How Do You Dose Vancomycin in Obese Patients?

It’s ok to give 1 g of vancomycin, as long as the patient is obese and the dosing interval is adjusted to follow the 2-compartment distribution model.

Single, double, or triple? In terms of vancomycin dosing kinetics, it’s an important question.

Pharmacokinetic teachings tell us to select the simplest model and fewest compartments necessary to adequately describe the data. Thus, the single-compartment model is frequently used in initial dosing of vancomycin.

For the most part, vancomycin-dosing teachings include solving patient cases using 1-compartment pharmacokinetic formulas such as the Sawchuck-Zaske.¹ However, this simple view ignores vancomycin’s need to distribute into tissue where the infection exists, such as the skin, lung, bone, or central nervous system (CNS).

It is well known that vancomycin demonstrates a 2-phased distribution: alpha, lasting about 30 minutes to 1 hour after the end of an infusion, and beta, the terminal elimination half-life.

Simplified single-compartment models don’t fully take this into account, if at all. Nevertheless, we get away with the assumption of adequate distribution in most situations involving vancomycin dosing.

In models with altered volumes of distribution or clearance, such as in obesity [>30% above ideal body weight (IBW)], however, the single-compartment model falls apart where troughs cannot be predicted accurately.

A 2-compartment model acknowledges the distribution of vancomycin from plasma into tissues. Although it is much more mathematically complex, this method can be simplified into the weight-based dosing models with loading doses and some nomograms (modified Matzke).²

However, we also encounter limitations with these models. Particularly in obese patients, following loading dosing recommendations leads to compromises in either adjusting the dose to 2 g or less, or accepting the increased risk of nephrotoxicity.³ As a result, success rates for achieving desired troughs in obese patients float around 39% to 42%.^4,5

Troughs as a surrogate for AUC(0-24)/MIC is a debate for another post, but in the real world, the practice is to follow trough.^6-8

Given this high rate of failure in such a prolific drug, I’m surprised that a recently published protocol of divided loading doses in obese patients that achieved a target trough in 97% of patients at 24 hours has flown so far under the radar. ⁹

This was a prospective analysis of the divided vancomycin loading protocol in consecutive patients weighing >137% IBW (mean weight: 111 + 31 kg) and admitted to a single community hospital (Marin General Hospital). Patients were excluded if they had long-term paralysis, were pregnant, received some other vancomycin protocol, or had monitoring errors.

Although there was no real control in this study, troughs were compared with historical patients who received a protocol by Reynolds et al.

Divided load protocol was dependent on the IBW, % over IBW, and CrCl. Most patients received 1g IV q6 x 4 doses unless they were very tall or had low CrCl.

The measured outcome was the percentage of patients within the target trough range within 12 to 24 hours of dosing initiation.

Within 12 hours:

• Trough 10-20, n=48 (89%); mean 14.5 + 3.2
• Trough >10, n=51 (94%), including the above 48 patients, with the remaining 3 (6%) having troughs >20 (20.5—22.5)

Thirty-one patients had troughs drawn at 24 hours, while 19 patients had dosing interval changes that moved the trough draw beyond 24 hours, though it is unclear why.

• Trough 10-20, n=30/32 (97%); mean 15.0 + 3.1

The author concluded that the “biphasic, divided-load obese protocol described here achieved vancomycin trough concentrations in the range of 10-20 within the first 12 hours of treatment for 89% of patients weighing up to 245.2 kg, and 97% of trough concentrations sampled during maintenance dosing for the patients were within target range.”

Of course, this study has limitations. First, there were no clinical or patient-oriented outcomes, and second, this was a small sample, although it did meet its predefined power at 12 hours.

Other limitations include the study being single-center, essentially using observational methods, and having no comparison. It may very well be that the expertise of the clinical pharmacist is the reason this result was observed, so it is unclear whether this could be externally extrapolated to hospitals with fewer or more limited clinical pharmacists.

Then, there is the question of whether this should be taken a step further to a 3-compartment model.

The 3-compartment model makes logical sense for vancomycin, given the different tissue distribution of the drug (eg, CNS, skin, bone, lung). But these models aren’t easily applied to functional nomograms or dosing protocols.

My knowledge and understanding of the mathematics involved here left me long ago, back when I was on an engineering track. A higher-level discussion that is beyond my pharmacokinetic understanding is hopefully taking place somewhere.

We’re still between a rock and a hard place when it comes to dosing vancomycin in obese patients. This new approach seems logical, and in this limited study, it appears to achieve the desired outcome, though not necessarily improved patient-oriented ones.

More evidence is clearly needed to figure out how to dose vancomycin in obese patients, but this protocol could play a role in the future.

References:

1. Winter ME. (1996) Basic Clinical Pharmacokinetics. 3^rd edition. Edited by Mary Anne Koda-Kimble, Applied Therapeutics Inc. Vancouver, WA.

2. Matzke GR et al. Pharmacokinetics of vancomycin in patients with various degrees of renal function. Antimicrob Agents Chemother 1984:25;433-7.

3. Rybak MJ, Lomaestro BM, Rotschafer JC et al. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. Nov 2009;29(11):1275—9.

4. Wesner AR, Brackbill ML, Coyle LL, Kidd RS. Prospective trial of a novel nomogram to achieve updated vancomycin trough concentrations. Interdiscip Perspect Infect Dis. 2013;2013:839456.

5. Reynolds DC, Waite LH, Alexander DP, DeRyke CA. Performance of a vancomycin dosage regimen developed for obese patients. Am J Health Syst Pharm. 2012;69:944-50.

6. Brown J, Brown K, Forrest A. Vancomycin AUC24/MIC ratio in patients with complicated bacteremia and infective endocarditis due to methicillin-resistant Staphylococcus aureus and its association with attributable mortality during hospitalization. Antimicrob Agents Chemother. 2012;56:634-8.

7. Lodise TP, Drusano GL, Butterfield JM, Scoville J, Gotfried M, Rodvold KA. Penetration of vancomycin into epithelial lining fluid in healthy volunteers. Antimicrob Agents Chemother. 2011;55:5507-11.

8. Skhirtladze K, Hutschala D, Fleck T, et al. Impaired target site penetration of vancomycin in diabetic patients following cardiac surgery. Antimicrob Agents Chemother. 2006;50:1372-5.

9. Denetclaw TH, Yu MK, Moua M, Dowling TC, Steinke D. Performance of a divided-load intravenous vancomycin dosing strategy for obese patients. Ann Pharmacother 2015;49(8):861-8.