Influencing Factors of Vancomycin Trough Level in Critically Ill Children With Sepsis

Timely antibiotic administration and optimal drug dosing are crucial to achieving therapeutic antibiotic levels in critically-ill pediatric patients with suspected bacterial infection. However, drug elimination through renal excretion is often enhanced in critically ill patients . This phenomenon, referred to as augmented renal clearance (ARC), may cause sub-therapeutic serum concentrations of antibiotics through enhanced glomerular filtration, resulting in treatment failure and the generation of antibiotic-resistant strains.

Vancomycin is a tricyclic glycopeptide antibiotic with broad spectrum activity against gram-positive bacteria. It is effective for the treatment of gram positive infections and is the drug of choice for methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is poorly absorbed following oral administration. Therefore, it is commonly administered as an intravenous infusion. Approximately 50% of vancomycin is protein bound in plasma with a variable volume of distribution. An initial distribution half-life ranging from 30 min to 1 h followed by a mean terminal elimination half-life ranging from 6 h to 12 h was determined following intravenous dosing in patients with normal renal function. Metabolism is negligible and elimination occurs primarily through glomerular filtration, such that advanced renal disease substantially reduces the clearance of vancomycin resulting in an elimination half-life of about 7.5 days compared to 4-6 h in normal patients. This means that in patients with kidney failure, the dosing of vancomycin must be adjusted.

Standard treatment guidelines recommend maintaining trough levels of vancomycin between 10 and 20 mg/L. The recommended trough levels are likely to ensure optimum bactericidal activity of vancomycin, based on the minimum inhibitory concentrations (MICs) for MRSA (the lowest concentration of the drug that can prevent growth of visible bacteria).

Studies have reported a threefold increase in the risk of worsening of infections if the MICs for MRSA exceed 1.5 mg/L. However, guidelines suggest maintaining a minimum trough level of 10 mg/L for vancomycin. On the other hand, higher trough levels of vancomycin increase the risk of nephrotoxicity by two times.

Investigators have reported a correlation between serum antibiotic concentration and glomerular filtration rate (GFR). The measured GFR (mGFR), based on urine creatinine clearance over a 24-hour period, is widely used to identify patients with ARC. However, prompt administration of the proper antibiotic dose enables the serum concentration to reach therapeutic levels quickly, and the 24-hour delay when using the mGFR to identify ARC may have an adverse effect on treatment outcome in critically-ill children.

Measured glomerular filtration rate (mGFR) is often used to identify augmented renal clearance (ARC). However, in the clinical setting, estimated GFR (eGFR) is obtained more quickly and inexpensively. Therefore, eGFR can be used to identify ARC by evaluating the correlation between the eGFR and vancomycin trough level (VTL).

At our institution, empirical vancomycin therapy is commonly used due to the elevated incidence of community-acquired methicillin-resistant Staphylococcus aureus infections in the PICU. Dose adjustments based on renal function are needed, necessitating vancomycin therapeutic drug monitoring. Comparing critically ill children with sepsis to patients with normal or decreased eGFR, we hypothesize that subtherapeutic VTL has been associated with ARC.