Antibiotics for Klebsiella Liver Abscess Study
Background: Klebsiella pneumoniae liver abscess is the most common etiology of liver abscess in Singapore and much of Asia, and its incidence is increasing. Current management includes prolonged intravenous antibiotic therapy, but there is limited evidence to guide oral conversion. The implicated K1/K2 capsule strain of Klebsiella pneumoniae is almost universally susceptible to ciprofloxacin, an antibiotic with high oral bioavailability. Our primary aim is to compare the efficacy of early (<1 week) step-down to oral antibiotics, to continuing 4 weeks of intravenous antibiotics, in patients with Klebsiella liver abscess.
Methods/Design: The study is designed as a multi-centre randomised open-label active comparator-controlled non-inferiority trial, with a non-inferiority margin of 12%. Eligible participants will be inpatients over the age of 21 with a CT or ultrasound scan suggestive of a liver abscess, and Klebsiella pneumoniae isolated from abscess fluid or blood. Randomisation into intervention or active control arms will be performed with a 1:1 allocation ratio. Participants randomised to the active control arm will receive IV ceftriaxone 2 grams daily to complete a total of 4 weeks of IV antibiotics. Participants randomised to the intervention arm will be immediately converted to oral ciprofloxacin 750mg twice daily. At week 4, all participants will have abdominal imaging and be assessed for clinical response (CRP <20 mg/l, absence of fever, plus scan showing that the maximal diameter of the abscess has reduced). If criteria are met, antibiotics are stopped; if not, oral antibiotics are continued, with reassessment for clinical response fortnightly. If criteria for clinical response are met by week 12, the primary endpoint of clinical cure is met. A cost analysis will be performed to assess the cost saving of early conversion to oral antibiotics, and a quality-of-life analysis will be performed to assess if treatment with oral antibiotics is less burdensome than prolonged IV antibiotics.
Discussion: Our results would help inform local and international practice guidelines regarding the optimal antibiotic management of Klebsiella liver abscess. A finding of non-inferiority may translate to the wider adoption of a more cost-effective strategy that reduces hospital length of stay and improves patient-centered outcomes and satisfaction.
Liver Abscess, Pyogenic
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Multi-centre Randomised Open-label Active Comparator-controlled Non-inferiority Trial Comparing Oral to Intravenous Antibiotics in the Early Management of Klebsiella Pneumoniae Liver Abscess|
- Clinical cure [ Time Frame: Week 12 ] [ Designated as safety issue: No ]The primary endpoint is "clinical cure", determined at Week 12 post-randomisation, and defined as CRP< 20 mg/l, plus absence of documented fever ≥38°C in the preceding week, plus most recent abdominal imaging showing that the maximal diameter of the abscess has reduced.
- Clinical response [ Time Frame: Week 4 ] [ Designated as safety issue: No ]The main secondary endpoint is "clinical response", determined at Week 4 post-randomisation, and defined as CRP <20 mg/l, plus absence of documented fever ≥38°C in the preceding week, plus most recent abdominal imaging showing that the maximal diameter of the abscess has reduced.
- all-cause mortality at any point between randomisation and week 12 [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
- • unplanned readmission for any cause at any point between hospital discharge and week 12 [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
- • unplanned need for drainage after enrolment at any point between randomisation and week 12 (the screening visit will document any plans for elective drainage) [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
- • metastatic complications occurring at any point between randomisation and week 12 [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
- new K. pneumoniae bacteraemia occurring at any point between the first negative blood culture, and week 12, with the same strain of K. pneumoniae as the original blood culture or abscess fluid culture [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
- • length of hospital stay (from the date of randomisation to the end of inpatient stay, censored at week 12) [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
- • length of time the subject requires medical leave following hospital discharge (censored at week 12) [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
- • subject quality of life as defined by the WHOQOL-BREF assessed at week 4 and week 12 post-randomisation [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
- • overall cost of each treatment strategy from the payer and total societal perspective for the course of the study until the final twelve week follow-up [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
- • level of adherence during the entire study period, assessed at twelve weeks. Subject deemed to be compliant if 80% or more of prescribed antibiotics have been taken [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
|Study Start Date:||November 2013|
|Estimated Study Completion Date:||December 2015|
|Estimated Primary Completion Date:||August 2015 (Final data collection date for primary outcome measure)|
Experimental: Oral antibiotics
The intervention arm switched to oral antibiotics to complete 4 weeks of therapy. Oral antibiotics will be ciprofloxacin (or trimethoprim/sulfamethoxazole if the isolate is resistant).
|Drug: Ciprofloxacin Drug: Trimethoprim/sulfamethoxazole|
Active Comparator: Intravenous antibiotics
The active comparator arm continues intravenous antibiotics to complete 4 weeks of therapy. Intravenous antibiotics will be ceftriaxone (or ertapenem if the isolate is resistant).
|Drug: Ceftriaxone Drug: Ertapenem|
Please refer to this study by its ClinicalTrials.gov identifier: NCT01723150
|National University Hospital||Recruiting|
|Contact: Sophia Archuleta firstname.lastname@example.org|
|Tan Tock Seng Hospital||Recruiting|
|Contact: David Lye email@example.com|
|Singapore General Hospital||Not yet recruiting|
|Contact Thuan Tong Tan firstname.lastname@example.org|
|Principal Investigator:||Sophia Archuleta, MD||National University Hospital, Singapore|