Monday, November 26, 2012

Vancomycin Loading Dose In The ED


Vancomycin dosing in EDs has been on a journey from “a gram” for everyone towards a weight based dosing scheme.  This shift has been driven by a number of sources, but namely by the Infectious Disease Society of America, American Society of Health-System Pharmacists and Society of Infectious Disease Pharmacists' (IDSA/ASHP/SIDP) guideline recommendations for vancomycin therapeutic monitoring.1
The change in dosing strategy is similar to other ID discussion nowadays; resistance and multidrug resistant pathogens are the impetus for pushing the envelope when it comes to antimicrobial dosing.  Usually this discussion involves gram-negative pathogens and their antimicrobial counterparts.  But, S. aureus, particularly MRSA (both community and hospital organisms) is becoming more resistant to vancomycin.  Resistant pathogens like hVISA and VRSA, although rare, are starting to pop up in the US.
In a collaboration of ID docs and ID pharmacists, these guidelines bring to light the importance of utilizing the pharmacokinetics of vancomycin to improve our dosing practices. Since the conventional dosing strategies (i.e., vancomycin 1g every 12 hours) were not developed to reach the target therapeutic troughs (15 – 20 mg/dL) more aggressive, weight based doses are recommended (IIIB). The recommended strategies to achieve target trough concentration consist of employing a loading dose (25 - 30 mg/kg) followed by a maintenance dose (15 – 20 mg/kg/dose divided every 8 to 12 hours).1 These strategies make sense; with linear pharmacokinetics more drug equals higher concentration. Unfortunately, there is little prospective evidence to support the safety and efficacy of vancomycin loading doses, reflected by a IIIB recommendation. 
For us in the ED, identifying who should receive vancomycin loading doses can be challenging. Striking a balance between achieving a therapeutic trough and safety (particularly nephrotoxicity) is a constant experiment.  I think it is clear that the higher we push vancomycin dosing, the risk of nephrotoxicity increases.  Selecting the patients who are thought to have a benefit from higher dosing mirrors the population who is at highest risk of nephrotoxicity. Through retrospective data (again) independent risk factors associated with vancomycin nephrotoxicity include: total daily doses >4g, actual body weight >101.4kg, GFR < 86.6mL/min and admission to an intensive care unit. 2,3,4
We can however, limit the risk of toxicity by creating a threshold of the total daily dosing to < 4g and no more than 2g/dose, using adjusted body weight for obese patients to avoid overdosing and employing intensive therapeutic monitoring.  But what by way of efficacy are we sacrificing while adjusting for this risk?
While I hope to see prospective data on the efficacy and safety of these vancomycin-dosing strategies, I am not holding my breath.  Fortunately there are alternatives out there. Similar to the fosphyenytoin/phenytoin discussion vancomycin alternatives like linezolid, tigecycline, ceftaroline and daptomycin are expensive… for now.  Sure one agent alone cannot replace vancomycin, but using each in their own niches is certainly plausible. 
But for now, this is how I try to determine who is a candidate for vancomycin loading doses:
·       Age > 18 years
·       Creatinine clearance > 86.6 mL/min
·       Patients with suspected or proven infection caused by S. aureus
o   Bacteremia, endocarditis, osteomyelitis, meningitis, HCAP/HAP
·       With one of the following:
o   WBC < 4,000 cells/mm3, or > 12,000 cells/mm3, or > 10% bands
o   Temperature < 97 °F, or > 100.4 °F
o   Heart rate > 90 bpm
o   Respiratory rate > 20 bpm or PaCO2 < 32 mmHg

1.     Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American society of health-system pharmacists, the infectious disease society of American, and the society of infectious disease pharmacists. CID 2009;49:325-7
2.     Hidayat LK, Hsu DI, Quist, et al. High-Dose Vancomycin Therapy for Methicillin-Resistant Staphylococcus aureus Infections: Efficacy and Toxicity. Arch Intern Med, 2006:166:2138-2144
3.     Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrobial agents and chemotherapy, 2008;52(4):1330-36
4.     Lodise TP, Patel N, Lomaestro GM, et al. Relationship between Initial Vancomycin Concentration-Time Profile and Nephrotoxicity among Hospitalized Patients. Clinical Infectious Diseases 2009;49:507-14
5.     Wang JT, Fang CT, Chen YC, Chang SC. Necessity of a loading dose when using vancomycin in critically ill patients. J Antimicrobe Chemother 2001; 47:246