Daptomycin + Meropenem Versus Ceftazidime in the Treatment of Nosocomial Spontaneous Bacterial Peritonitis

Daptomycin + Meropenem Versus Ceftazidime in the Treatment of Nosocomial Spontaneous Bacterial Peritonitis: an Open, Randomized, Controlled Clinical Trial

Nosocomial spontaneous bacterial peritonitis (SBP) is frequently caused by multi drug resistant bacteria. Standard treatment of SBP could be ineffective. The aim of the study is to compare daptomycin + meropenem vs ceftazidime in the treatment of nosocomial SBP.

Study Overview

• Status: Terminated
• Conditions: Cirrhosis; Ascites; Nosocomial Spontaneous Bacterial Peritonitis
• Intervention / Treatment: Drug: Daptomycin + Meropenem; Drug: Ceftazidime

Detailed Description

Spontaneous bacterial peritonitis (SBP) is a well known complication in patients with liver cirrhosis and ascites. Nosocomial SBP is defined as SBP that occurs after 48 hours of hospitalization. It has been shown that patients with nosocomial SBP have a worse prognosis than patients with community-acquired SBP. It has also been shown that nosocomial SBP is frequently caused by multi drug resistant bacteria such as extended-spectrum-beta-lactamase (ESBL) producing enterobacteria or meticillin - resistant staphylococcus aureus. Currently the empirical treatment of SBP is the use of third generation cephalosporins or amoxicillin/clavulanic acid. In patients affected by nosocomial SBP these treatment could be ineffective. Up to now an empirical approach with a broader spectrum strategy (such as an association between meropenem and daptomycin) has never been compared to standard therapy in the treatment of nosocomial SBP. Thus, the aim of the study is to compare daptomycin + meropenem vs ceftazidime in the treatment of nosocomial SBP in patients with cirrhosis.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Italy
  • PD
    • Padova, PD, Italy, 35128
      • Dept. of Clinical and Experimental Medicine, University of Padova

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with liver cirrhosis and ascites

• Meets all criteria for nosocomial SBP as outlined below

  • Ascitic fluid polymorphonuclear cells count >250/mm3
  • Onset of signs and symptoms of infection after 72 hours of hospitalization

Exclusion Criteria:

• Hepatocellular carcinoma beyond the Milan criteria
• Abdominal surgery within 4 weeks
• Evidence of secondary peritonitis, pancreatitis or peritoneal carcinomatosis
• Significant heart or respiratory failure
• Allergy to ceftazidime, meropenem or daptomycin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Daptomycin + Meropenem; 30 patients with cirrhosis and nosocomial SBP	Drug: Daptomycin + Meropenem; Daptomycin will be administered at the dose of 6 mg/kg every 24 hours and 6 mg/kg every 48 hours for an estimated creatinine clearance (CKD-EPI) of > 30 ml/min and < 30 ml/min respectively. Meropenem will be administered at the dose of 1 g t.i.d., 1 g b.i.d., 0.5 g every 24 hours for an estimated creatinine clearance of >50 ml/min, 10-50 ml/min, and < 10 ml/min respectively. The treatment will go on for 7 days. In the patients without response to treatment after 48 hours will be added a rescue therapy with fluconazole. In patients in which cultures shown a bacterial species resistant to therapy, daptomycin and meropenem will be discontinued and replaced by a therapy based on antibiotic susceptibility of isolated species.
ACTIVE_COMPARATOR: Ceftazidime; 30 patients with cirrhosis and nosocomial SBP	Drug: Ceftazidime; Ceftazidime will be administered at the dose of 2 g t.i.d, 2 g b.i.d and 2 g at every 24 hours by intravenous infusion for an estimated creatinine clearance (CKD-EPI) of >50 ml/min, 10-50 ml/min, and < 10 ml/min respectively. The treatment will go on for 7 days. In the patients without response to treatment after 48 hours, or in which cultures shown a bacterial species resistant to therapy, ceftazidime will be discontinued and replaced by a rescue therapy with meropenem and daptomycin as provided for the experimental arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary end-point of the study is the response to therapy	The response to therapy is defined as the reduction of polymorphonuclear leukocytes (PMN) count in ascitic fluid more than 25 % from baseline after 48 hours and as a PMN count in ascitic fluid less then 250/mm³ after seven days.	48 hours and seven days

Secondary Outcome Measures

Outcome Measure	Time Frame
30 days mortality	30 days
90 days mortality	90 days
Mortality during hospitalization	participants will be followed for the duration of hospital stay, an expected average of 6 weeks

Collaborators and Investigators

• Sponsor: University of Padova
• Investigators: Principal Investigator: Paolo Angeli, MD, PhD, Dept. of Clinical and Experimenatl Medicine, University of Padova, Italy

Publications and helpful links

General Publications

• Rimola A, Garcia-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, Inadomi JM. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol. 2000 Jan;32(1):142-53. doi: 10.1016/s0168-8278(00)80201-9. No abstract available.
• Fasolato S, Angeli P, Dallagnese L, Maresio G, Zola E, Mazza E, Salinas F, Dona S, Fagiuoli S, Sticca A, Zanus G, Cillo U, Frasson I, Destro C, Gatta A. Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features. Hepatology. 2007 Jan;45(1):223-9. doi: 10.1002/hep.21443.
• Angeli P, Guarda S, Fasolato S, Miola E, Craighero R, Piccolo F, Antona C, Brollo L, Franchin M, Cillo U, Merkel C, Gatta A. Switch therapy with ciprofloxacin vs. intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis: similar efficacy at lower cost. Aliment Pharmacol Ther. 2006 Jan 1;23(1):75-84. doi: 10.1111/j.1365-2036.2006.02706.x.
• Cheong HS, Kang CI, Lee JA, Moon SY, Joung MK, Chung DR, Koh KC, Lee NY, Song JH, Peck KR. Clinical significance and outcome of nosocomial acquisition of spontaneous bacterial peritonitis in patients with liver cirrhosis. Clin Infect Dis. 2009 May 1;48(9):1230-6. doi: 10.1086/597585.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (ACTUAL): April 1, 2014
• Study Completion (ACTUAL): July 1, 2014

Study Registration Dates

• First Submitted: October 13, 2011
• First Submitted That Met QC Criteria: October 17, 2011
• First Posted (ESTIMATE): October 19, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): October 15, 2014
• Last Update Submitted That Met QC Criteria: October 11, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: Sepsis; Cirrhosis; Ascites; Albumin; Meropenem; Daptomycin; Nosocomial infection; Ceftazidime; Nosocomial Spontaneous Bacterial Peritonitis; Multi drug resistant bacteria
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Peritoneal Diseases; Intraabdominal Infections; Fibrosis; Ascites; Peritonitis; Anti-Infective Agents; Anti-Bacterial Agents; Meropenem; Daptomycin; Ceftazidime
• Other Study ID Numbers: 2059P; 2010-019625-34 (EUDRACT_NUMBER)