Antibiotics for Klebsiella Liver Abscess Study

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

Sponsoren

Hauptsponsor: National University Hospital, Singapore

Mitarbeiter: Tan Tock Seng Hospital
Singapore General Hospital

Quelle National University Hospital, Singapore
Kurze Zusammenfassung

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.

Gesamtstatus Completed
Anfangsdatum November 5, 2013
Fertigstellungstermin January 16, 2018
Primäres Abschlussdatum January 16, 2018
Phase Phase 4
Studientyp Interventional
Primärer Ausgang
Messen Zeitfenster
Clinical cure Week 12
Sekundäres Ergebnis
Messen Zeitfenster
Clinical response Week 4
Einschreibung 152
Bedingung
Intervention

Interventionsart: Drug

Interventionsname: Ciprofloxacin

Armgruppenetikett: Oral antibiotics

Interventionsart: Drug

Interventionsname: Ceftriaxone

Armgruppenetikett: Intravenous antibiotics

Interventionsart: Drug

Interventionsname: Trimethoprim/sulfamethoxazole

Armgruppenetikett: Oral antibiotics

Anderer Name: Bactrim

Interventionsart: Drug

Interventionsname: Ertapenem

Armgruppenetikett: Intravenous antibiotics

Teilnahmeberechtigung

Kriterien:

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

Geschlecht: All

Mindestalter: 21 Years

Maximales Alter: N/A

Gesunde Freiwillige: No

Insgesamt offiziell
Nachname Rolle Zugehörigkeit
Sophia Archuleta, MD Principal Investigator National University Hospital, Singapore
Ort
Einrichtung:
Singapore General Hospital | Singapore, 169856, Singapore
National University Hospital | Singapore, Singapore
Tan Tock Seng Hospital | Singapore, Singapore
Standort Länder

Singapore

Überprüfungsdatum

August 2018

Verantwortliche Partei

Art: Sponsor

Schlüsselwörter
Hat den Zugriff erweitert No
Bedingung Durchsuchen
Anzahl der Waffen 2
Armgruppe

Etikette: Oral antibiotics

Art: Experimental

Beschreibung: 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).

Etikette: Intravenous antibiotics

Art: Active Comparator

Beschreibung: 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).

Studiendesign Info

Zuweisung: Randomized

Interventionsmodell: Parallel Assignment

Hauptzweck: Treatment

Maskierung: None (Open Label)

Quelle: ClinicalTrials.gov