Antibiotics for Klebsiella Liver Abscess Study

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by National University Hospital, Singapore
Sponsor:
Collaborators:
Tan Tock Seng Hospital
Singapore General Hospital
Information provided by (Responsible Party):
National University Hospital, Singapore
ClinicalTrials.gov Identifier:
NCT01723150
First received: October 22, 2012
Last updated: December 2, 2013
Last verified: December 2013
  Purpose

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.


Condition Intervention
Liver Abscess, Pyogenic
Drug: Ciprofloxacin
Drug: Ceftriaxone
Drug: Trimethoprim/sulfamethoxazole
Drug: Ertapenem

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by National University Hospital, Singapore:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Other Outcome Measures:
  • 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 ]

Estimated Enrollment: 152
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)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Inpatient at time of enrollment
  2. Age >= 21 years
  3. Computed tomography (CT) or ultrasound (US) within the preceding 7 days suggestive of a liver abscess, as defined by presence of one or more focal areas of hypo- or hyper-attenuation within the liver
  4. Klebsiella pneumoniae isolated from abscess fluid or blood collected within the preceding 7 days
  5. Able and willing to give informed consent

Exclusion Criteria

All subjects meeting any of the following exclusion criteria at baseline will be excluded from participation:

1) Polymicrobial abscess - additional organisms isolated from blood or abscess fluid within the preceding 7 days 2a) Klebsiella pneumoniae resistant to Ceftriaxone AND Ertapenem 2b) Klebsiella pneumoniae resistant to Ciprofloxacin AND Cotrimoxazole 3) On effective* IV antibiotics > 7 days 4a) Hypersensitivity to cephalosporins AND carbapenems; as defined by history of rash, urticaria, angiodema, bronchospasm or circulatory collapse following prior administration.

4b) Hypersensitivity to fluoroquinolones AND sulpha drugs; as defined by history of rash, urticaria, angioedema, bronchospasm or circulatory collapse following prior administration.

4c) History of penicillin anaphylaxis (angioedema, bronchospasm or circulatory collapse). Subjects with a history of only rash or urticaria or unknown reaction to penicillin can be included.

5) Inability to take oral medications for any reason 6) Severe sepsis or septic shock defined as unresolved hypotension (MAP<70) or tachycardia (HR>110), or requirement of inotropic support or ventilation at time of eligibility. Should the subject's hypotension or tachycardia subsequently resolve, and they cease to require inotropes and ventilation within 7 days, they may be reconsidered for eligibility.

7) Established endophthalmitis at time of screening (patients with visual symptoms should have ophthalmology review prior to enrollment) 8) Established central nervous system abscess at time of screening (patients with focal neurology should have CT head prior to enrollment) 9) Women who are pregnant or breastfeeding 10) Inability to obtain consent from subject 11) Patients on tizanidine or theophylline 12) Patients on concomitant drugs that can result in prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) 13) Patients whose K. pneumoniae tests resistant to ciprofloxacin, and those with contraindications to ciprofloxacin will be tested for G6PD deficiency, and excluded if deficient 14) Severe immunocompromise (e.g., active leukemia or lymphoma, generalized malignancy, aplastic anemia, solid organ transplant, bone marrow transplant within 2 years of transplantation, or transplants of longer duration still on immunosuppressive drugs or with graft-versus-host disease, congenital immunodeficiency, current radiation therapy, HIV/AIDS with CD4 lymphocyte count <200 and patients or on immunosuppressant medications) 15) Creatinine clearance <15 ml/min

*defined as antibiotics to which the Klebsiella pneumoniae isolate in blood or abscess fluid is susceptible

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01723150

Locations
Singapore
National University Hospital Recruiting
Singapore, Singapore
Contact: Sophia Archuleta       sophia@nus.edu.sg   
Singapore General Hospital Not yet recruiting
Singapore, Singapore
Contact    Thuan Tong Tan    tan.thuan.tong@sgh.com.sg   
Tan Tock Seng Hospital Recruiting
Singapore, Singapore
Contact: David Lye       david_lye@ttsh.com.sg   
Sponsors and Collaborators
National University Hospital, Singapore
Tan Tock Seng Hospital
Singapore General Hospital
Investigators
Principal Investigator: Sophia Archuleta, MD National University Hospital, Singapore
  More Information

Publications:
Responsible Party: National University Hospital, Singapore
ClinicalTrials.gov Identifier: NCT01723150     History of Changes
Other Study ID Numbers: A-KLASS
Study First Received: October 22, 2012
Last Updated: December 2, 2013
Health Authority: Singapore: Domain Specific Review Boards
Singapore: Health Sciences Authority

Keywords provided by National University Hospital, Singapore:
Klebsiella pneumoniae

Additional relevant MeSH terms:
Klebsiella Infections
Abscess
Liver Abscess
Liver Abscess, Pyogenic
Abdominal Abscess
Bacterial Infections
Digestive System Diseases
Enterobacteriaceae Infections
Gram-Negative Bacterial Infections
Infection
Inflammation
Liver Diseases
Pathologic Processes
Suppuration
Anti-Bacterial Agents
Antibiotics, Antitubercular
Ceftriaxone
Ciprofloxacin
Ertapenem
Sulfamethoxazole
Trimethoprim
Anti-Infective Agents
Anti-Infective Agents, Urinary
Antimalarials
Antineoplastic Agents
Antiparasitic Agents
Antiprotozoal Agents
Antitubercular Agents
Enzyme Inhibitors
Folic Acid Antagonists

ClinicalTrials.gov processed this record on October 23, 2014