Prevention of Cefoperazone-induced Coagulopathy

Study Overview
=================
Brief Summary
-----------------
Evaluating the effect of prophylactic doses of vitamin K in preventing the adverse effect of cefoperazone/sulbactam induced coagulopathy in critically ill patients.

Detailed Description
-----------------
One of the most challenging issues in the intensive care unit is treating multidrug-resistant (MDR) bacterial infections weighing benefit to risk ratio. MDR bacterial infection in ICU is a major public health problem and the main cause of mortality in ICUs in Egypt. A study published in the American Journal of Infection Control pointed out that the prevalence of MDR bacterial infections in the ICU was 54%. Cefoperazone is a 3rd generation cephalosporin antibiotic covering many Gram-positive and Gram-negative bacteria, sulbactam is a beta-lactamase inhibitor which is used in combination with many antibiotics to overcome beta-lactamase producing bacteria, therefore the combination of cefoperazone/sulbactam has activity against MDR gram-negative bacteria. On the other hand, cefoperazone has been shown to have the adverse effects of inducing coagulopathy which is reported in many case reports and retrospective cohort studies. In most cases, coagulopathy events occur within a few days from the start of using cefoperazone/sulbactam, therefore the ICU staff was obliged to discontinue the antibiotic and choose another alternative leading to increasing the risk of resistant bacteria and treatment failure. Therefore, discontinuing the antibiotic due to its serious adverse events will lead to poor outcomes, more bacterial resistance, and more cost therapeutic plans for treating the infection and managing the severe adverse drug events which have been occurred such as bleeding. There are 2 mechanisms for cefoperazone-induced coagulopathy. The first the mechanism is related to N-methylthiotetrazole (NMTT), a side chain in cefoperazone molecule, which is responsible for the inhibition of a vitamin K-dependent carboxylation process leading to antagonizing blood clotting factors. The the second mechanism is antibiotics, in general, kill the normal flora in the gut which produce vitamin K. This cefoperazone/sulbactam-induced coagulopathy is not found in healthy volunteers or patients with adequate vitamin K activity, therefore, could consider cefoperazone/sulbactam-induced coagulopathy in critically ill patients, as related to nutritional status of these patients specifically with regard to vitamin K. This study aimed at studying the effect of co-administration of prophylactic doses of vitamin k during the administration of cefoperazone/sulbactam to keep the normal daily requirements of vitamin k, therefore preventing coagulopathy.

Official Title
-----------------
Preventing Cefoperazone/Sulbactam Induced Coagulopathy in Critically Ill Egyptian Patients: Efficacy of Vitamin K Prophylactic Doses

Conditions
-----------------
Antibiotic Side Effect

Intervention / Treatment
-----------------
* Drug: Vitamin K


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ICU admitted patients on treatment or prophylactic doses of cefoperazone/sulbactam. Exclusion Criteria: Patients' aged <18 years Pregnancy or breastfeeding women Active bleeding or bleeding disorder Patients having an abnormal baseline coagulation profile. Patients administer total parenteral nutrition with regular vitamin k supplements. Refusal to sign the written informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>vitamin K is used as a prophylactic dose to prevent cefoperazone/sulbactam coagulopathy. | Drug: Vitamin K<br>* Coadministration of vitamin K with the first dose of cefoperazone/sulbactam<br>|
| No Intervention: Control group<br> | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with changes in INR level | comparing INR level between baseline INR (before starting the antibiotic) and during the treatment with the antibiotic | During the duration of cefoperazone/sulbactam treatment up to 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with bleeding incidence | Internal bleeding as hematemesis or melena | During the duration of cefoperazone/sulbactam treatment up to 2 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Coagulopathy, Cefoperazone, Vitamin K, Cefoperazone/sulbactam