Antibiotics for Klebsiella Liver Abscess Study
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.
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