = 57) or intravenous ceftriaxone (1 g/day; n = 54) for 7 days. The end point of the trial was the prevention of bacterial infections within 10 days after inclusion. Results: Clinical data were comparable between groups. The probability of developing proved or possible infections, proved infections, and spontaneous bacteremia or spontaneous bacterial peritonitis was significantly higher in patients receiving norfloxacin (33% vs 11%, P = .003; 26% vs 11%, P = .03; and 12% vs 2%, P = .03, respectively). The type of antibiotic used (norfloxacin), transfusion requirements at inclusion, and failure to control bleeding were independent predictors of infection. Seven gram-negative bacilli were isolated in the norfloxacin group, and 6 were quinolone resistant. Nonenterococcal streptococci were only isolated in the norfloxacin group. No difference in hospital mortality was observed between groups. Conclusions: Intravenous ceftriaxone is more effective than oral norfloxacin in the prophylaxis of bacterial infections in patients with advanced cirrhosis and hemorrhage. Background & Aims: Oral norfloxacin is the standard of therapy in the prophylaxis of bacterial infections in cirrhotic patients with gastrointestinal hemorrhage. However, during the last years, the epidemiology of bacterial infections in cirrhosis has changed, with a higher incidence of infections caused by quinolone-resistant bacteria. This randomized controlled trial was aimed to compare oral norfloxacin vs intravenous ceftriaxone in the prophylaxis of bacterial infection in cirrhotic patients with gastrointestinal bleeding. Methods: One hundred eleven patients with advanced cirrhosis (at least 2 of the following: ascites, severe malnutrition, encephalopathy, or bilirubin >3 mg/dL) and gastrointestinal hemorrhage were randomly treated with oral norfloxacin (400 mg twice daily; n = 57) or intravenous ceftriaxone (1 g/day; n = 54) for 7 days. The end point of the trial was the prevention of bacterial infections within 10 days after inclusion. Results: Clinical data were comparable between groups. The probability of developing proved or possible infections, proved infections, and spontaneous bacteremia or spontaneous bacterial peritonitis was significantly higher in patients receiving norfloxacin (33% vs 11%, P = .003; 26% vs 11%, P = .03; and 12% vs 2%, P = .03, respectively). The type of antibiotic used (norfloxacin), transfusion requirements at inclusion, and failure to control bleeding were independent predictors of infection. Seven gram-negative bacilli were isolated in the norfloxacin group, and 6 were quinolone resistant. Nonenterococcal streptococci were only isolated in the norfloxacin group. No difference in hospital mortality was observed between groups. Conclusions: Intravenous ceftriaxone is more effective than oral norfloxacin in the prophylaxis of bacterial infections in patients with advanced cirrhosis and hemorrhage. See CME Quiz on page 1285. See CME Quiz on page 1285. 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Continuous versus inpatient prophylaxis of the first episode of spontaneous bacterial peritonitis with norfloxacin.Hepatology. 1997; 25: 532-536Crossref PubMed Scopus (180) Google Scholar caused by these organisms have increased substantially during the last years. However, a significant number of infections in cirrhotic patients with gastrointestinal hemorrhage are caused by gram-positive bacteria related to the invasive procedures used in these patients.24Fernandez J. Navasa M. Gomez J. Colmenero J. Vila J. Arroyo V. Rodés J. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.Hepatology. 2002; 35: 140-148Crossref PubMed Scopus (740) Google Scholar These considerations led us to perform the current study, which consisted of a randomized controlled trial aimed at comparing oral norfloxacin vs intravenous ceftriaxone in the prophylaxis of bacterial infections in cirrhotic patients with gastrointestinal hemorrhage and severe liver failure. Intravenous ceftriaxone was selected for 2 reasons. First, we have recently shown that most quinolone-resistant bacteria isolated in cirrhotic patients with spontaneous bacteremia, spontaneous bacterial peritonitis, and other infections are susceptible to third-generation cephalosporins.24Fernandez J. Navasa M. Gomez J. Colmenero J. Vila J. Arroyo V. Rodés J. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.Hepatology. 2002; 35: 140-148Crossref PubMed Scopus (740) Google Scholar Second, antibiotics administered by intravenous route are theoretically more appropriate than those administered orally in the prophylaxis of infection in patients with active upper gastrointestinal bleeding. The end point of the study was to assess whether intravenous ceftriaxone is more effective than oral norfloxacin in reducing the rate of bacterial infections within the first 10 days after the hemorrhage because this is the period within which most infections occur. The study was performed in patients with cirrhosis admitted to 4 Spanish hospitals for the treatment of an upper gastrointestinal hemorrhage between February 2000 and April 2004. Diagnosis of cirrhosis was based on clinical, laboratory, and ultrasonographic data or on histology. Inclusion criteria were as follows: age 18–80 years, hematemesis and/or melena within 24 hours prior to inclusion, and advanced cirrhosis as defined by the presence of 2 or more of the following signs of liver failure: severe malnutrition (as defined by the presence of clear signs of muscle wasting), serum bilirubin >3 mg/dL, ascites (confirmed by paracentesis), and hepatic encephalopathy (grade 1 or more). Diagnosis of ascites, severe malnutrition, and encephalopathy was made clinically. Exclusion criteria were as follows: allergy to cephalosporins or quinolones, presence of any of the following signs of infection (fever >37.5°C, white blood cell count >15,000 mm3, immature neutrophils >500 mm3, polymorphonuclear cell count in ascitic fluid >250/mm3, more than 15 leukocytes/field in the fresh urine sediment, or data compatible with pneumonia on the chest x-ray), treatment with antibiotics within 2 weeks before the hemorrhage (excluding oral norfloxacin for prophylaxis of spontaneous bacterial peritonitis), previously diagnosed advanced hepatocellular carcinoma (1 nodule greater than 5 cm, 3 nodules with 1 greater than 3 cm, or more than 3 nodules), and human immunodeficiency virus (HIV) infection. The study was approved by the ethics committee of each hospital participating in the study. Written informed consent was obtained from the patients and, in those with encephalopathy, from their families. The protocol conformed to the Helsinki Declaration and Guidelines for Good Clinical Practice in Clinical Trials. Following admission, a history and physical examination were obtained, and 2 short intravenous cannulas and a nasogastric tube were placed. A central line was also placed in most patients. Urinary catheter was inserted only if indicated. Laboratory measurements including standard liver and renal function tests, blood and ascitic fluid cell count and cultures (samples were inoculated into aerobic and anaerobic blood culture bottles at patient’s bedside), and fresh urine sediment and culture were then performed as well as a chest x-ray. Emergency endoscopy and endoscopic treatment (if indicated, sclerotherapy or banding) were done within the first 24 hours after onset of the hemorrhage in all cases. Patients with severe hepatic encephalopathy (grade 3 or 4) were intubated prior to endoscopy. Patients with bleeding from esophageal or gastric varices or from portal hypertensive gastropathy received somatostatin or terlipressin. In cases with uncontrolled variceal bleeding, ballon tamponade was applied after prophylactic orotracheal intubation. Endoscopic treatment was repeated during the hospital admission until eradication of varices if indicated. A transjugular intrahepatic portosystemic shunt (TIPS) or surgical portacaval shunt were performed in patients in whom other treatments failed to control the bleeding. Patients with peptic ulcer or esophagitis received proton-pump inhibitors. Blood transfusions were given to maintain hematocrit levels between 25% and 30%. Definitions regarding the course of the hemorrhage (failure to control the bleeding and early rebleeding) were based on those proposed by the Baveno III Consensus Workshop.27de Franchis R. Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension.J Hepatol. 2000; 33: 846-852Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar Failure to control the bleeding within the first 6 hours after inclusion was considered when transfusion requirements were equal to or greater than 4 units of blood together with an inability to achieve an increase in systolic arterial blood pressure by 20 mm Hg or to 70 mm Hg or higher. Failure to control the bleeding within the period from 6 to 24 hours after inclusion was considered if there was a new hematemesis together with a decrease in systolic arterial blood pressure equal to or greater than 20 mm Hg and/or transfusions requirements equal to or greater than 2 units to increase hemoglobin levels to 9 g/dL. Whenever balloon tamponade had to be used within these 2 periods, failure to control the bleeding was also considered. Early rebleeding and study rebleeding were defined as new hematemesis or melena from 24 hours to 5 days after inclusion and within the study period (10 days), respectively, with transfusion requirements equal to or greater than 2 units of blood in any of the 24-hour periods and at least 1 of the following: systolic arterial blood pressure lower than 100 mm Hg, decrease in arterial pressure after postural change greater than 20 mm Hg, or heart rate greater than 100 beats/min. Patients who fulfilled the inclusion criteria were randomly allocated into 2 groups. Patients in the first group received oral norfloxacin 400 mg every 12 hours during 7 days. Patients in the second group received intravenous ceftriaxone 1 g per day during 7 days. Antibiotics were initiated following the emergency endoscopy and always within the first 12 hours after admission into the hospital. Randomization was done using consecutively numbered computer-generated envelopes containing treatment assignment. Randomization was independent at each hospital. Patients were followed up closely, with special emphasis on the detection of bacterial infections. Physical examination and blood cell count were performed daily, urinary sediment every 48 hours, and chest x-ray every 3 days for 10 days. Blood, ascitic fluid, and urine cultures were taken whenever a patient developed signs of infection. Diagnosis of proved infection was performed as follows: (1) spontaneous bacteremia: positive blood cultures in the absence of any potential source of infection; (2) spontaneous bacterial peritonitis: ascitic fluid polymorphonuclear count equal to or greater than 250/mm3 (Rimola et al20Rimola A. Garcia-Tsao G. Navasa M. Piddock L.J. Planas R. Bernard B. Inadomi J.M. International Ascites ClubDiagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document.J Hepatol. 2000; 32: 142-153Abstract Full Text Full Text PDF PubMed Scopus (846) Google Scholar); (3) urinary tract infection: urinary leukocyte count greater than 15 cells per high-power field and positive urine culture28Sobel J.D. Kaye D. Urinary tract infections.in: Mandell G.L. Bennet J.E. Dolin R. Principles and practice of infectious diseases. 4th ed. Churchill Livingstone, New York1995: 662-690Google Scholar; (4) other infections were diagnosed according to clinical, radiologic, and bacteriologic data. Possible infection was diagnosed in patients with fever (>37.5°C during more than 6 hours), leukocytosis (>15,000 mm3) or increased concentration of immature neutrophils in blood (>500/mm3), negative cultures, and no other signs of infection. Analysis was performed classifying the patients into 3 groups: (1) patients not developing infections; (2) patients developing proved infections; and (3) patients developing proved or possible infections. The sample size was calculated on the basis of an expected incidence of bacterial infections (proved plus possible) of 30% in the norfloxacin group and of 10% in the ceftriaxone group. Sixty-one patients had to be included in each group to obtain a P value < .05 with an α error of 5% and a β error of 20%. Continuous variables were compared by the Student t test. Discontinuous variables were compared by the χ2 test with the Yates correction when indicated. Probability curves were obtained by the Kaplan–Meier method and compared by the log-rank test. Univariate analysis using the Student t test and the Kaplan–Meier curves was performed to identify possible predictors of infection. Variables showing significant differences were subsequently introduced in a Cox proportional hazards regression model to identify independent predictors of infection. Results are given as relative hazard plus 95% confident interval (CI). The median values of the independent predictors of infection were considered as cut-off levels to identify groups of patients with different risks of infection. Calculations were performed with the SPSS Statistical Package (SPSS Inc. Version 11.0, 2000, Chicago, IL). Differences were considered significant at the level .05. Results are expressed as mean ± SD. A total of 1369 cirrhotic patients with gastrointestinal hemorrhage were screened. Of these, 1245 patients were not included because of absence of 2 signs of advanced liver failure (884 patients), presence of infection at admission (253 patients), presence of advanced hepatocellular carcinoma or other neoplasia (106 patients), antibiotic treatment other than oral norfloxacin at admission (54 patients), age over 80 years (21 patients), HIV infection (19 patients), and other causes including refusal to participate in the trial (32 patients). Of the 124 patients randomized, 63 in the norfloxacin group and 61 in the ceftriaxone group, 7 patients (4 in the norfloxacin group and 3 in the cefriaxone group) were excluded because of violation of the protocol (presence of only 1 sign of advanced liver failure) and 6 (2 in the norfloxacin group and 4 in the ceftriaxone group) because of occult infection (positive blood cultures obtained prior to randomization). Thus, 111 patients (57 in the norfloxacin group and 54 in the ceftriaxone group) were considered in the final analysis of the results (Figure 1). The median age of the patients was 58 ± 12 years, 77% were male, and the most frequent etiology was alcoholism (68%). Patients had advanced liver insufficiency with high serum bilirubin (4.4 ± 4.0 mg/dL), low serum albumin (26 ± 5 g/L), high INR (1.56 ± 0.39), and high Child–Pugh score (9.8 ± 1.5 points) and Model for End Stage Liver Disease (MELD) score (17.1 ± 4.8 points). Forty-seven percent of the patients were grade B and 53% grade C of the Child–Pugh classification. Seventy-nine percent of patients had ascites, 72% signs of severe malnutrition, 58% a serum bilirubin >3 mg/dL, and 37% hepatic encephalopathy. Forty-one percent of the patients had more than 2 signs of liver failure, and 12% had renal failure at inclusion. Hepatocellular carcinoma was present in 18% of patients and diabetes mellitus in 20%. Only 9% of the patients were receiving oral norfloxacin for prophylaxis of spontaneous bacterial peritonitis at inclusion. Table 1 shows that with the exception of the frequency of alcoholic cirrhosis, higher in the norfloxacin group, and the incidence of renal failure at inclusion, higher in the ceftriaxone group, there were no significant differences between groups in clinical data and laboratory measurements.Table 1Baseline Clinical and Analytical CharacteristicsCeftriaxone (n = 54)Norfloxacin (n = 57)Age (y)58 ± 1257 ± 12Male (%)7282Alcoholic cirrhosis (%)5777aP < .05 norfloxacin vs ceftriaxone group.Active alcoholism (%)bArbitrarily defined as a daily alcohol intake over 20 g in patients with alcoholic cirrhosis.3040Serum bilirubin (mg/dL)3.8 ± 3.54.9 ± 4.4Serum albumin (g/L)26 ± 526 ± 5Prothrombin time international normalized ratio1.56 ± 0.411.55 ± 0.37Child-Pugh score (points)9.7 ± 1.69.8 ± 1.5Child-Pugh score (% B/C)46/5447/53MELD score (points)17.1 ± 4.917.1 ± 4.7Serum bilirubin > 3 mg/dL (%)4866Ascites (%)8375Hepatic encephalopathy (%)3737Severe malnutrition (%)7867Signs of liver failure (2/3/4) (%)dTwo, 3, or 4 signs of liver failure (severe malnutrition, serum bilirubin >3 mg/dL, ascites, and hepatic encephalopathy).56/43/161/32/7Serum creatinine (mg/dL)1.2 ± 0.51.0 ± 0.4Serum sodium (mEq/L)134 ± 5133 ± 16Ascitic fluid protein (g/L)11 ± 711 ± 6Renal failure (%)cSerum creatinine >1.5 mg/dL.195aP < .05 norfloxacin vs ceftriaxone group.Hepatocellular carcinoma (%)2117Diabetes mellitus (%)2218Norfloxacin prophylaxis (%)135NOTE. Values represent mean ± standard deviation.a P < .05 norfloxacin vs ceftriaxone group.b Arbitrarily defined as a daily alcohol intake over 20 g in patients with alcoholic cirrhosis.c Serum creatinine >1.5 mg/dL.d Two, 3, or 4 signs of liver failure (severe malnutrition, serum bilirubin >3 mg/dL, ascites, and hepatic encephalopathy). Open table in a new tab NOTE. Values represent mean ± standard deviation. In the whole series of patients, the time elapsed between the initiation of bleeding and the emergency endoscopy was 4.6 × 5.1 hours. The site of bleeding was esophageal varices in 64% of patients, gastric varices in 5%, peptic ulcer in 10%, portal hypertensive gastropathy in 8%, an
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