#PharmToExamTable: What Weight Should be Used for Dosing Daptomycin in Obesity?

A #PharmToExamTable question about daptomycin dosing, answered by Terese Lewis, PharmD, a Graduate of UNMC College of Pharmacy who is now a Pharmacy Resident at UNMC.

(Reviewed by Andrew Watkins, PharmD)

Daptomycin is an antibiotic used to treat complicated gram-positive bacterial infections as it has good activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). At Nebraska Medicine, the susceptibilities of MRSA and VRE during 2021 were 100% and 75%, respectively. Daptomycin has been FDA approved for complicated skin and soft tissue infections, but due to its broader gram-positive coverage it is used off-label frequently. Off label uses include osteomyelitis (bone infections) due to MRSA, prosthetic joint infections caused by Staphylococcus spp. or Enterococcus spp., and left sided infective endocarditis (infection of heart muscle) due to Staphylococcus spp. or Enterococcus spp.  It is thought to work by depolarizing the bacterial cell membrane.¹ The use of daptomycin in skin and soft tissue infection has dosing recommendations of 4-6 mg/kg/day. As we use the antibiotic to treat more resistant bacteria or diseases with higher mortality, dosing off-label may increase to 12 mg/kg/day.²  

Daptomycin’s most concerning side effect is a risk of myopathy. Creatinine phosphokinase (CPK) increases can be seen while on therapy, which can be indicative of stress or damage to the muscle. There is some concern about the frequency of adverse events as doses, and weights, get higher. 

Product labeling suggests the use of total body weight (TBW) to dose obese patients, but that is based on 4 mg/kg PK data for a single dose. Obese patients, however, have routinely shown larger than expected drug levels attributed to overdosing due to increased TBW. These increases contributed to changes in renal clearance.²

One trial compared obese patients who received actual body weight (ABW) vs adjusted body weight (AdjBW) dosing. The most common indications for daptomycin in this study included osteomyelitis, skin and soft tissue infections, and abscesses. Doses used in this study were <8 mg/kg/day, so extrapolation of results to doses greater than that will require more data. Treatment failure was found to be statistically equivalent between the two groups, as well as 90-day mortality, suggesting that adjusting dosing to AdjBW may not be necessary. ³

Another study concluded that does up to 12 mg/kg/day followed linear kinetics and were shown to be safe and efficacious. They found that the safety profile and clinical efficacy necessitated no dose adjustments solely based on BMI. ⁴

ACCP guidance for dosing in obesity recommends the use of actual body weight for obese patients to ensure treatment efficacy. They also recommend close monitoring of patients weighing more than 111 kg for increases in CPK as elevated BMI classes are inherently associated with increased CPK elevation.⁵

The first study that presented ideal body weight (IBW) dosing outcomes concluded that regardless of infection and bacteria type ABW and IBW dosing may provide similar outcomes. They do recommend that certain infections may favor one dosing weight over another and they recommend further studies. ⁶ More research with larger sample sizes are needed to firmly demarcate which specific pathogens may be better treated with altered dosing strategies.

In conclusion, even though we do not have randomized control trials or retrospective studies analyzing all doses, the data we have points to the safety of using TBW in obese and extremely obese patients. Consideration should be made to close monitoring of CPK levels.

References:

1. Daptomycin. In: Lexi-Drugs [online database]. Hudson, OH: Lexicomp (accessed 2021, August 6).
2. Daptomycin [package insert]. Whitehouse Station, NJ. Merck & Co., Inc. 2017. 
3. Fox, AN, Smith WJ, Kupiec KE, et. al. Daptomycin dosing in obese patients: analysis of the use of adjusted body weight versus actual body weight. Therapeutic Advances in Infectious Disease. 2019 Jan 30.
4. Gonzalez-Ruiz A, Gargalianos-Kakolyris P, Timerman A, et al. Daptomycin in the clinical setting: 8-year experience with Gram-positive bacterial infections from the EU-CORE(SM) registry. Adv Ther. 2015;32(6):496–509
5. Meng L, Mui E, Holubar M, et al. Comprehensive Guidance for Antibiotic Dosing in Obese Adults. ACCP Journals. Pharmacotherapy 2017;37(11):1415–1431. 
6. Ng JK, Schulz LT, Rose WE, et al. Daptomycin dosing on ideal body weight versus actual body weight: comparison of clinical outcomes. American Society for Microbiology. 21 October 2013.