Routine Antibiotic vs. Directed Antibiotic Treatment in Snake Bite

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Snake Bites

Intervention / Treatment
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* Drug: Co-amoxiclav
* Biological: Tetanus toxoid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Routine use arm<br>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<br>* 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.<br>* Other names: Augmentin;Biological: Tetanus toxoid<br>* Injection Tetanus toxoid 0.5 ml intramuscularly Stat<br>|
| Experimental: Clinically-directed use arm<br>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<br>* 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.<br>* Other names: Augmentin;Biological: Tetanus toxoid<br>* Injection Tetanus toxoid 0.5 ml intramuscularly Stat<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Snake Envenomation, Antibiotic Prophylaxis, Viperidae