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Featured Clinical Topic: Infectious Diseases

17 Nov 2017 11:16 AM | Deleted user

Vancomycin Utilization in the Obese Population and Future Monitoring Strategies

Authors: Ryan Buckman, UMKC Pharm.D. Candidate, 2018
Kathryn Burnett, Pharm.D., Kansas City VAMC PGY-2 Infectious Diseases Pharmacy Resident

Vancomycin was isolated in 1957 by an Eli Lilly chemist, Dr. E.C. Kornfield, from a soil sample collected in the jungle of Borneo.1,2 The sample was isolated from a fungus that yielded bactericidal activity against Staphylococci. The U.S. Food and Drug Administration (FDA) fast tracked the compound, due to concerns over growing resistance of Staphylococci. The compound was given the generic name vancomycin, a term derived from the word vanquish.1,2 Fast forward nearly 60 years and there is still controversy surrounding the optimal dose monitoring parameters for vancomycin.

Vancomycin is a glycopeptide antibiotic widely used in the United States for serious gram-positive infections involving methicillin resistant Staphylococcus aureus (MRSA). Vancomycin exhibits multicompartmental pharmacokinetics. Several strategies have been studied to determine pharmacokinetic and pharmacodynamics monitoring parameters for predicting vancomycin outcomes. Strategies for dose monitoring include: percentage of time the dosing interval that the drug concentration remains above the minimum inhibitory concentration (T>MIC), the area under the concentration-time curve (AUC): MIC ratio, and the maximum concentration: MIC (Cmax: MIC) ratio. Optimal dosing and monitoring for vancomycin will assist in reducing the occurrence of subtherapeutic and supratherapeutic levels leading to resistance and/or toxicity.

In 2009, the American Society of Health-System Pharmacists (ASHP), Infectious Diseases Society of America (ISDA), and the Society of Infectious Diseases Pharmacists (SIDP) addressed vancomycin therapeutic drug monitoring.11 The panel recommended that trough serum vancomycin concentrations, as a marker for AUC, as the most accurate and practical method at monitoring vancomycin effectiveness (Level of evidence II, Grade B). Trough concentrations should be measured at steady-state, which occurs approximately before the fourth dose. Dosing is based on actual body weight and concentrations of 15-20mg/kg every 8-12 hours to be utilized in complicated infections for most patients (normal renal function) to achieve target concentrations.11 Trough concentrations of 15 to 20 μg/mL to achieve efficacy in complicated infections while maintaining trough concentrations > 10 μg/mL to prevent the development of resistance.

According to the current consensus recommendation, vancomycin dosages should be calculated on adjusted body weight (ABW) for all patients, including the obese population, and then adjusted based on serum vancomycin concentrations to achieve therapeutic trough concentrations.

Challenges with Vancomycin Dosing in Obese Patients A 2009-2010 National Health and Nutrition examination survey revealed more than 78 million (35.7%) adults in the United States are obese (body mass index (BMI) > 30kg/m2).5 Projections for 2030 estimate more than half of adults in the U.S. will be obese.8 These numbers are concerning because obesity is associated with an increased risk of infection, as well as increased morbidity and mortality.5,6 Vancomycin dosing for obese and extremely obese patients provides challenges. Increase in body weight can affect vancomycin pharmacodynamics and pharmacokinetics. It has been observed that obese patients display physiological changes that include increased adipose tissue and muscle mass that can alter vancomycin’s volume of distribution.1,2 Additionally, increased kidney mass, increased renal blood flow, increased creatinine clearance and increased vancomycin clearance.1,2,4 Due to the altered physiological changes and dosing challenges, obese patients may be at greater risk for nephrotoxicity.

Dosing Strategies
Divided load strategy
Denetclaw and colleagues developed a divided-load dosing strategy for obese patients. The study was designed as an 8-month prospective, uncontrolled analysis of 54 patients at a single community hospital. Patients initially received 750mg, 1000mg, or 1250mg dose intravenously every 6 hours. The initial dose given was based upon patient’s ideal body weight ≥ 137% and body weight ±83 kg IBW (Table 1). The first trough concentration was drawn before the third dose. If the first pre-steady state trough concentration was within target range, then the initial dose was maintained and frequency was altered according to estimated creatinine clearance using the modified Cockcroft-Gault equation (Table 2 and 3). If first pre-steady state trough concentration was below range then the initial frequency was maintained and a second pre-steady state trough concentration was drawn before the fifth dose. If the second trough was within goal range then they followed the previous mentioned strategy of maintaining dose and adjusted the frequency of administration (Table 4). If either of the two troughs were above target range the dose was held and then restarted with the same initial dose but change in frequency according to estimated creatinine clearance and followed traditional dosing guidelines. They found that 89% of patients exhibited pre-steady-state concentrations between 10 to 20 µg/mL with 12 hours after dose initiation. The mean non-steady-state concentration was 14.5 ± 3.2 µg/mL.

Based upon the study protocol developed by Denetclaw and colleagues, Dr. Burnett implemented a divided-load dosing strategy in morbidly obese patients assessed in an urban hospital. The study sought to determine the safety and efficacy of the alternative dosing strategy. The study was designed as a retrospective study that examined patients who met inclusion criteria between December 2015 and March 2016 for a baseline group and from December 2016 to March 2017 for divided dose implementation group.

Utilizing the primary outcome measure of percentage of time in therapeutic range after maintenance regimen had been initiated, 36 of 99 patients reached target trough concentrations and were in the therapeutic range 41.9% ± 22.5% in the pre-implementation group. In the divided-dose group 11 of 19 patients reached target trough concentrations and were in the therapeutic range 24.4% ± 26.1%. The results revealed no statistical significance between the two groups (pre 41.9 + 22.5% vs post 35.6 + 34.4; p=0.579). A limitation of small sample size was due to patients missing doses, levels not drawn per protocol and vancomycin therapy being discontinued prior to a level being drawn during the maintenance regimen. The results were not anticipated for the divided-dose patients based upon the study done by Denetclaw et al.

Allometric strategy
Brown and colleagues examined allometric versus consensus dosing strategies to achieve target vancomycin trough concentrations.7 Allometric dosing aims to optimize empirical therapy across all body weights by improving the attainment of target drug concentrations. Allometric theory can be used to extrapolate drug dosing that utilizes a two-variable mathematical power to approximate doses according to body size. Dosing was based upon allometric equation, which is expressed as follows: allometric dose (mg) = average dose (mg) X {TBW (kg) / average TBW (kg)] β, where β is the allometric exponent that is scaled according to patient’s body size.7 The trial was a retrospective pre-and post-protocol implementation from January to June 2013 and January to June 2014. The primary outcome measure was percentage of patients achieving initial vancomycin trough concentrations between 10-20 mg/L. Eighty-one patients were included in each group. Allometric dosing resulted in 77% of patients achieving vancomycin trough concentration targets versus 57% for consensus guideline dosing.7 Since allometric dosing adjusts for patient’s body size, use could be considered for obese patients.

Conclusion
Even though vancomycin has been around for decades, dosing methods have varied and leaders in the area are still determining the best strategy. The 2009 consensus statement recommended trough levels to determine vancomycin effectiveness because of its practicality and relative accuracy. Although this model can be applied to most patients with reliable results, in obese patients dosing provides challenges due to physiological changes that can alter vancomycin volume of distribution. Dr. Burnett and others have studied divided dosing in obesity with mixed results but more data needs to be obtained to determine utility of this strategy in therapy. The updated consensus statement for vancomycin will include AUC/MIC as the preferred monitoring method over trough concentrations based on discussion from Michael Ryback, PharmD, MPH at IDWeek 2017. This method of dosing and monitoring will hopefully obtain better outcomes for all subsets of patients and reduce the development of resistance.

References:

  1. Davies SW, Efird JT, Girdry CA, et al. Vancomycin-associated nephrotoxicity: The obesity factor.
  2. Denetclaw TH, Yu MK, Moua M, et al. Performance of a divided-load intravenous vancomycin dosing strategy for obese patients. Annals of Pharmacotherapy. 2015; 49(8): 861-868.
  3. Rybak MJ, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adults: Summary of consensus recommendations from the American Society of Heath-System Pharmacists, the Infectious Diseases Society of America, and Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm. 2009; 66: 82- 98.
  4. Grace E. Altered vancomycin pharmacokinetics in obese and morbidly obese patients: What we have learned over the past 30 years. J Antimicrob Chemother. 2012; 67; 1305-1310.
  5. Ogden CL, Carrol MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. United States Department of Health and Human Services: Centers for Disease Control and Prevention. National Center for Health Statistics. Available at www. Cdc.gov/nchs/data/databriefs/db82.pdf Accessed 08/22/2017.
  6. Wang YC, McPherson K, Marsh T, et al. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet. 2011; 379 (9793): 815-825.
  7. Brown ML, Hutchison AM, McAtee AM et al. Allometric versus consensus guideline dosing in achieving target vancomycin trough concentrations. Am J Health-Syst Pharm. 2017; 74: e312-e320.
  8. Holmes NE, Tumidge JD, Munchof WJ et al. Vancomycin AUC/MIC ratio and 30-day mortality in patients with Staphylococcus aureus bacteremia. Antimicrobial Agents in Chemotherapy. 2013; 57(4): 1654-1663.
  9. Moellering RC. Vancomycin: A 50-year reassessment. Clin Infect Diseases. 2006; 42: s1-4.
  10. Morill HJ, Caffrey AR, Noh E, et al. Vancomycin dosing considerations in a real-world cohort of obese and extremely obese patients. Pharmacotherapy. 2015; 35(9): 869-875.
  11. Moise-Broder PA, Forrest A, Birmingham MC, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43(13):925-42.
  12. Rubinstein E, Keynan Y. Vancomycin revisted-60 years later. 2014; 217(2): 1-7.

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