December 2017 FAQs

What information has been yielded from the cardiovascular safety studies on new anti-hyperglycemic agents?

Introduction

Diabetes mellitus is a major risk factor for cardiovascular (CV) events and CV-related mortality.¹ Due to this increased risk and reports of worsening of CV adverse events with rosiglitazone, the Food and Drug Administration (FDA) released guidance in 2008 recommending that trials for new antihyperglycemic agents investigate the risk of CV events.² The guidance required that these safety trials include patients at high CV risk and are at a minimum of 2 years in length. It also provides a restriction for approval based on the estimated risk ratio. It requires that the upper bound of the 2-sided 95% confidence interval for the risk ratio of CV events is less than 1.8 when compared to the control group. Therefore, if the confidence interval crosses 1.8, the CV risk associated with the medication will be considered too high for FDA approval. Since the implementation of these recommendations, several large randomized controlled trials of the newer antihyperglycemic agents have been completed. ^3-10 These safety trials all had a primary outcome of major acute cardiac events (MACE), defined as the composite of CV death, non-fatal myocardial infarction and non-fatal ischemic stroke.

In response to the FDA guidance, randomized controlled studies have been conducted to evaluate the CV safety of glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors and are summarized in the Table below.^3-10 GLP-1 agonists and DPP-4 inhibitors are both incretin-based agents that lead to activation of pancreatic GLP-1 receptors and increased insulin secretion.¹¹ GLP-1 receptors are also expressed on cardiac and vascular tissue potentially leading to the CV effects of these agents. SGLT-2 inhibitors act on the sodium-glucose co-transporter in the kidney and result in increased secretion of both sodium and glucose in the urine. Unlike GLP-1, SGLT-2 receptors are isolated to the kidney. Thus, cardiac effects are postulated to be due to downstream effects of glucose and sodium excretion.

Table. Cardiovascular safety trials of DPP-4 inhibitors, GLP-1 agonists and SGLT-2 Inhibitors.^3-10

All of the 8 large randomized controlled trials (RCT) described above showed non-inferiority to placebo for their primary and composite endpoints.^3-10 Cardiovascular benefits were seen with the GLP-1 agonists liraglutide and semaglutide as well as the SGLT-2 inhibitors empagliflozin and canagliflozin.^7-10 Of note, the results of the EMPA-REG and LEADER trials led to additional FDA-approved cardiac indications for patients with type 2 diabetes with established CV disease for empagliflozin and liraglutide, respectively.¹² For this specific patient population, empagliflozin was approved for reduction in risk of cardiac death and liraglutide was approved for reduction in risk of major CV events, heart attack, stroke and CV death. Additionally, semaglutide is currently in the regulatory approval process with the FDA, and is not yet available in the United States.

The results from these RCTs are reinforced by two recent meta-analyses.^13,14 One analysis evaluated the CV outcomes of 6 of the prospective, RCTs summarized above with DPP-4 inhibitors and GLP-1 agonists.¹³ Results showed that GLP-1 agonists reduced all-cause death (relative risk [RR] 0.90; 95% confidence interval [CI] 0.82 to 0.98) and CV mortality (RR 0.84, 95% CI 0.73 to 0.90) and DPP-4 inhibitors had no effect on any of the CV outcomes. The other study analyzed prevention of CV mortality and morbidity with oral antidiabetic agents including metformin, sulfonylureas, thiazolidinediones (TZDs), DPP-4 inhibitors and SGLT-2 inhibitors in 73 RCTs.¹⁴ The results showed that SGLT-2 inhibitors reduced CV mortality compared to placebo in both a pairwise meta-analysis (RR 0.63; 95% CI 0.51 to 0.78) and a network meta-analysis (RR 0.61; 95% CI 0.50 to 0.76). The pairwise analysis included only within study comparisons and the network analysis included both direct and indirect evidence to assess CV outcomes. The network analysis also showed a reduction in CV mortality with SGLT-2 inhibitors compared to sulfonylureas, TZDs, and DPP-4 inhibitors (RR 0.52; 95% CI 0.31 to 0.88; RR 0.66; 95% CI 0.49 to 0.91; and RR 0.61; 95% CI 0.48 to 0.77, respectively).  There was no significant difference found between the SGLT-2 inhibitors and metformin. Additionally, the meta-analysis limited its evaluation to oral agents and as a result, CV safety trials of GLP-1 agonists were not included.

Recommendations for clinical practice

The 2017 American Diabetes Association (ADA) diabetes care guidelines and the 2017 American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACA) diabetes management algorithm reference significant outcomes from these CV safety trials.^15,16 The ADA guidelines acknowledge the CV benefits found for both empagliflozin and liraglutide and recommend that these agents be considered in patients with long-standing suboptimally controlled type 2 diabetes and established atherosclerotic CV disease (CVD).¹⁵ However, they also discuss that these effects can not necessarily be extended to other agents within the same classes or to patients with lower risk of adverse CV outcomes. The AACE/ACA guideline also acknowledges the CV benefit associated with empagliflozin, but does not make any specific treatment recommendations.¹⁶

Based on the studies summarized in this review, GLP- agonists, DPP-4 inhibitors and SGLT-2 inhibitors have not demonstrated an increased risk of CV events when added on to current therapy in high CV risk patient groups and a decreased risk has been demonstrated with certain agents.^3-10,13,14 However, all of these RCTs were compared to placebo, so they provide no evidence comparing the CV risk amongst each other or to older antihyperglycemic agents.^3-10 The network analysis results do provide data indicating that there may be a decreased CV risk with SGLT-2 inhibitors compared to DPP-4 inhibitors, TZDs, and sulfonylureas.¹⁴ However, this conclusion was not based on head-to-head comparisons of these agents. In addition, it is important to consider that because these studies were done in patients with high CV risk, the benefits seen in some of these agents cannot be implied for patients with lower CV risk. Overall, based on the results of these studies and the cardiac safety indications for empagliflozin and liraglutide, these two medications should be considered preferentially, after failure of metformin monotherapy, in patients with existing CVD. However, it is still important to take into consideration other patient specific factors including comorbid disease states and insurance coverage, as well as the side effect profiles and dosage forms of these medications when selecting an agent.

References

1. Benjamin E, Blaha M, Chiuve S, et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135:146-603.
2. Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed October 20, 2017.
3. Scirica S, Bhatt D, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326.
4. White W, Cannon C, Heller S, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-1335.
5. Green J, Bethel M, Armstrong P, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232-242.
6. Pfeffer M, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247-2257.
7. Marso S, Daniels G, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
8. Marso S, Bain S, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.
9. Zinman B, Wanner C, Lachin J, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.
10. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657.
11. Secrest M, Udell J, Kristian F. The cardiovascular safety trials of DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors. Trends Cardiovasc Med. 2017;27:194-202.
12. Drugs@FDA: FDA Approved Drug Products. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed October 20, 2017.
13. Zhang Z, Chen X, Lu P, et al. Incretin-based agents in type 2 diabetic patients at cardiovascular risk: compare the effect of GLP-1 agonists and DPP-4 inhibitors on cardiovascular and pancreatic outcomes. Cardiovasc Diabetol. 2017;16(1):1-10.
14. Lee G, Oh SW, Hwang SS, et al. Comparative effectiveness of oral antidiabetic drugs in preventing cardiovascular mortality and morbidity: A network meta-analysis. PLoS ONE. 2017;12(5):e0177646. https://doi.org/10.1371/journal.pone.0177646.
15. American Diabetes Association. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017;40(suppl 1):S64-S74.
16. Garber A, Abrahamson M, Barzilay J, et al. Consensus statement by the American Association of Clinical Endocrinologist and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2017 executive summary. Endocr Pract. 2017;23(2):207-237.

Prepared by:

Elizabeth Eitzen, PharmD

PGY1 Pharmacy Practice Resident

University of Illinois at Chicago College of Pharmacy

December 2017

The information presented is current as October 2, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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Should tranexamic acid be added to the standard of care in treating postpartum hemorrhage?

Introduction

Postpartum hemorrhage (PPH) is defined as a greater than 500 mL of blood loss in the first 24 hours after a vaginal delivery or cesarean section.¹ It is a major cause of maternal deaths worldwide and it is estimated to cause 125,000 deaths per year.² The overall prevalence of PPH has been reported to occur in about 6% of all deliveries. The prevalence of PPH is higher in undeveloped countries compared to developed countries. However, it was found that there was a 26% relative risk increase in PPH in the United States from 1994 to 2006.³ One in 5 hemorrhages can also develop into severe PPH (SPPH), which is defined as greater that 1000 mL of blood loss.² Severe PPH can compromise the mother’s fertility in the future and lead to further complications. The worldwide prevalence of SPPH is 1.86%.

Postpartum hemorrhage can occur due to uterine atony, abnormal placentation, coagulation disorders, vessel malformation, lower genital tract lacerations, and uterine ruptures.^1,4 Women may have an increased risk for PPH if they have a history of previous PPH, primiparity, obesity, prolonged labor, previous cesarean sections, or macrosomia. However, many women have low risk pregnancies and no known risk factors for PPH, thus it is important to institute standard measures to prevent PPH.¹ The World Health Organization (WHO) recommends that uterotonics should be used in the third stage of labor during all births to prevent PPH.⁵ Oxytocin is the drug of choice for prevention of PPH as it has been found to reduce the risk of blood loss by 50%.^1,5

Tranexamic Acid

Tranexamic acid is a competitive inhibitor for plasminogen activation.⁶  This inhibition results in anti-fibrinolytic action and can increase a patient’s own hemostatic actions.¹ Endothelial injury due to trauma or childbirth causes an increase in endothelial tissue plasminogen activator.⁷ This results in plasmin activation, and then fibrin degradation and increased bleeding. However, tranexamic acid inhibits plasminogen activation and helps promote hemostasis. Tranexamic acid has a half-life of 2 hours and its anti-fibrinolytic actions can last up to 7 to 8 hours.¹

Tranexamic acid has been found to improve outcomes in trauma patients, cardiovascular surgery, and other elective surgeries.⁶ In 2010, a randomized controlled trial by the CRASH-2 trial collaborators was published on the use of tranexamic acid in trauma patients within 8 hours of injury compared to placebo.⁸ The primary outcome of the trial was all-cause mortality at 4 weeks after the injury. This trial showed that tranexamic acid significantly reduced all-cause mortality in these patients (14.5% with tranexamic acid vs 16.0% with placebo, relative risk [RR] 0.91, 95% confidence interval [CI] 0.85 to 0.97, p=0.0035). Tranexamic acid also significantly reduced the risk of death due to bleeding (4.9% with tranexamic acid vs 5.7% with placebo, RR 0.85, 95% CI 0.76 to 0.96, p=0.0077). Further, tranexamic acid did not increase the risk for a vascular occlusion event (0.3% with tranexamic acid vs 0.5% with placebo, RR 0.69, 95% CI 0.44 to 1.07, p=0.096). Overall, this study demonstrated that early administration of tranexamic acid helps prevent mortality, but is not associated with an increased risk for vascular occlusions. Evidence also shows that tranexamic acid is effective in preventing PPH after both vaginal births and cesarean sections.¹ Tranexamic acid reduces the amount of bleeding and the use of other uterotonic agents, such as oxytocin, when used preventatively. However, it has been noted that the trials on preventing PPH with tranexamic acid are of mixed quality and more robust randomized controlled trials are needed.⁷

Literature Review

Until recently there were minimal data available on the use of tranexamic acid for the treatment of PPH.¹ Two randomized controlled trials have been conducted to evaluate the use of tranexamic acid to treat PPH (Table). In 2011, the EXADELI trial was published by Ducloy-Bouthors and colleagues.⁹ This randomized, open-label trial was completed in France with 144 women. Women who had lost >800 mL of blood after vaginal delivery were randomized to tranexamic acid given as a 4-g loading dose followed by an infusion of 1 g/h for 6 hours or to no treatment. The authors found significantly less blood loss in women treated with tranexamic acid at end of the infusion. Potential limitations of this study include that it was a rather small study in France and was an open-label design.  In May 2017, the international WOMAN trial was published, which was a randomized, double-blind, placebo-controlled trial.¹⁰ This trial enrolled over 20,000 women in 21 counties around the world, including both developed and under-developed countries. Women with PPH after vaginal or cesarean delivery were given either placebo or a 1-g dose of tranexamic acid, in addition to usual care.  The trial had a composite primary endpoint of all-cause mortality or hysterectomies within 42 days. There was no difference found in the primary endpoint, but treatment with tranexamic acid was associated with significantly fewer deaths due to bleeding. Stratification of the results by time of administration showed that tranexamic acid was most effective in reducing bleeding-related deaths in women who received it within 3 hours of giving birth. While the large and diverse sample size of this study are definite strengths, each country’s specific health-related issues must be considered when applying these results. The authors note that tranexamic acid might have more of an effect on all-cause mortality when other causes of death, such as sepsis, are low.

Table. Studies Evaluating Use of Tranexamic Acid in Postpartum Hemorrhage.^9,10

Safety of Tranexamic Acid

The EXDELI trial reported that patients treated with tranexamic were more likely to have mild and transient adverse effects.⁹ These reactions were mostly gastrointestinal or neurological. The WOMAN trial reported no difference in adverse events, including thrombotic events, between the tranexamic acid and the placebo group.¹⁰ In the CRASH- 2 trial in trauma patients, there was also no increase in the rate of vascular occlusive events in patients given tranexamic acid.⁸

Tranexamic acid is renally cleared and is contraindicated in women with significant renal disease.¹ It has been found that women with a GFR of <15 mL/min had a greater length of exposure to tranexamic acid.¹¹ There are also reports that tranexamic acid can cause acute renal failure secondary to thrombosis-induced cortical necrosis.¹ Tranexamic has been reported to cross the placenta, but there are is limited evidence that it causes any harm to the neonate.⁷ Additionally, tranexamic acid is found in very small concentrations in breast milk and is considered to be safe during breastfeeding.

Guidelines Recommendations

In 2012, WHO published recommendations on the prevention and treatment of PPH.⁵ WHO recommends that tranexamic acid be used for treatment of PPH if oxytocin and other uterotonics fail to stop bleeding or if the bleeding is thought to be secondary to trauma. However, this was before the larger international WOMAN trial. In September 2017, the American Congress of Obstetricians and Gynecologists (ACOG) posted a new bulletin on PPH.¹² They recommend that all hospitals have a system in place to help manage PPH to decrease morbidity and mortality. This includes a risk assessment for excessive bleeding and management with oxytocin, uterine massages, and umbilical cord tractions. These options are recommended first to use less invasive methods initially. Utilizing the results from the WOMAN trial, ACOG now recommends that tranexamic acid be considered after initial therapies fail. They also note that early administration, within 3 hours of delivery, is most likely to have a benefit for women with PPH.

Conclusion

While data on tranexamic acid for the treatment of PPH are still limited, the results from the 2017 international WOMAN trial show a significant benefit, especially with the difference in bleeding-related mortality found and when treatment was administered within 3 hours. Since this was an international trial, the results might be hard to apply to patients specifically in the United States because this study was done in such a diverse patient population all around the world. However, these results offer an additional treatment option for women who might have not had other options in the past. Further studies are warranted to ensure women can be effectively managed with tranexamic acid with minimal serious adverse events. With the recent guideline recommendations from ACOG, the treatment of women with PPH has become clearer, but the risks and benefit of each treatment option must still be considering when deciding the best course of therapy for each patient.

References

1. Sentilhes L, Lasocki S, Ducloy-Bouthors AS, et al. Tranexamic acid for prevention and treatment of postpartum haemorrhage. Br J Anaesth. 2015;114(4):576–587.
2. Carroli G, Cuesta C, Abalos E, Gulmezoglu AM. Epidemiology of postpartum haemorrhage: a systematic review. Best Pract Res Clin Obstet Gynaecol. 2008; 22(6):999-1012.
3. Callaghan WM, Kuklina EV, Berg CJ. Trends in postpartum hemorrhage: United States, 1994-2006. Am J Obstet Gynecol. 2010;202(4):353.
4. Oyelese Y, Ananth CV. Postpartum hemorrhage: epidemiology, risk factors, and causes. Clin Obstet Gynecol. 2010;53(1):147-156.

5. WHO. WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva: World Health Organization, 2012.
6. Cyklokapron [package insert]. New York, NY: Pfizer; 2011.
7. Pacheco LD, Hankins GDV, Saad AF, Costantine MM, Chiossi G, Saade GR. Tranexamic acid for the management of obstetric hemorrhage. Obstet Gynecol. 2017;130(4):765-769.
8. CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376(9734):23-32.
9. Ducloy-Bouthors AS, Jude B, Duhamel A, et al. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care. 2011;15(2):R117.
10. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10084):2105-2116.
11. Frimat M, Decambron M, Lebas C, et al. Renal cortical necrosis in postpartum hemorrhage: a case series. Am J Kidney Dis. 2016;68(1):50-57.
12. Committee on Practice Bulletins-Obstetrics. Practice bulletin no. 183: postpartum hemorrhage. Obstet Gynecol. 2017;130(4):e168-e186.

Prepared by:

Emily Armgardt, PharmD

PGY1 Pharmacy Practice Resident

University of Illinois at Chicago College of Pharmacy

December 2017

The information presented is current as of October 9, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What evidence is available on adult dosing of vancomycin in obesity?

Introduction

Vancomycin is a glycopeptide antibiotic and is most commonly used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections.¹ Over the years, pharmacokinetic studies have allowed for targeting serum concentrations in narrow ranges, in order to effectively use the drug while preventing drug-induced toxicity such as nephrotoxicity and ototoxicity. The most recent guidelines regarding dosing of vancomycin were published by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists (ASHP/IDSA/SIDP) in 2009. The ASHP/IDSA/SIDP guidelines state a 24-hour area under the concentration-time curve to minimum inhibitory concentration (AUC:MIC) ratio ≥ 400 is needed for clinical effectiveness, which is thought to be achieved by targeting a trough concentration of 15 to 20 mg/L. A dosing regimen of 15 to 20 mg/kg every 8 to 12 hours, based on actual body weight (ABW; also referred to as total body weight), is recommended for most patients with normal renal function. In seriously ill patients, a loading dose of 25 to 30 mg/kg (ABW) is recommended to obtain a target trough serum concentration more rapidly. In order to prevent resistance, guidelines recommend maintaining a trough concentration >10 mg/L, and targeting a trough concentration of 15 to 20 mg/L for complicated infections.

Pharmacokinetics Alterations in Obesity

The World Health Organization classifies obesity based on body mass index (BMI) into obesity class I (BMI 30 to 34.99 kg/m²), obesity class II (BMI 35 to 39.99 kg/m²), and obesity class III, also referred to as morbid obesity (BMI ≥ 40 kg/m²).² Vancomycin should be monitored in order to both achieve efficacy and prevent potential toxicity, which is a major challenge in the obese population.³ Due to the lack of data, obese patients often receive insufficient doses. Obesity is typically associated with an increase of adipose tissue and muscle mass, which likely leads to an increase in V_d of vancomycin.⁴ Alterations in free serum vancomycin levels are also associated with obesity because of increased circulating proteins. Clearance (CL) has also been shown to increase, likely due to increased kidney size and blood flow secondary to increased cardiac output and blood volume. Studies have also reported that increases in vancomycin CL correlate with ABW.^2,5 Due to altered pharmacokinetics in obesity, it has historically been recommended to dose vancomycin based on ABW.²  Some experts argue that weight-based dosing assumes a proportional increase in drug CL and distribution to size; however, most drugs exhibit nonlinear kinetics in regards to ABW and CL variables.⁴ Therefore, weight-based dosing of vancomycin in obese patients has led to overestimation of doses and elevated trough concentrations.^4,6,7

Data on dosing vancomycin in obese patients are limited, and the optimal dosing strategy in this population is yet to be determined; therefore, the purpose of this article is to summarize current literature on adult dosing of vancomycin in obese patients.

Guideline Recommendations

In obese patients, the ASHP/IDSA/SIDP guideline recommends initial dosages be based on ABW and adjusted based on serum vancomycin concentrations to achieve therapeutic levels; however, the guideline notes there are limited data on dosing vancomycin in obese patients.¹ The Sanford Guide to Antimicrobial Therapy (47^th Edition) provides similar recommendations of dosing initially based on ABW, and adjusting subsequent doses based on measured trough serum levels and goals.⁸ However, it also provides specific dosing recommendations for the obese population. Specifically, in non-critically ill patients with morbid obesity (BMI ≥ 40 kg/m²) and creatinine clearance (CrCl) ≥ 50 ml/min, it recommends 30 mg/kg per day divided every 8 to 12 hours. For patients with morbid obesity who are critically ill, it recommends a loading dose (LD) of 25 to 30 mg/kg (ABW) followed by 15 to 20 mg/kg (ABW) intravenously every 8 to 12 hours. It recommends no single dose over 2 grams.

Review of Literature

The current literature evaluating intermittent vancomycin dosing in obesity is limited, and mostly includes retrospective analyses assessing vancomycin dosing at single institutions (Table).^4,7,9-12 Most of the published data on vancomycin dosing in obesity assesses the most effective weight-based dosing method and dosage for achieving target vancomycin serum concentrations; however, study methods are not standardized.

Alternative Dosing Regimens

Reynolds and colleagues compared an original-protocol (ie, guideline dosing) to a revised, lower dose protocol.⁷ A higher frequency of target trough concentrations and a lower frequency of supratherapeutic trough concentrations were observed in the revised-protocol group; however, a higher frequency of subtherapeutic trough concentrations was also observed in the revised-protocol group. A noncomparative study that also evaluated a reduced maintenance dose of vancomycin in obese patients found that a majority of patients had subtherapeutic trough concentrations.¹¹ Further analysis found an association between younger age and CrCl ≥ 100 mL/min with subtherapeutic trough concentrations. A study by Brown and colleagues found a higher frequency of initial trough concentrations within target range were achieved with allometric dosing compared to consensus guideline dosing in the subgroup of obese patients.⁴ One real-world cohort study found that a dose of ~30 mg/kg/day may be appropriate in patients with BMI 30 to 40 kg/m² while a lower dose may be appropriate in patients with BMI ≥ 40 kg/m².¹² A prospective study of 54 patients with obesity (≥ 137% ideal body weight [IBW]) found a high number of patients achieved target trough concentrations with a divided-load dosing regimen based on IBW and CrCl.⁹ Another study found that obtaining  peak and trough vancomycin levels to calculate individualized vancomycin maintenance doses improved therapeutic trough concentrations compared to obtaining trough levels alone.¹⁰ Overall, available evidence is limited on the optimal vancomycin weight-based dosing regimen in the obese population.³

Table. Studies Evaluating Vancomycin Dosing in Obesity.^4,7,9-12

Safety

Common adverse effects of vancomycin unrelated to serum drug concentration include fever, chills, and phlebitis.¹ Red man syndrome is most likely to occur when large doses of vancomycin are infused too rapidly which leads to tingling and flushing of the face, neck and upper torso. Vancomycin has also been considered to be nephrotoxic and ototoxic in relation to elevated serum drug concentrations. Literature reports are conflicting in regards to increased nephrotoxicity in the obese population, likely associated with the higher doses used in this population.^13-15 In a retrospective cohort study assessing nephrotoxicity in 150 nonobese and 260 obese patients receiving vancomycin, documented cases of nephrotoxicity were observed in 8.7%, 14.3% and 26.3% of non-obese, obesity class I and II, and obesity class III patients, respectively (p=0.002).¹⁴ Nephrotoxicity was defined as a minimum of 2 consecutive increases in creatinine (a total of 0.5 mg/dL or ≥ 50% increase from baseline) after regularly scheduled vancomycin achieved steady state. Risk factors included longer durations of therapy, higher initial maintenance doses, and trough levels >20 mg/L. Another retrospective cohort reported no difference in nephrotoxicity in 323 non-obese (BMI < 30 kg/m²) versus 207 obese (BMI ≥ 30 kg/m²) patients generally treated with a vancomycin dose of 15 mg/kg ABW every 12 hours (initial dose capped at 1750 to 2000 mg per dose).¹⁵ They observed no difference between the 2 groups regarding trough concentrations, changes in serum creatinine, or nephrotoxicity. Supratherapeutic trough concentrations (>20 mg/L) approached but did not reach a statistically significant association with nephrotoxicity in a subset analysis (p=0.054).

Conclusion

Vancomycin is the drug of choice for the treatment of serious gram-positive infections of MRSA. Current guidelines recommend dosing vancomycin based on ABW and adjusting maintenance doses based on obtained serum trough concentrations; however, these recommendations are from 2009. The Sanford Guide provides similar recommendations and includes specific recommendations in patients with morbid obesity (BMI ≥ 40 kg/m²). The current body of literature reports conflicting evidence on the optimal dosing strategy of vancomycin in the obese population. Further studies evaluating new dosing strategies are needed to determine the optimal dosing regimen in these patients in order to achieve both efficacy and safety.

References:

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 Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009;66(1):82-98.
2. Pai MP, Bearden DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy. 2007;27(8):1081-1091.
3. Alvarez R, Lopez Cortes LE, Molina J, Cisneros JM, Pachon J. Optimizing the clinical use of vancomycin. Antimicrob Agents Chemother. 2016;60(5):2601-2609.
4. Brown ML, Hutchinson AM, McAtee AM, Gaillard, Childress DT. Allometric versus consensus guideline dosing in achieving target vancomycin trough concentrations. Am J Health Syst Pharm. 2017;74(14):1067-1075.
5. Bauer LA, Black DJ, Lill JS. Vancomycin dosing in morbidly obese patients. Eur J Clin Pharmacol. 1998;54(8):621-625.
6. Richardson J, Scheetz M, O'Donnell EP. The association of elevated trough serum vancomycin concentrations with obesity. J Infect Chemother. 2015;21(7):507-511.
7. 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(11): 944-950.
8. Gilbert DN, Chambers HF, Eliopoulos GM, et al, eds. The Sanford Guide to Antimicrobial Therapy 2017. 47th ed. Sperryville, VA: Antimicrobial Therapy, Inc; 2017.
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):861-868.
10. Hong J, Krop LC, Johns T, Pai MP. Individualized vancomycin dosing in obese patients: a two-sample measurement approach improves target attainment. Pharmacotherapy. 2015;35(5):455-463.
11. Kosmisky DE, Griffiths CL, Templin MA, Norton J, Martin KE. Evaluation of a new vancomycin dosing protocol in morbidly obese patients. Hosp Pharm. 2015;50(9):789-797.
12. Morrill HJ, Caffrey AR, Noh E, LaPlante K. Vancomycin dosing considerations in a real-world cohort of obese and extremely obese patients. Pharmacotherapy. 2015;35(9):869-875.
13. Alobaid AS, Hites M, Lipman J, Taccone FS, Roberts JA. Effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients: A structured review. Int J Antimicrob Agents. 2016;47(4):259-268.
14. Choi YC, Saw S, Soliman D, et al. Intravenous vancomycin is associated with the development of nephrotoxicity in patients with class III obesity [published online ahead of print July 14, 2017]. Ann Pharmacother. doi: 10.1177/1060028017720946.
15. Davies SW, Efird JT, Guidry CA, et al. Vancomycin-associated nephrotoxicity: the obesity factor. Surg Infect. 2015;16(6):684-693.

Prepared by:

Hannah Underwood, PharmD

PGY1 Pharmacy Practice Resident

University of Illinois at Chicago College of Pharmacy

The information presented is current as August 4, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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