Routine Antibiotic vs. Directed Antibiotic Treatment in Snake Bite (RADIANS)

Routine vs. Clinically-Directed Antibiotic Treatment in Snake Bite With Local Envenomation: a Randomised Controlled Trial

Clinicians tend to overuse antibiotics in snake bite despite evidence from three previous clinical trials that failed to show a benefit. But, none of these trials was done in India. Further, the species of snake in two of these trials was quite different from that seen in the Indian setting limiting generalization of these findings. Hence, home-grown evidence is needed to persuade clinicians to use antibiotics rationally.

Study Overview

• Status: Unknown
• Conditions: Snake Bites
• Intervention / Treatment: Drug: Co-amoxiclav; Biological: Tetanus toxoid

Detailed Description

Snake bite is a common clinical problem in India and elsewhere, affecting agricultural workers and rural population, resulting in thousands of deaths every year. Apart from causing systemic manifestations such as coagulopathy, acute renal failure, and neuroparalysis, local effects of the venom manifest as swelling of the bitten limb. Despite administration of adequate antivenom, the limb swelling progresses in the first 48-72 hours accompanied by considerable pain. Often the limb swelling is accompanied by formation of blebs and gangrenous skin changes. At times, the limb swelling is severe enough to result in compartment syndrome, necessitating surgical interventions such as fasciotomy and debridement. Animal bites are typically associated with a risk of infection by the oral flora. Likewise, apart from releasing the venom, inoculation of oral flora as a result of snake bite could result in local infectious complications adding to the deleterious effects of the snake venom.

Observational studies suggest that the risk of infection following simple bites on the lower limbs is much less than what is often believed, and evidence from clinical trials also does not support routine use of antibiotics in snake bite. For this reason, clinical practice guidelines do not recommend routine prophylactic use of antibiotics in snake bite. But, in reality, many clinicians continue to use antibiotics routinely in all venomous snake bites hoping to prevent a local infection. While such a strategy may not reduce the risk of infection, it would result in overuse of antibiotics promoting antimicrobial resistance and escalating treatment costs.

The investigators hypothesize that clinically-directed use of antibiotics would be non-inferior to routine use in preventing local infectious complications of snake bite, while being superior in reducing the antibiotic consumption. Non-inferiority would be inferred if the one-sided 95% CI of the difference does not exceed 10% in favour of the routine use arm.

• Study Type: Interventional
• Enrollment (Anticipated): 130
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Tamilarasu Kadhiravan, M.D.; Phone Number: 6244 +91-413-2296000; Email: kadhir@jipmer.edu.in
• Study Contact Backup: Name: Aditya Gautam, M.B.,B.S.; Phone Number: +91-9047460760; Email: aytida.gautam@gmail.com

Study Locations

• India
  • Puducherry
    • Pondicherry, Puducherry, India, 605006
      • Recruiting
      • Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research
      • Principal Investigator: Tamilarasu Kadhiravan, M.D.
      • Sub-Investigator: Chanaveerappa Bammigatti, M.D.
      • Sub-Investigator: Aditya Gautam, M.B.,B.S.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-65 years
• History of snake bite with features of local envenomation with/without systemic features
• Less than 24 hours since bite, AND
• No prior antibiotic treatment

Exclusion Criteria:

• Upper limb bites
• Multiple (> 1) bites
• Wound manipulation
• Extensive local necrosis or blebs
• Seriously-ill patients with hypotension/capillary leak/life threatening bleeding.
• Suspected cobra bite, OR
• Pregnant/breast-feeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Routine use arm; All participants allocated to this arm will be given; Injection Tetanus toxoid 0.5 ml intramuscularly Stat; Antibiotic (Co-amoxiclav) will be given to all patients for a minimum duration of 5 days.; Daily clinical assessment would be done. Change of antibiotics is allowed if clinical failure occurs. Use of antibiotics for emergent indications unrelated to the bitten limb such as nosocomial infections would be allowed at the treating physician's discretion.	Drug: Co-amoxiclav; Injection Co-amoxiclav 1.2 g intravenously q8h for a minimum of 48-72 hours; switched to oral Co-amoxiclav 625 mg b.i.d. when clinically appropriate.; Other Names: Augmentin; Biological: Tetanus toxoid; Injection Tetanus toxoid 0.5 ml intramuscularly Stat
Experimental: Clinically-directed use arm; Participants allocated to this arm will be given; Injection Tetanus toxoid 0.5 ml intramuscularly Stat; Daily clinical assessment would be done. Antibiotic (Co-amoxiclav) will be started only if clinical failure occurs. Use of antibiotics for emergent indications unrelated to the bitten limb such as nosocomial infections would be allowed at the treating physician's discretion.	Drug: Co-amoxiclav; Injection Co-amoxiclav 1.2 g intravenously q8h for a minimum of 48-72 hours; switched to oral Co-amoxiclav 625 mg b.i.d. when clinically appropriate.; Other Names: Augmentin; Biological: Tetanus toxoid; Injection Tetanus toxoid 0.5 ml intramuscularly Stat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical failure	Defined as occurrence of any one of the following on daily assessments - Abscess formation at any point of time; Surgical debridement/fasciotomy at any time; Worsening limb swelling beyond 72-96 hours or appearance of necrosis or blebs along with any one of the following: fever, persistent or worsening leucocytosis, or global deterioration on clinical assessment.	up to 4 weeks
Antibiotic consumption	Defined as the total amount of all antibiotics consumed regardless of clinical indication expressed in terms of defined daily doses (DDD).	up to 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of hospital stay	Number of days from hospital admission until discharge	up to 4 weeks
Anti-snake venom consumption	The total number of vials of the anti-venom administered including doses received prior to being brought to JIPMER.	up to 4 weeks
New-onset organ failure	This includes acute kidney injury (AKI) defined as peak serum creatinine > 2 mg/dL, shock defined as systolic blood pressure < 90 mm Hg requiring use of vasopressors; bleeding from any site necessitating transfusion of blood/blood products; and capillary leak syndrome.	up to 4 weeks
Death/need for surgical intervention	This would be a composite measure of death and/or need for surgical intervention. Death indicates in-hospital death due to any cause during the index hospitalisation. Surgical intervention would include need for any surgical intervention such as incision and drainage of abscess, wound debridement for necrosis or gangrene, fasciotomy for compartment syndrome, etc.	up to 4 weeks
Drug-related adverse events	Any suspected or confirmed adverse drug reaction	up to 4 weeks

Collaborators and Investigators

• Sponsor: Jawaharlal Institute of Postgraduate Medical Education & Research
• Investigators: Principal Investigator: Tamilarasu Kadhiravan, M.D., Jawaharlal Institute of Postgraduate Medical Education & Research

Publications and helpful links

General Publications

• Terry P, Mackway-Jones K. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. The use of antibiotics in venomous snake bite. Emerg Med J. 2002 Jan;19(1):48-9. doi: 10.1136/emj.19.1.48.
• Terry P, Mackway-Jones K. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Antibiotics in non-venomous snakebite. Emerg Med J. 2002 Mar;19(2):142. doi: 10.1136/emj.19.2.142.
• Jorge MT, Malaque C, Ribeiro LA, Fan HW, Cardoso JL, Nishioka SA, Sano-Martins IS, Franca FO, Kamiguti AS, Theakston RD, Warrell DA. Failure of chloramphenicol prophylaxis to reduce the frequency of abscess formation as a complication of envenoming by Bothrops snakes in Brazil: a double-blind randomized controlled trial. Trans R Soc Trop Med Hyg. 2004 Sep;98(9):529-34. doi: 10.1016/j.trstmh.2003.12.009.
• Kularatne SA, Kumarasiri PV, Pushpakumara SK, Dissanayaka WP, Ariyasena H, Gawarammana IB, Senanayake N. Routine antibiotic therapy in the management of the local inflammatory swelling in venomous snakebites: results of a placebo-controlled study. Ceylon Med J. 2005 Dec;50(4):151-5. doi: 10.4038/cmj.v50i4.1405.
• Kerrigan KR, Mertz BL, Nelson SJ, Dye JD. Antibiotic prophylaxis for pit viper envenomation: prospective, controlled trial. World J Surg. 1997 May;21(4):369-72; discussion 372-3. doi: 10.1007/pl00012255.
• Mohapatra B, Warrell DA, Suraweera W, Bhatia P, Dhingra N, Jotkar RM, Rodriguez PS, Mishra K, Whitaker R, Jha P; Million Death Study Collaborators. Snakebite mortality in India: a nationally representative mortality survey. PLoS Negl Trop Dis. 2011 Apr 12;5(4):e1018. doi: 10.1371/journal.pntd.0001018.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2016
• Primary Completion (Anticipated): August 1, 2022
• Study Completion (Anticipated): August 1, 2022

Study Registration Dates

• First Submitted: October 5, 2015
• First Submitted That Met QC Criteria: October 5, 2015
• First Posted (Estimate): October 7, 2015

Study Record Updates

• Last Update Posted (Actual): August 12, 2020
• Last Update Submitted That Met QC Criteria: August 11, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Antibiotic Prophylaxis; Snake Envenomation; Viperidae
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Wounds and Injuries; Poisoning; Bites and Stings; Snake Bites; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Amoxicillin-Potassium Clavulanate Combination
• Other Study ID Numbers: JIP/IEC/2015/17/649