Norfloxacin Versus Ciprofloxacin for Spontaneous Bacterial Peritonitis (SBP) Prevention

Comparison of Daily Norfloxacin Versus Weekly Ciprofloxacin for the Prevention of Spontaneous Bacterial Peritonitis in Cirrhotic Patients

• For the prevention of spontaneous bacterial peritonitis (SBP) in patients with liver cirrhosis, norfloxacin 400mg per day is a standard regimen.
• Ciprofloxacin 750 mg per week is also known to be effective for prevention of SBP. In addition, ciprofloxacin once weekly administration is more convenient and less costly.
• Therefore ciprofloxacin once weekly could be more useful if the the efficacy is comparable to norfloxacin once daily.
• This study aims to prove ciprofloxacin once weekly administration is as effective as norfloxacin once daily administration for the prevention of SBP in cirrhotic patients with ascites.

Study Overview

• Status: Completed
• Conditions: Adverse Reaction to Other Drugs and Medicines
• Intervention / Treatment: Drug: Norfloxacin; Drug: ciprofloxacin

Detailed Description

Spontaneous bacterial peritonitis (SBP) is one of the most serious complication of liver cirrhosis.

The short term mortality reaches 20-30% mainly due to sepsis, hepatorenal syndrome, and liver failure. In addition, patients who suffered SBP show poor prognosis with 1 year-mortality of 50-70%. The high recurrence rate is also problematic. Therefore appropriate prevention of SBP is critically needed to improve survival as well as quality of life.

Selective intestinal decontamination (SID) is eradicating gram negative bacterial in the gut lumen, and effectively prevent development of SBP. Patients with gastrointestinal hemorrhage, low ascitic protein level, high bilirubin, or history of SBP need SID.

Norfloxacin 400 mg daily administration decreased the incidence of SBP to 2% compared with 17% of no prevention group's among patients with ascitic protein less than 1.5 g/dL. Also, in high risk patients (Child-Pugh score > or = 9 points and serum bilirubin level > or = 3 mg/dL, serum creatinine level > or = 1.2 mg/dL, blood urea nitrogen level > or = 25 mg/dL, or serum sodium level < or = 130 mEq/L), norfloxacin 400 mg/day improved 1 year-survival to 60% compared with 48% of no prevention group's. Therefore norfloxacin is now primarily recommend for the prevention of SBP in cirrhotic patients. However, norfloxacin should be administered on daily basis, so efforts to reduce cost and frequency have been made.

Ciprofloxacin 750 mg weekly administration has been evaluated, and shown to be effective as 3.6% versus 22% in prevention versus no prevention arm, respectively. Therefore, ciprofloxacin 750 mg/week is a reasonable option for prevention of SBP. However, comparison of efficacy of these two methods (norfloxacin 400 mg daily versus ciprofloxacin 750 mg weekly) has not been performed, yet.

The investigators aim to compare the efficacy and safety of norfloxacin 400 mg daily and ciprofloxacin 750 mg weekly for the proper management of cirrhotic patients with ascites.

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Bucheon, Korea, Republic of
    • Soonchunhyang University College of Medicine, Bucheon Hospital
  • Cheonan, Korea, Republic of
    • Soonchunhyang University College of Medicine, Cheonan Hospital
  • Daegu, Korea, Republic of
    • Kyungpuk National University Hospital
  • Seoul, Korea, Republic of
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of
    • Soonchunhyang University College of Medicine, Seoul Hospital
  • Seoul, Korea, Republic of
    • Sungkyunkwan University Gangbuk Samsung Hospital
  • Gyeonggi-do
    • Ansan, Gyeonggi-do, Korea, Republic of
      • Korea University Ansan Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age between 20-75 years old
• Liver cirrhosis with ascites
• Ascitic polymorphonucleated cells (PMN) count < 250/mm3
• Ascitic protein <= 1.5 g/dL or History of SBP

Exclusion Criteria:

• Incompatibility with inclusion criteria
• Hypersensitivity or intolerability with quinolones
• Hepatocellular carcinoma beyond Milan Criteria
• Hepatic encephalopathy over stage 2
• History of treatment with antibiotics within 2 weeks of enrollment
• HIV infection
• Untreated malignancy
• Women with child-bearing age not willing to use effective contraception.
• Pregnant or breast feeding women
• Not able to give informed consents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Norfloxacin; norfloxacin 400 mg once daily administration	Drug: Norfloxacin; Norfloxacin 400 mg per day
Experimental: Ciprofloxacin; Ciprofloxacin 750 mg per week	Drug: ciprofloxacin; Ciprofloxacin 750 mg per week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The prevention rate of spontaneous bacterial peritonitis (SBP)	The incidence of SBP will measured in each the group. Thereby, prevention rate will also be compared between the groups.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1 year mortality	liver related mortality and overall mortality will be assessed.	12 months ( 1 year)
Incidence of infectious event other than SBP	Bacteremia, urinary tract infection, pneumonia, and other infections will be included.	12 months
Hepatorenal syndrome	Diagnostic criteria of hepatorenal syndrome is defined by the latest version of Internation ascites club consensus.	12 months
Hepatic encephalopathy	Will follow the Western Heaven Criteria.	12 months
Adverse event of drugs	Any of adverse event suspected by study drugs will be recorded.	12 months

Collaborators and Investigators

• Sponsor: Korea University
• Collaborators: Kyungpook National University Hospital; Soon Chun Hyang University; Sungkyunkwan University
• Investigators: Principal Investigator: Soon Ho Um, M.D., Ph.D., Korea University Anam Hospital; Study Director: Hyung Joon Yim, M.D., Ph.D., Korea University Ansan Hospital

Publications and helpful links

General Publications

• European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53(3):397-417. doi: 10.1016/j.jhep.2010.05.004. Epub 2010 Jun 1. No abstract available.
• Fernandez J, Navasa M, Gomez J, Colmenero J, Vila J, Arroyo V, Rodes J. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology. 2002 Jan;35(1):140-8. doi: 10.1053/jhep.2002.30082.
• Fernandez J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, Vila C, Pardo A, Quintero E, Vargas V, Such J, Gines P, Arroyo V. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology. 2007 Sep;133(3):818-24. doi: 10.1053/j.gastro.2007.06.065. Epub 2007 Jul 3.
• Mowat C, Stanley AJ. Review article: spontaneous bacterial peritonitis--diagnosis, treatment and prevention. Aliment Pharmacol Ther. 2001 Dec;15(12):1851-9. doi: 10.1046/j.1365-2036.2001.01116.x.
• Koulaouzidis A, Bhat S, Karagiannidis A, Tan WC, Linaker BD. Spontaneous bacterial peritonitis. Postgrad Med J. 2007 Jun;83(980):379-83. doi: 10.1136/pgmj.2006.056168.
• Rolachon A, Cordier L, Bacq Y, Nousbaum JB, Franza A, Paris JC, Fratte S, Bohn B, Kitmacher P, Stahl JP, et al. Ciprofloxacin and long-term prevention of spontaneous bacterial peritonitis: results of a prospective controlled trial. Hepatology. 1995 Oct;22(4 Pt 1):1171-4. doi: 10.1016/0270-9139(95)90626-6.
• Grange JD, Roulot D, Pelletier G, Pariente EA, Denis J, Ink O, Blanc P, Richardet JP, Vinel JP, Delisle F, Fischer D, Flahault A, Amiot X. Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites: a double-blind randomized trial. J Hepatol. 1998 Sep;29(3):430-6. doi: 10.1016/s0168-8278(98)80061-5.

Helpful Links

• Korea University (PI of SBP_prevention study is belong to this university)

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: February 26, 2012
• First Submitted That Met QC Criteria: March 1, 2012
• First Posted (Estimate): March 2, 2012

Study Record Updates

• Last Update Posted (Estimate): December 28, 2016
• Last Update Submitted That Met QC Criteria: December 27, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Effect of Preventive Antibiotics
• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Peritoneal Diseases; Intraabdominal Infections; Peritonitis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Ciprofloxacin; Norfloxacin
• Other Study ID Numbers: SBP_prevention