Use of a Loading Dose of Vancomycin in Pediatric Dosing

• Sponsor: Boston Children's Hospital (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01290237
• Collaborator: (none)
• Enrollment: 59
• Location: 1
• Arms: 2
• Duration (Months): 12.9
• Patients Per Site Per Month: 4.6

Study Details

Study Description

Brief Summary

Vancomycin is an antibiotic administered to children or adults for many types of infections. While it has been used to treat infections of children for more than 50 years we are still not completely certain about the best dose to use when starting treatment with this medication.

This study is intended to evaluate whether giving a new higher dose of vancomycin for the first dose will help us get to the desired amount in the body more quickly then the usual first dose. Half of the patients would get the new higher dose and the other half of patients will get the typical first dose. Only the first dose is changed and all doses that follow are the same in both groups and are doses typically used for children.

Condition or Disease	Intervention/Treatment	Phase
Infection	Drug: vancomycin hydrocloride	N/A

Detailed Description

Setting and Patients We conducted a double-blind randomized controlled trial of children aged 2 to 18 years hospitalized at Boston Children's Hospital between February 1, 2011, and January 15, 2012, who required antimicrobial therapy with vancomycin (Hospira, Inc., Lake Forest, IL, lot #896188EO-4) for a suspected or documented infection. We excluded patients with a body weight above 67 kg (to limit the maximum loading dose to 2 g), preexisting severe renal dysfunction, defined as creatinine clearance <50 mL/min/1.73m2 using the original Schwartz equation,7 known hearing impairment, intravenous vancomycin treatment in the prior 7 days or undergoing a procedure with anticipated moderate to severe blood loss (eg, cardiac surgery or extensive orthopedic procedure).

For all participants enrolled in the study, relevant baseline demographic, medical history and safety data were recorded. Medical history data included primary and secondary diagnoses; other comorbidities such as obesity or cystic fibrosis; and presence of systemic inflammatory response syndrome, defined as 2 or more of the following: temperature >38.5°C or <36°C; mean heart rate >2 standard deviations above normal for age; mean respiratory rate >2 standard deviations above normal for age; or high or low white blood cell count for age.

Randomization and Concealment Participants were randomized in blocks of 2 and 4 to receive either a loading dose of 30 mg/kg of vancomycin as a single intravenous infusion over 2 hours (intervention group) or an initial vancomycin dose of 20 mg/kg intravenously over 2 hours (comparison group). The initial dose was administered over 2 hours in both groups to preserve allocation concealment. All patients subsequently received a 20 mg/kg dose every 8 hours as was the standard of care in our hospital for treatment of severe infections at the time of the study. Subsequent doses were administered over 1 hour, unless the patient developed red man syndrome (as identified by the clinical team), in which case the infusion time was increased to 2 hours. The investigators, family and primary care teams were blinded to group assignment, and the first dose of vancomycin for all participants was prepared so that the solution volumes were identical. The computer-generated randomization was concealed in a locked binder until the intervention was assigned.

Vancomycin Concentration Sampling and Analysis Trough serum vancomycin concentrations were obtained within 60 minutes before the second (8-hour) and third (16-hour) vancomycin doses. In order to increase the likelihood of having a cloud of sparse data for population pharmacokinetic analysis, 1 or 2 additional serum vancomycin samples were obtained from each participant within the first 32 hours of therapy at a time coinciding with blood collection for clinical care. These samples were obtained only from participants with an indwelling catheter whose family provided written consent for additional sampling.

Vancomycin concentrations were measured using a fluorescence polarization immunoassay (Roche Diagnostics, Indianapolis, IN) on the Roche Integra 800 instrument. The assay had a limit of quantitation of 0.74 mg/L and an interassay coefficient of variability of <3%.

Study Design

• Study Type: Interventional
• Actual Enrollment: 59 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: The Use of a Loading Dose of Intravenous Vancomycin Will Achieve Therapeutic Concentration Earlier Than Conventional Pediatric Dosing: A Randomized Controlled Trial
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vancomycin loading dose Intervention: administer intravenous vancomycin 30 mg/kg/dose once, followed 8 hours later by 20 mg/kg/dose every 8 hours	Drug: vancomycin hydrocloride; see description of study arms; Other Names: Vancomycin
Active Comparator: Control No intervention. Administer intravenous vancomycin 20 mg/kg/dose every 8 hours as per hospital guideline.	Drug: vancomycin hydrocloride; see description of study arms; Other Names: Vancomycin

Outcome Measures

Primary Outcome Measures

1. Count of Participants With Vancomycin Trough Between 15 and 20 [8 hours after the first dose of vancomycin]

   proportion of participants whose vancomycin trough was between 15 and 20 mcg/mL, 8 hours after the first vancomycin dose, in loading dose group as compared to control group

Secondary Outcome Measures

1. AUC/MIC for Vancomycin in the Study Population [within 48 hours after receiving the first dose of vancomycin]

   AUC/MIC using hypothetical MIC = 1 mg/L

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Receiving care at Children's Hospital Boston

• Prescribed intravenous vancomycin by their physician

Exclusion Criteria:

• Weight above 67 kg

• Pre-existing renal dysfunction (creatinine clearance < 50 ml/min/1.73m2)

• Known hearing impairment

• Recent intravenous vancomycin treatment (within 7 days)

• Undergoing procedure with anticipated moderate-severe blood loss

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Boston	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Boston Children's Hospital

Investigators

• Principal Investigator: Alicia A Demirjian, MD, Boston Children's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

• Frymoyer A, Hersh AL, Benet LZ, Guglielmo BJ. Current recommended dosing of vancomycin for children with invasive methicillin-resistant Staphylococcus aureus infections is inadequate. Pediatr Infect Dis J. 2009 May;28(5):398-402. doi: 10.1097/INF.0b013e3181906e40.
• Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray BE, J Rybak M, Talan DA, Chambers HF; Infectious Diseases Society of America. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011 Feb 1;52(3):e18-55. doi: 10.1093/cid/ciq146. Epub 2011 Jan 4. Erratum in: Clin Infect Dis. 2011 Aug 1;53(3):319.
• Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr, Craig W, Billeter M, Dalovisio JR, Levine DP. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009 Jan 1;66(1):82-98. doi: 10.2146/ajhp080434. Review. Erratum in: Am J Health Syst Pharm. 2009 May 15;66(10):887.

• Responsible Party: Alicia Demirjian, Clinical Fellow, Pediatric Infectious Diseases, Boston Children's Hospital
• ClinicalTrials.gov Identifier: NCT01290237
• Other Study ID Numbers: 10-11-0561
• First Posted: Feb 4, 2011
• Last Update Posted: Jun 19, 2018
• Last Verified: May 1, 2018

• Keywords provided by Alicia Demirjian, Clinical Fellow, Pediatric Infectious Diseases, Boston Children's Hospital: vancomycin; loading dose; pharmacokinetic; pediatric; Methicillin-Resistant Staphylococcus aureus (MRSA); Serious infection with Gram positive bacteria
• Additional relevant MeSH terms: Infections; Vancomycin

Study Results

Participant Flow

Arm/Group Title	Vancomycin Loading Dose	Control
Arm/Group Description	Intravenous vancomycin 30 mg/kg/dose once, followed 8 hours later by 20 mg/kg/dose every 8 hours intravenous vancomycin hydrochloride: see description of study arms	Intravenous vancomycin 20 mg/kg/dose every 8 hours intravenous vancomycin hydrochloride: see description of study arms
Period Title: Overall Study
STARTED	30	29
COMPLETED	19	27
NOT COMPLETED	11	2

Baseline Characteristics

Arm/Group Title	Vancomycin Loading Dose	Control	Total
Arm/Group Description	Intravenous vancomycin 30 mg/kg/dose once, followed 8 hours later by 20 mg/kg/dose every 8 hours intravenous vancomycin hydrochloride: see description of study arms	Intravenous vancomycin 20 mg/kg/dose every 8 hours intravenous vancomycin hydrochloride: see description of study arms	Total of all reporting groups
Overall Participants	30	29	59
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.63 (4.4)	8.76 (4.04)	8.70 (4.22)
Sex: Female, Male (Count of Participants)
Female	12 40%	15 51.7%	27 45.8%
Male	18 60%	14 48.3%	32 54.2%
Region of Enrollment (participants) [Number]
United States	30 100%	29 100%	59 100%

Outcome Measures

1. Primary Outcome

Title	Count of Participants With Vancomycin Trough Between 15 and 20
Description	proportion of participants whose vancomycin trough was between 15 and 20 mcg/mL, 8 hours after the first vancomycin dose, in loading dose group as compared to control group
Time Frame	8 hours after the first dose of vancomycin

Outcome Measure Data

Analysis Population Description

Loading dose - trough at 8 hours was not collected for 11 participants: vancomycin was discontinued prior to second dose (7), participant changed their mind (1), other reason (3) Among participants allocated to conventional treatment, trough at 8 hours was not collected for 2: vancomycin discontinued prior to second dose (1), changed mind (1)

Arm/Group Title	Vancomycin Loading Dose	Control
Arm/Group Description	Intravenous vancomycin 30 mg/kg/dose once, followed 8 hours later by 20 mg/kg/dose every 8 hours intravenous vancomycin hydrochloride: see description of study arms	Intravenous vancomycin 20 mg/kg/dose every 8 hours intravenous vancomycin hydrochloride: see description of study arms
Measure Participants	19	27
Count of Participants [Participants]	2 6.7%	0 0%

2. Secondary Outcome

Title	AUC/MIC for Vancomycin in the Study Population
Description	AUC/MIC using hypothetical MIC = 1 mg/L
Time Frame	within 48 hours after receiving the first dose of vancomycin

Outcome Measure Data

Analysis Population Description

Number of measurements reflects the number of participants with blood samples available for testing

Arm/Group Title	Loading Dose	Conventional Dose
Arm/Group Description	As above	as above
Measure Participants	25	26
Mean (Standard Deviation) [AUC/MIC ratio]	446.5 (195.5)	434.0 (153.2)

Adverse Events

Arm/Group Title	Vancomycin Loading Dose		Control
Arm/Group Description	Intravenous vancomycin 30 mg/kg/dose once, followed 8 hours later by 20 mg/kg/dose every 8 hours intravenous vancomycin hydrochloride: see description of study arms		Intravenous vancomycin 20 mg/kg/dose every 8 hours intravenous vancomycin hydrochloride: see description of study arms
All Cause Mortality
	Vancomycin Loading Dose		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/29 (0%)
Serious Adverse Events
	Vancomycin Loading Dose		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)		0/29 (0%)
Renal and urinary disorders
acute kidney injury	1/30 (3.3%)	1	0/29 (0%)	0
Other (Not Including Serious) Adverse Events
	Vancomycin Loading Dose		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/30 (66.7%)		11/29 (37.9%)
General disorders
Escalation of care within 7 days	2/30 (6.7%)	2	3/29 (10.3%)	3
Renal and urinary disorders
Doubling of baseline creatinine	4/30 (13.3%)	4	1/29 (3.4%)	1
Skin and subcutaneous tissue disorders
Red man syndrome	14/30 (46.7%)	14	7/29 (24.1%)	7

Limitations/Caveats

trial underpowered to detect an increase of ≥40% in concentrations (small sample size) more cases excluded in the high-dose group than in reference group (possible analysis bias) increase in red man syndrome in the high-dose group

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.