Vancomycin Loading Doses in Morbidly Obese Patients
Vancomycin Loading Doses in Morbidly Obese Patients
Abstract & Commentary
Jessica C. Song, MA, PharmD, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.
Jessica C. Song reports no financial relationships relevant to this field of study.
In January 2009, the publication of an updated vancomycin monitoring guideline1 gave clinicians a set of recommendations on: 1) timing of monitoring, 2) optimal trough concentration, 3) dosing to achieve optimal trough concentrations, 4) loading doses for complicated infections, 5) criteria for monitoring, and 6) frequency of monitoring. The recent vancomycin therapeutic monitoring guideline, a joint publication from the American Society of Health-System Pharmacists and the Infectious Diseases Society of America (IDSA), advocated the use of a loading dose of 25-30 mg/kg (based on actual body weight) for patients with complicated infections (IIIB level of evidence/grade of recommendation). Of note, this recommendation was based on expert opinion and descriptive studies and, hence, remains somewhat controversial.
Over the past two decades, the prevalence of morbid obesity has nearly doubled, from 2.9% in 1988-1994 to 4.7% in 1999-2000.2 Morbid obesity, defined as a body mass index of 40 kg/m2 or more,2 can pose a challenge to clinicians who must develop optimal antimicrobial drug-dosing regimens. Moreover, the use of standard formulae for calculating the creatinine clearance (Clcr) does not apply to morbidly obese patients, given the lack of validation of such methods in this population.3
The purpose of this review is to discuss the pharmacokinetics of vancomycin observed in morbidly obese patients and to provide recommendations on loading doses of this drug in this patient population.
Pharmacokinetics in Obese Patients
The development of an optimal dosing regimen of vancomycin (loading and maintenance doses) is dependent upon volume of distribution (Vd), clearance, and half-life in order to produce maximum efficacy and minimal toxicity.4 Unfortunately, the altered physiologic state of morbidly obese patients, along with inter-individual variations in this population, cause the relevant pharmacokinetic parameters to change significantly.5
The Vd represents a key parameter in determining the loading dose of drugs that require more rapid attainment of therapeutic serum concentrations.1,4 The volume of distribution of vancomycin has been shown to approach 0.7 L/kg in non-obese patients, using total body weight (TBW) for calculating Vd.4,5 In contrast, Bauer et al5 found that using TBW in 24 morbidly obese patients (average weight, 165 kg) yielded a mean Vd of 0.32 L/kg. Similarly, Blouin et al6 determined that the Vd of six morbidly obese patients (TBW, 111-226 kg) was approximately 0.26 L/kg.
The differences in Vd observed in obese patients compared with non-obese patients may be due to the fact that Vd is a function of the physiologic volume of blood and organs, along with drug binding in the blood and organs. While obese patients have large quantities of excess adipose tissue, the increased size of their body organs and larger blood volumes contribute to higher Vds. Moreover, adipose tissue does contain extracellular fluid to which vancomycin may distribute.5
Another important physiologic alteration noted in morbidly obese patients is creatinine clearance, a surrogate marker of glomerular filtration rate. Because of their larger kidneys, obese patients have a greater number of functional nephrons than non-obese patients. Consequently, the clearance of vancomycin, a renally eliminated drug, has been shown to be accelerated in morbidly obese patients.5 Salazar et al devised a method for estimating creatinine clearance in morbidly obese patients, as standard methods such as the Cockcroft-Gault equation do not yield accurate creatinine clearances in this patient population.3 Salazar et al used an equation, found in Table 1, to calculate creatinine clearances in morbidly obese males and females.
Changes in Vd and clearance ultimately shorten the half-life of vancomycin in morbidly obese patients.5 Because of the markedly accelerated clearance found in obese patients without a commensurate modification in Vd, the half-life of vancomycin has been shown to be considerably shorter (3.3 hours) in obese patients, compared with non-obese patients (7.2 hours).5
On the basis of the data from published pharmacokinetic studies of vancomycin, morbidly obese patients may require larger doses (> 1 gram) and shorter dosage intervals (6-8 hours) compared with non-obese patients, in order to achieve target serum trough concentrations.
Loading Dose of Vancomycin
There is limited data regarding the administration of vancomycin loading doses in critically ill, morbidly obese patients. If clinicians follow the IDSA recommendation of a loading dose of 25 mg/kg in a 200 Kg patient, a dose of 5 grams would need to be administered, given that total body weight has been shown to be a more accurate predictor of vancomycin pharmacokinetic parameters. However, since rapid infusion (< 1 hour) of first-dose vancomycin can cause red man syndrome,7 an infusion-related reaction that consists of facial, neck, and upper trunk pruritus, infusion times of at least a few hours would be required to deliver loading doses to obese patients.
Many institutions have limited the maximum loading dose of vancomycin to 2,000 mg. See the recommended doses of vancomycin from the Hartford Hospital loading-dose protocol (personal communication from Robert Quercia, Pharm.D; Drug Information Service Supervisor) in Table 2.
Of note, the IDSA recommends extension of infusion times to 1.5 to 2.0 hours when individual doses exceed 1 gram (i.e., 1.5 and 2.0 grams).1
Some clinical pharmacokinetic specialists4 estimate the appropriate loading dose to achieve an initial vancomycin concentration of 30 mg/L, using the equation in Table 3.
Conclusion
As a population, morbidly obese patients exhibit numerous physiologic changes that can impact dosing of antimicrobial agents, such as vancomycin. As a result, the pharmacokinetics, as well as dose requirements of vancomycin differ considerably in obese patients, compared with non-obese patients. Therapeutic drug monitoring helps to individualize therapy to the patient, as well as accommodate the patient's physical condition (renal function, age, body weight).
References
- Rybak M, et al. 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;66:82-98.
- Flegal KM, et al. Prevalence and trends in obesity among US adults, 1999-2000. JAMA. 2002;288:1723-1727.
- Salazar DE, Corcoran GB. Predicting creatinine clearance and renal drug clearance in obese patients from estimated fat-free body mass. Am J Med. 1988;84:1053-1060.
- Koda-Kimble MA, ed. Basic Clinical Pharmacokinetics, 3rd edition. Winters M. Chapter 18: Vancomycin, pages 474-99. Applied Therapeutics Inc., Vancouver, WA; 1994.
- Bauer LA, et al. Vancomycin dosing in morbidly obese patients. Eur J Clin Pharmacol. 1998;54:621-625.
- Blouin RA, et al. Vancomycin pharmacokinetics in normal and morbidly obese subjects. Antimicrob Agent Chemother. 1982;21:575-580.
- Sivagnanam S, Deleu D. Commentary: red man syndrome. Crit Care. 2003;7:119-120.
- Wang JT, et al. Necessity of a loading dose when using vancomycin in critically ill patients. J Antimicrob Chemother. 2001;47:239-246.
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