Safety and TDM of Continuous Infusion Vancomycin Through Continuous Renal Replacement Therapy Solution

Treatment Patients deemed candidates for CRRT and antimicrobial therapy for a proven or
suspected Gram-positive bacterial infection that includes vancomycin at the time of CRRT
initiation or at any time during the CRRT course. If vancomycin is part of the empiric
regimen or needed for definitive therapy an assessment will be made whether the vancomycin
can be administered via a continuous infusion by mixing the vancomycin in the CRRT
solution(s).

Intervention Administration of continuous infusion vancomycin via mixing vancomycin in the
CRRT solution(s). The CRRT solution will be prepared at the time it is needed following
current standard operating procedures of the Department of Pharmacy at St. Christopher's
Hospital for Children for sterile product compounding. The amount of vancomycin to be added
to the CRRT solution will be determined by the clinical condition such as the site of
infection,infecting organism(s), and serum drug levels. The mixed solution will be infused
for the duration it is prescribed for CRRT. Vancomycin is stable with the components of the
CRRT solution for at least 96 hours, therefore the frequency with which each CRRT solution
bag will be prepared will not exceed 96 hours.

Vancomycin dosing and concentration adjustments:

For patients started on vancomycin after initiation of CRRT, a single loading dose of 15-20
mg/kg of total body weight will be given intravenously over 60 minutes, after which the
vancomycin will be added directly to the CRRT solution(s). Vancomycin will be added at a
final concentration of 30 mg/L at CRRT initiation, regardless of age. For patients receiving
vancomycin prior to the initiation of CRRT, if the last dose administered is > 8 hours prior
to CRRT initiation, a loading dose of 15-20 mg/kg of total body weight will be given
intravenously over 60 minutes, after which the vancomycin will be added directly to the CRRT
solution(s). Vancomycin will be added at a final concentration of 30 mg/L at CRRT initiation,
regardless of age. The first serum vancomycin level will be determined 8-12 hours after
initiation of CRRT mixed with vancomycin. All serum for vancomycin concentrations
determination will be obtained directly from the patient via a central line, arterial line or
peripheral venipuncture and no vancomycin concentrations will obtained from the CRRT circuit
for analysis.

Vancomycin concentrations in the CRRT solution(s) will be adjusted based on the initial
vancomycin serum plateau level, and subsequent levels will be obtained based on these
changes. The target vancomycin plateau serum concentrations range is 15-30 mg/L. If the first
vancomycin plateau level obtained is within range, daily vancomycin plateau levels will be
obtained for the duration the vancomycin is mixed in the CRRT solution. If the first
vancomycin plateau level is not within range, the vancomycin concentration in the CRRT
solution will be adjusted. Subsequent vancomycin plateau levels will be obtained 8-12 hours
after the vancomycin concentration change and this process will continue until a therapeutic
plateau level is obtained. Once a therapeutic plateau level is obtained, daily vancomycin
plateau levels will be obtained for the duration the vancomycin is mixed in the CRRT
solution.

Blood samples for vancomycin analysis will be obtained 8-12 hours after starting the CRRT
solution mixed with vancomycin. Based on the first drug level obtained, changes to the
concentration may be made to adjust to the desired serum concentration and serum levels will
be obtained 8-12 hours after each change to the vancomycin concentration in the CRRT
solution. Once a therapeutic level is obtained, serum levels will be obtained as needed but
usually not more frequently than daily.

If the first vancomycin plateau level is < 10 mcg/mL, then a single, supplemental dose of 10
mg/kg of vancomycin will be given while the vancomycin CRRT concentration is being adjusted.

Inclusion Criteria

Patients eligible to participate in the study must meet all of the following criteria prior
to any study-related procedure:

1. The need for continuous renal replacement therapy (CRRT) of any modality

1. CVVH-continuous veno-venous hemofiltration

2. CVVHD-continuous veno-venous hemodialysis

3. CVVHDF-continuous veno-venous hemodiafiltration

2. Documented or suspected Gram-positive bacterial infection necessitating the use of
vancomycin while receiving CRRT.

Exclusion Criteria

Patients will be considered ineligible if they meet any of the following criteria:

1. History of any moderate or severe hypersensitivity or allergic reaction to vancomcyin
(a history of mild rash followed by uneventful re-exposure and/or red man syndrome is
not a contraindication)

2. Any rapidly-progressing disease or immediately life-threatening illness (defined as
imminent death within 48 hours in the opinion of the investigator)

3. Any condition or circumstance that, in the opinion of the investigator, would
compromise the safety of the patient or the quality of study data

4. Planned or prior participation in any other interventional drug study within 30 days

5. Females that are pregnant or breastfeeding