Susceptible Dose-Dependent Dosing Guidance: Daptomycin and Ceftaroline

Summary The Clinical & Laboratory Standards Institute (CLSI) includes a susceptible dose-dependent (SDD) category for certain drug and organism combinations. The SDD is a breakpoint category for which the susceptibility of an isolate depends on the dosing regimen used. For isolates with SDD susceptibility results, dosing regimens that achieve higher drug exposure are necessary. For the highest probability of adequate coverage of an SDD isolate, consideration should be given to using the maximum, literature-supported dosing regimens.1

UNC Medical Center’s Microbiology Lab includes an SDD category for E. faecium: daptomycin and S. aureus: ceftaroline.

SDD: E. faecium--Daptomycin

Background The FDA-approved dosing for daptomycin was originally based on treatment of infections due to staphylococci. Though not a labeled indication, daptomycin is an important for treatment of infections due to -resistant . Daptomycin MICs for E. faecium are often higher than MICs for other Gram-positive organisms. Studies have found that applying labeled daptomycin dosing to severe infections due to E. faecium lead to poorer outcomes.2 In two cohort studies, high-dose daptomycin was associated with lower mortality in patients with vancomycin-resistant E. faecium bacteremia. “High-dose” was considered to be ≥10 mg/kg daily and ≥9mg/kg daily, respectively. In both studies, the daptomycin MIC was 4 mg/L in ~ 70% of patients.3,4 Studies have also shown that high-dose daptomycin is generally well-tolerated and safe. It is recommended to monitor (CK) weekly in all patients receiving daptomycin.5

Recommendations

Daptomycin MIC (mg/L) breakpoints for Enterococcus faecium1 Susceptible dose- Susceptible (S) Resistant (R) dependent (SDD) Daptomycin MIC - ≤4 ≥8 Recommended dosing* - 8-12 mg/kg Q24H - *Recommended dosing is for adult patients with normal renal function. Please see UNC Pharmacy Clinical Guidelines for dosing adjustments in patients with renal dysfunction: https://unchcs.intranet.unchealthcare.org/dept/Pharmacy/mc/Pages/ClinicalGuidelines.aspx Dose based on actual total body weight for non-obese patients. For BMI > 30 use adjusted body weight. AdjBW= IBW + 0.4(TBW-IBW)

For serious infections caused by E. faecium reported as SDD (MIC ≤4 mg/L), dosing regimens of daptomycin 8-12 mg/kg per day are recommended. In these cases, consider consultation with Infectious Diseases. These recommendations apply to adult patients only. Equivalent high-dose daptomycin strategies have not been studied in children. Consider consultation with Pediatric Infectious Diseases. For serious infections due to other Enterococcus spp. or S. aureus, high- dose daptomycin strategies may also be appropriate. Contact the Antimicrobial Stewardship Program (ASP) for assistance with daptomycin dosing (pager 216-2398).

References: 1. CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 29th ed. CLSI supplement M100. Wayne, PA: Clinical Laboratory Standards Institute; 2019. 2. Moise PA, Sakoulas G, McKinnell JA, et al. Clinical outcomes of daptomycin for vancomycin-resistant Enterococcus bacteremia. Clin Ther. 2015;37(7):1443- 1453. 3. Britt NS, Potter EM, Patel N, Steed ME. Comparative effectiveness and safety of standard-,medium-, and high-dose daptomycin strategies for the treatment of vancomycin-resistant enterococcal bacteremia among Veterans Affairs patients. Clin Infect Dis. 2017;64(5):605-613. 4. Chuang YC, Lin HY, Chen PY, et al. Effect of daptomycin dose on the outcome of vancomycin-resistant, daptomycin-susceptible bacteremia. Clin Infect Dis. 2017;64(8):1026-1034. 5. Seaton RA, Menichetti F, Dalekos G, et al. Evaluation of effectiveness and safety of high-dose daptomycin: results from patients included in the European Cubicin® Outcomes Registry and Experience. Adv Ther. 2015;32:1192-1205. 6. Fox AN, Smith WJ, Kupiec KE, et al. Daptomycin dosing in obese patients: analysis of adjusted versus actual body weight. Ther Adv Infect Dis 2019;6:1-10. 7. Dvorchik BH, Damphousse D. The of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects. J Clin Pharmacol. 2005;45:48-56.

Prepared by the UNC Medical Center Antimicrobial Stewardship Program Updated 6-17-2019

SDD: S. aureus: Ceftaroline

Background The FDA-approved adult dosing for ceftaroline is 600 mg IV every 12 hours given over 5-60 minutes. Most S. aureus isolates in the United States have a ceftaroline MIC of < 1 mg/L, however isolates with higher MICs have been reported.1 In the Phase 3 clinical trials using doses of ceftaroline 600 mg IV every 12 hours, the majority of S. aureus clinical isolates had ceftaroline MICs of < 1 mg/L.2 Pharmacokinetic/pharmacodynamics (PD/PD) modeling data support dosage regimens of 600 mg IV every 8 hours infused over 2 hours for S. aureus organisms with MICs of 2-4 mg/L.2 In a randomized controlled trial, this higher dosing regimen was shown to be safe and effective in patients with complicated skin and soft tissue infections with evidence of systemic inflammation.3

Recommendations

Ceftaroline MIC (mg/L) breakpoints for aureus4 Susceptible dose- Susceptible (S) Resistant (R) dependent (SDD) Ceftaroline MIC ≤1 2-4 ≥8 600 mg every 12 hours 600 mg every 8 hours over Recommended dosing* - over 5-60 minutes 2 hours *Recommended dosing is for adult patients with normal renal function. Please see UNC Pharmacy Clinical Guidelines for dosing adjustments in patients with renal dysfunction: https://unchcs.intranet.unchealthcare.org/dept/Pharmacy/mc/Pages/ClinicalGuidelines.aspx

For infections caused by S. aureus reported as SDD (MIC 2-4 mg/L), ceftaroline 600 mg every 8 hours (2 hour infusion) is recommended. In these cases, consider consultation with Infectious Diseases. These recommendations apply to adult patients only. Equivalent high-dose ceftaroline strategies have not been studied in children. Consider consultation with Pediatric Infectious Diseases.

References: 1. Jones RN, Mendes RE, Sader HS. Ceftaroline activity against pathogens associated with complicated skin and skin structure infections: results from an international surveillance study. J Antimicrob Chemother 2010; 65:17-31. 2. Das S, Li J, Iaconis J. et al. doses and breakpoints for S. aureus in complicated skin and soft tissue infections. J Antimicrob Chemother 2018; 74:425-431. 3. Dryden, M, Zhang, Y, Wilson Y., et al. A phase III randomized controlled non-inferiority trial of ceftaroline fosamil 600 mg every 8 h versus vancomycin plus in patients with complicated skin and soft tissue infection with systemic inflammatory response or underlying comorbidities. J Antimicrob Chemother. 2016; 71:3575-3584. 4. CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 29th ed. CLSI supplement M100. Wayne, PA: Clinical Laboratory Standards Institute; 2019.

Prepared by the UNC Medical Center Antimicrobial Stewardship Program Updated 6-17-2019