Ciprofloxacin Plus Metronidazole Vs Cefixime Plus Metronidazole Therapy for the Treatment of Liver Abscess

Study Overview
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Brief Summary
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Liver abscess is purulent collections in the liver parenchyma that result from microbial infection spread to the liver through the biliary tree, hepatic or portal vein and by extension of adjacent infection or as a result of trauma. Liver abscesses are most commonly pyogenic followed by amoebic and rarely tuberculous or fungal in immunocompromised patients. In the developing country amoebic liver abscess is more frequent than the developed country but secondary bacterial infection of amoebic liver abscess and polymicrobial pyogenic liver abscess are also common. Pyogenic liver abscess is commonly a polymicrobial infection caused by mixed enteric facultative and anaerobic pathogens. The most commonly isolated organisms are Escherichia coli, Klebsiella pneumoniae, Streptococcus constellatus, Streptococcus anginosus, Streptococcus intermedius, Enterococcus and anaerobes, including Bacteroidesfragilis and Fusobacteriumnecrophorum. Amoebic liver abscess most frequently occur following infection with the parasite Entamoeba histolytica. Liver abscess is a common medical emergency. Prompt empirical antimicrobial with or without percutaneous aspiration or drainage of the abscess is therapeutic. An empiric antimicrobial regimen for liver abscess should cover enteric gram-negative bacilli, streptococci, anaerobes and antamoebahistolytica. Presently a Fluoroquinolone (Ciprofloxacin, Levofloxacin) or a Third or Fourth generation Cefalosporine (Cefixime, Ceftriaxone, cefepime) or a Beta-lactam-beta-lactamase inhibitor combination (piperacillin-tazobactam or ticarcillin-clavulanate) or a Carbapenem (Imipenem-cilastatin, Meropenem, Doripenem, Ertapenem) are being used in combination with or without Metronidazole as the empirical antimicrobial regime for the treatment live abscess. There is no randomized controlled clinical trial to evaluated and compare efficacy of the antimicrobial regimens for the treatment of liver abscess as well as there is no specific treatment guideline for the use of empirical antibiotics. There is also no definite proven rational for using Cefalosporine, Beta-lactam-beta-lactamase inhibitor combination or Carbapenem upfront, not using Fluoroquinolone in empirical antibiotic regimen for the treatment of liver abscess. Injudicious use of broader spectrum antibiotics may also lead to rise in antibiotic resistance in future. Both ciprofloxacin and Cefixime are effective oral antibiotics as they are well-absorbed orally with good oral bioavailability and achieve plasma concentration well above the minimal inhibitory concentrations require for the killing of the microorganism. Using intravenous (IV) antibiotics upfront, for the treatment of liver abscess in patients who can take orally may unnecessary increase the duration of hospital stay, healthcare burden and the cost of therapy, as well as the risk of hospital acquired infection. So the investigators have planned this randomized controlled double blind study to evaluate the efficacy of empirical Ciprofloxacin plus Metronidazole and Cefixime plus Metronidazole therapy for the treatment of liver abscess and to compare the outcomes of two different empirical antibiotics regimen.

Official Title
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Efficacy of Empirical Ciprofloxacin Plus Metronidazole and Cefixime Plus Metronidazole Therapy for the Treatment of Liver Abscess: A Randomised Controlled Clinical Trial

Conditions
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Liver Abscess

Intervention / Treatment
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* Drug: Ciprofloxacin
* Drug: Cefixime


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Irrespective of gender Age ≥ 18 years Symptomatic patients of liver abscess confirmed with radiology imaging, either by ultrasonography (USG) or computed tomographgy (CT) scan Exclusion Criteria: Past history of liver abscess Chronic kidney disease (CKD) History of hypersensitivity to either Ciprofloxacin or Metronidazole or Cefixime Shock (blood pressure <90/60 mmHg) at presentation ARDS (PaO2/FiO2≤300) Encephalopathy (altered sensorium with GCS <15) Acute kidney injury (AKI, Increase in serum creatinine to ≥1.5 times from the baseline) Pregnancy at presentation Already received antibiotics for more than 48 hours prior to the admission Not able to take orally Receiving blood thinners like anti-platelets, anti-coagulation agents within 4 weeks of presentation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ciprofloxacin plus Metronidazole therapy<br>Will receive tablet Ciprofloxacin (500 mg BDS) and tablet Metronidazole (800 mg TDS) orally for 2 weeks. Percutaneous aspiration or drainage of the liver abscess will be done for all the participants when there is enough liquid content/pus which is amenable for aspiration or drainage. Percutaneous drainage or aspiration will be done in liver abscess with size of ≥ 5 cm and <5 cm respectively. After 2 weeks of empirical antibiotic therapy, asymptomatic patients with persistent drainage with USG showing significant drainable collection in the liver will receive another 2 weeks of extended antimicrobial therapy of same combination. | Drug: Ciprofloxacin<br>* will receive tablet Ciprofloxacin (500 mg BDS) and tablet Metronidazole (800 mg TDS) for 2 weeks orally. Percutaneous aspiration or drainage of the liver abscess will be done when there is enough liquid content/pus amenable for aspiration or drainage. Percutaneous drainage or aspiration will be done in liver abscess with size of ≥ 5 cm and <5 cm respectively.<br>* Other names: Percutaneous drainage or aspiration of the liver abscess;|
| Active Comparator: Cefixime plus Metronidazole Therapy<br>Will receive tablet Cefixime (200 mg BDS) and tablet Metronidazole (800 mg TDS) orally for 2 weeks.Percutaneous aspiration or drainage of the liver abscess will be done for all the participants when there is enough liquid content/pus which is amenable for aspiration or drainage. Percutaneous drainage or aspiration will be done in liver abscess with size of ≥ 5 cm and <5 cm respectively. After 2 weeks of empirical antibiotic therapy, asymptomatic patients with persistent drainage with USG showing significant drainable collection in the liver will receive another 2 weeks of extended antimicrobial therapy of same combination. | Drug: Cefixime<br>* will receive tablet Cefixime (200 mg BDS) and tablet Metronidazole (800 mg TDS) for 2 weeks orally. Percutaneous aspiration or drainage of the liver abscess will be done when there is enough liquid content/pus amenable for aspiration or drainage. Percutaneous drainage or aspiration will be done in liver abscess with size of ≥ 5 cm and <5 cm respectively.<br>* Other names: Percutaneous drainage or aspiration of the liver abscess;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical cure | Asymptomatic and afebrile for more than 48 hours, along with USG showing no drainable collection in the liver with removal of the pigtail catheter if any | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment failure | Defined as any one of the following condition Persistently symptomatic with fever for more than 72 hours even after starting empirical antibiotics and percutaneous aspiration or drainage Development of new collection in the liver during the course of antibiotic therapy Development of shock and new onset organ failure ( Encephalopathy, ARDS, AKI) during the course of therapy, leading to shifting to IV antibiotics If culture of the aspirated or drained pus show growth of microorganism not sensitive to either Ciprofloxacin or Cefixime | 8 weeks | 
| All-cause mortality | Total number of death | 8 weeks | 
| Recurrence of liver abscess | Development new liver abscess after clinical cure during the 8 weeks follow up period | 8 weeks | 
| Need for surgical intervention | number of patients needing surgical intervention for the treatment of liver abscess | 8 weeks | 
| Need for mechanical ventilation | Number of patients needing mechanical ventilation for the respiratory failure. | 8 weeks | 
| Need for prolong antibiotics 11. | Number of asymptomatic patients receiving 2 weeks of extended antibiotic therapy due to persistent drainage or aspiration even after 2 weeks of empirical antibiotics | 8 weeks | 
| Duration of hospital stay | Number of days of hospital stay for the treatment of liver abscess | 8 weeks | 
| Adverse drug events (ADE) | Number of adverse drug events | 8 weeks | 
| Localised bio-availability of the drugs (Ciprofloxacin, Metronidazole and Cefixime) | Concentration of the drug in drained pus/Concentration of drug in the serum X100 on the day-three of the drainage (when applicable) | 8 weeks |