Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients

• ClinicalTrials.gov Identifier: NCT01619982
• Recruitment Status: Completed
• First Posted: June 15, 2012
• Results First Posted: January 12, 2018
• Last Update Posted: May 16, 2018
• Sponsor: Stanford University
• Information provided by (Responsible Party): Chandra Ramamoorthy, Stanford University

Study Description

Brief Summary:

The investigators hope to learn 1) if the addition of prophylaxis with vancomycin will decrease the rate of cefazolin non-susceptible surgical site infections (SSI), in high risk population 2) to develop better understanding of vancomycin and cefazolin pharmacokinetics in children undergoing cardiopulmonary bypass (CPB) 3) to assess the barriers to vancomycin dosing peri-operatively 4) to assess side effects and risks associated with peri-operative vancomycin administration. This will allow us to improve patient care by better understanding the benefits or the risks of peri-operative vancomycin administration and potentially decrease cefazolin-resistant surgical site infections.

In addition, this study gives us the opportunity to evaluate cefazolin and vancomycin pharmacokinetics (pK) on children on CPB.

The investigators will take blood samples from 20 patients. In 10 patients the investigators will do Cefazolin pK analysis and in the other 10 the investigators will do pK Vancomycin analysis. For the remainder of 292 patients, only prospective chart review will be done to determine the incidence of SSIs.

This data will be compared with 936 controls who received only Cefazolin pre-operatively as prophylaxis for SSI's.

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Condition or disease	Intervention/treatment	Phase
Congenital Heart Diseases; Aortic Valve Disorder	Drug: Cefazolin 25 mg/kg body weight and Vancomycin hydrochloride; Drug: Cefazolin 30 mg/kg body weight	Phase 4

Detailed Description:

With 100% compliance with the surgical infection prevention (SIP) bundle, the risk of surgical site infections (SSIs) has decreased considerably, but is still greater than the baseline rate at the best comparison hospital (2.5%). Recent analysis of SSI's in cardiovascular surgery patients identified more than half being caused by cefazolin resistant gram positive bacteria (methicillin resistant coagulase negative staphylococci- MRSE (methicillin resistant Staphylococcus epidermidis, or methicillin resistant Staphylococcus aureus- MRSA). Cefazolin is routinely given pre-operatively as surgical prophylaxis in patients undergoing cardiovascular surgery. Vancomycin is not routinely recommended for prophylaxis due to concerns of developing vancomycin resistance, however patients with MRSE and MRSA SSIs end up needing additional surgery to remove or replace infected hardware or grafts and/or additional weeks to months of intravenous vancomycin therapy. This results in significant morbidity to the children and cost to the institution. Several published guidelines suggest the use of pre-operative prophylaxis with vancomycin (alone or in conjunction with cefazolin) in instances where patients may be at higher risk for infection with MRSE or MRSA. The purpose of this study is to determine whether the addition of vancomycin to standard pre-operative prophylaxis with cefazolin in selected high risk subjects along with the full SIP bundle will decrease the incidence of cefazolin-resistant SSI's.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 32 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Effect of Pre-operative Prophylaxis With Vancomycin on Rate of Cefazolin Non-susceptible Gram Positive Surgical Site Infections in Cardiovascular Surgery Patients
• Study Start Date: February 2012
• Actual Primary Completion Date: December 2014
• Actual Study Completion Date: December 2014

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Cefazolin 25 mg/kg body weight and vancomycin; All infants < 1 year of age with congenital heart diseases requiring cardiac surgery with cardiopulmonary bypass or any patient who requires surgery involving the aorta or the aortic valve will receive both Cefazolin and Vancomycin as preoperative prophylaxis against Surgical Site Infections. This has been recommended in recently published guidelines but not evaluated in children. Intervention: Cefazolin 25 mg/kg body weight and Vancomycin hydrochloride 15 mg/kg body weight	Drug: Cefazolin 25 mg/kg body weight and Vancomycin hydrochloride; Cefazolin 25 mg/kg/dose administered intravenously over 5 minutes within 60 minutes of surgical incision and then re-dosed (25 mg/kg: maximum 2 grams/dose) every 4 hours intra-operatively depending on the duration of surgery as per standard peri-operative prophylaxis for cardiac surgery and Vancomycin 15 mg/kg (max 1.5 gram/dose) will be administered intravenously over 1-2 hours (after completion of cefazolin infusion) For patients younger than 1 month of age, a one-time repeat dose of 15 mg/kg can be given intraoperatively 12 hours after the beginning of the first vancomycin dose if the procedure is > 12 hours in duration. For patients equal to or older than 1 month, a one-time repeat dose of 15 mg/kg (max 1.5 grams) will be given intra-operatively 8 hours after the beginning of the first vancomycin dose if the procedure is > 8 hours in duration.; Other Names: Cefazolin: Brand Names Ancef; Vancomycin HCL: Brand name Vancocin
Cefazolin only 30mg/kg body weight; All infants less than one year of age with congenital heart diseases requiring cardiac surgery with cardiopulmonary bypass or all patients who required surgery involving the aorta or the aortic valve received cefazolin 30 mg/kg body weight as preoperative prophylaxis against surgical site infections	Drug: Cefazolin 30 mg/kg body weight; Intervention: Drug: Cefazolin pre-operative prophylaxis Other Names: Cefazolin: Brand Names Ancef, Kefzol Cefazolin 30 mg/kg/dose administered intravenously over 10 minutes within 60 minutes of surgical incision and then re-dosed (30 mg/kg: maximum 2 grams/dose) every 4 hours intra-operatively depending on the duration of surgery as per standard peri-operative prophylaxis for cardiac surgery.; Other Name: Cefazolin: Brand Names Ancef, Kefzol

Outcome Measures

Primary Outcome Measures :

1. Number of Patients Who Receive Preoperative Vancomycin and Cefazolin Who Develop a Surgical Site Infection Compared to Those Whose Received Only Cefazolin. [ Time Frame: Patients will be monitored for superficial SSIs for 30 days from the date of surgery. Patients will be monitored for 30 days for deep SSIs if no foreign material was implanted and for 1 year if foreign material is present. ]
   Number of patients who receive preoperative vancomycin and cefazolin who develop a surgical site infection (SSI) compared to those whose received only cefazolin. Surveillance was done with standard procedures and definitions.

Secondary Outcome Measures :

1. Cefazolin Pharmacokinetics [ Time Frame: Drug levels will be sampled only during the peri-operative time period (0 to 12 hours) ]
   Cefazolin Pharmacokinetics was measured as Central Volume, Peripheral Volume (Fast), Peripheral Volume (Slow)
2. Cefazolin Pharmacokinetics [ Time Frame: Drug levels will be sampled only during the peri-operative time period (0 to 12 hours) ]
   Measured as Elimination Clearance Inter-tissue Clearance (Fast) Inter-tissue Clearance(Slow)
3. Vancomycin Pharmacokinetics (Plasma Concentration vs Time Curve) in Children During the Peri-operative Period in Infants Undergoing Cardiac Surgery With Cardiopulmonary Bypass (CPB) [ Time Frame: Drug levels will be sampled only during the peri-operative time period (0 to 12 hours) ]
   Vancomycin pharmacokinetics measured as Central Volume, Peripheral Volume (Fast), Peripheral Volume (Slow)
4. Vancomycin Pharmacokinetics (Plasma Concentration vs Time Curve) in Children on Cardiopulmonary Bypass (CPB) [ Time Frame: Drug levels will be sampled only during the peri-operative time period (0 to 12 hours) ]
   Vancomycin pharmacokinetics measured as Elimination Clearance, Inter-tissue Clearance (Fast), Inter-tissue Clearance (Slow).
5. Count of Participants Experiencing Adverse Events Commonly Associated With Peri-operative Vancomycin Prophylaxis [ Time Frame: Adverse events to vancomycin will be assessed on each patient in the study during the time the patient is in the operating room (0-<24 hours) ]

   Will evaluate for vancomycin associated pre or intraoperative adverse events:

   1. Hypotension requiring treatment
   2. Rash, flushing or Red Man's syndrome
   3. Other changes in vital signs (decrease in baseline 02 sat, increased heart or respiratory rate, elevated body temperature) felt to be associated with vancomycin administration
   4. An event associated with vancomycin administration which results in delay in surgery

Eligibility Criteria

• Ages Eligible for Study: up to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patient less than or equal to 1 year of age who is undergoing cardiovascular surgery requiring CPB or patient under 18 years of age undergoing procedures involving aortic valve or aorta
2. Patients with a positive MRSA screen or a history of MRSA infections who are undergoing any cardiac surgery

Exclusion Criteria:

1. Patients who have known hypersensitivity to vancomycin or cephalosporins
2. Patients with renal insufficiency
3. Patients who have received vancomycin or cephalosporins 48 hours prior to the day of surgery
4. Patients whose surgery is due to an infection-related diagnosis such as endocarditis
5. Patients whose parents do not wish to have them receive vancomycin prophylaxis
6. Neonates born at less than 38 weeks gestational age

Contacts and Locations

Locations

United States, California

Lucile Packard Children's Hospital at Stanford

Palo Alto, California, United States, 94304

Sponsors and Collaborators

Stanford University

Investigators

• Principal Investigator: Kathleen Gutierrez, MD; Stanford University

More Information

Publications:

Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol. 1999 Apr;20(4):250-78; quiz 279-80.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ingrande J, Gutierrez K, Lemmens HJ, Verma A, Nicolau DP, Sutherland CA, Ramamoorthy C. Pharmacokinetics of Cefazolin and Vancomycin in Infants Undergoing Open-Heart Surgery With Cardiopulmonary Bypass. Anesth Analg. 2019 May;128(5):935-943. doi: 10.1213/ANE.0000000000003876.

• Responsible Party: Chandra Ramamoorthy, Professor, Anesthesiology, Department of Pediatric Cardiac Anesthesia, Stanford University
• ClinicalTrials.gov Identifier: NCT01619982
• Other Study ID Numbers: SU-11112011-8670
• First Posted: June 15, 2012
• Results First Posted: January 12, 2018
• Last Update Posted: May 16, 2018
• Last Verified: April 2018

Additional relevant MeSH terms:

Heart Diseases; Heart Defects, Congenital; Aortic Valve Disease; Cardiovascular Diseases; Cardiovascular Abnormalities; Congenital Abnormalities; Heart Valve Diseases; Vancomycin; Cefazolin; Anti-Bacterial Agents; Anti-Infective Agents