Clinical trial NCT01723150: Antibiotics for Klebsiella Liver Abscess Study
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Liver Abscess, Pyogenic
Keywords: Klebsiella pneumoniae
Lead sponsor: National University Hospital, Singapore
Sponsor class: OTHER
Collaborators: name: Tan Tock Seng Hospital
name: Singapore General Hospital
First posted: 2012-11-07
Enrollment: 152
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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

Primary outcomes:
measure: Clinical cure
timeFrame: Week 12
Secondary outcomes:
measure: Clinical response
timeFrame: Week 4
Other outcomes:
measure: all-cause mortality at any point between randomisation and week 12
timeFrame: Week 12
measure: • unplanned readmission for any cause at any point between hospital discharge and week 12
timeFrame: Week 12
measure: • unplanned need for drainage after enrolment at any point between randomisation and week 12 (the screening visit will document any plans for elective drainage)
timeFrame: Week 12
measure: • metastatic complications occurring at any point between randomisation and week 12
timeFrame: Week 12
measure: 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
timeFrame: Week 12
measure: • length of hospital stay (from the date of randomisation to the end of inpatient stay, censored at week 12)
timeFrame: Week 12
measure: • length of time the subject requires medical leave following hospital discharge (censored at week 12)
timeFrame: Week 12
measure: • subject quality of life as defined by the WHOQOL-BREF assessed at week 4 and week 12 post-randomisation
timeFrame: Week 12
measure: • 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
timeFrame: Week 12
measure: • 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
timeFrame: Week 12
Locations:
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
Study officials:
affiliation: National University Hospital, Singapore
name: Sophia Archuleta, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Molton J, Phillips R, Gandhi M, Yoong J, Lye D, Tan TT, Fisher D, Archuleta S. Oral versus intravenous antibiotics for patients with Klebsiella pneumoniae liver abscess: study protocol for a randomized controlled trial. Trials. 2013 Oct 31;14:364. doi: 10.1186/1745-6215-14-364.
citation: Molton JS, Chan M, Kalimuddin S, Oon J, Young BE, Low JG, Salada BMA, Lee TH, Wijaya L, Fisher DA, Izharuddin E, Koh TH, Teo JWP, Krishnan PU, Tan BP, Woon WWL, Ding Y, Wei Y, Phillips R, Moorakonda R, Yuen KH, Cher BP, Yoong J, Lye DC, Archuleta S. Oral vs Intravenous Antibiotics for Patients With Klebsiella pneumoniae Liver Abscess: A Randomized, Controlled Noninferiority Study. Clin Infect Dis. 2020 Aug 14;71(4):952-959. doi: 10.1093/cid/ciz881.