It Is a "VRE" Serious Controversy
What are the advantages and disadvantages of linezolid versus daptomycin for vancomycin-resistant enterococcus bacteremia?
Vancomycin-resistant Enterococcus (VRE) is a common nosocomial pathogen associated with significant morbidity and mortality.1
Among enterococci, E faecalis tends to be the more common organism causing infection. However, E faecium is intrinsically more resistant to antimicrobials. About 80% of E faecium and 5% to 10% of E faecalis strains are vancomycin resistant.2 Aminopenicillins may maintain susceptibility in select cases, but when Enterococcus isolates are resistant to both aminopenicillins and vancomycin, choosing the optimal agent can be challenging. Not surprisingly, VRE bacteremia has been associated with a 2.5-fold higher mortality rate compared with vancomycin-susceptible enterococcal bacteremia.3
The 2 most commonly used antibiotics for VRE bacteremia are linezolid and daptomycin. Both agents are recommended by professional guidelines for the treatment
of VRE bloodstream infections, including infective endocarditis and intravascular catheter-related bacteremia.4,5 However, despite widespread use of each agent, there is still conflicting evidence and controversy regarding the therapeutic efficacy of daptomycin versus linezolid. This article reviews the body of literature and comparative advantages and disadvantages of each antibiotic for the treatment of VRE bacteremia.
Linezolid is an oxazolidinone antibiotic with broad gram-positive bacterial activity, including VRE. It is available in both intravenous and oral formulations with excellent
bioavailability and the recommended dose is 600 mg twice daily. Linezolid is the only agent with an FDA-approved indication for VRE infections, including bacteremia.6 It is also recommended by professional guidelines as a first-line treatment option for bacteremia secondary to infective endocarditis, because of ampicillin-resistant VRE.4 Despite the clinical data supporting its use, a theoretical issue with linezolid lies in its bacteriostatic nature, which may hinder its activity against VRE, especially in cases of bacteremia with high inoculum burden or complicated by endovascular seeding. Treatment failures with linezolid have been reported, particularly in cases of infective endocarditis.7 Additionally, a mortality imbalance was noted in a study comparing linezolid with vancomycin for catheter-related bloodstream infections,
although enterococcal bacteremia accounted for less than 10% of all cases.8
Toxicities may arise with long-term use of linezolid exceeding 2 weeks. These include lactic acidosis, peripheral neuropathy, optic neuritis, and thrombocytopenia. There are also concerns regarding serotonin syndrome as a result of potential drug-drug interactions with serotonergic agents, given linezolid’s weak monoamine oxidase inhibition properties.
Daptomycin is a lipopeptide antibiotic with rapid bactericidal activity against enterococci. It is only available as an intravenous formulation and is FDA approved for complicated skin and skin structure infections and Staphylococcus aureus bacteremia, at doses ranging from 4 to 6 mg/kg/day. Although not FDA approved for VRE bacteremia, it has demonstrated both clinical and in vitro efficacy in this particular setting.9,10 As with linezolid, there are concerns with daptomycin that may affect its efficacy for VRE bacteremia. These include elevated daptomycin minimum inhibitory concentrations (MICs) that may hinder optimal pharmacodynamic target attainment, emerging resistance, and lack of standardized dosing for VRE bacteremia.
Prior to 2019, the susceptible breakpoint for daptomycin against Enterococcus spp was ≤4 mg/L. However, 2 major cohort studies concluded that daptomycin MICs of 3 to 4 mg/L were predictive of microbiological failure, suggesting that the breakpoint did not correlate with therapeutic efficacy.11,12 In early 2019, the Clinical and Laboratory Standards Institute updated daptomycin breakpoints against E faecium, removing the susceptible breakpoint for daptomycin and assigning all isolates with MICs ≤4 mg/L as “susceptible dose dependent.”13 Higher daptomycin doses of 8 to 12 mg/kg are recommended for susceptible dosedependent isolates of E faecium, particularly in the blood, to achieve clinical efficacy.
The benefit of “high dose” daptomycin for the treatment of VRE bacteremia has been demonstrated in clinical studies.14-18 For instance, Britt et al showed that higher doses (≥10 mg/kg) were associated with improved survival and microbiological clearance compared with lower doses (6 to 8 mg/kg) of daptomycin.15 Similarly, Chuang et al suggested that higher-dose daptomycin (≥9 mg/kg) was associated with decreased mortality compared with lower-dose daptomycin (<9 mg/kg) for VRE bacteremia. The majority of their VRE isolates (70%) possessed MICs of 4 mg/L.17
The main toxicity issue with daptomycin is creatine phosphokinase (CPK) elevations during the course of therapy, which may be asymptomatic or can progress to myopathy or rhabdomyolysis. It is recommended to discontinue daptomycin therapy in patients with signs and symptoms of myopathy and a CPK level >5 times the upper limit of normal (ULN) or >1000 units/L or in asymptomatic patients with a CPK ≥10 times ULN or >2,000 units/L.19 It is also recommended to temporarily discontinue therapy with other agents associated with rhabdomyolysis (eg, HMG-CoA reductase inhibitors) during daptomycin therapy. Myopathy and rhabdomyolysis occur more frequently in patients with renal impairment, and therefore, dosage adjustment in the setting of dysfunction is warranted. Finally, eosinophilic pneumonia may develop in rare instances, typically within 2 to 4 weeks after daptomycin initiation.
A literature review (table) was conducted to identify studies comparing daptomycin with linezolid for VRE bacteremia. These included 4 meta-analyses and systematic reviews, 2 retrospective studies, and 1 prospective study. It is clear that linezolid demonstrates superior survival outcomes compared with daptomycin when suboptimal doses of the latter are used. The majority of studies that demonstrated increased mortality with daptomycin used a median dose of ~6 mg/kg/day. These findings indicate that daptomycin is likely most effective for VRE bacteremia when dosed at the 8- to 12-mg/kg/day range.
Both daptomycin and linezolid are potential options for the management of VRE bacteremia. The literature supports the use of linezolid over daptomycin if suboptimal doses of daptomycin are used, implying that daptomycin doses in VRE bacteremia should be optimized (8-12mg/kg/day). In VRE bacteremia that is complicated by endovascular seeding, such as infective endocarditis, it may be prudent to use a bactericidal agent such as daptomycin over linezolid with consideration for even higher doses (10-12 mg/kg/day). The ultimate decision to choose daptomycin or linezolid for VRE bacteremia will depend on considerations for adverse effects of each respective antibiotic, comorbidities, patient-specific factors, and the source of infection.
Hongkai Bao, PharmD, is a PGY-2 infectious diseases pharmacy resident, and Shin-Pung Jen, PharmD, BCPS-AQ ID, AAHIVP, is a clinical pharmacotherapy specialist, infectious diseases, at NYU Langone Health in New York, New York.
- Song X, Srinivasan A, Plaut D, Perl TM. Effect of nosocomial vancomycin-resistant enterococcal bacteremia on mortality, length of stay, and costs. Infect Control Hosp Epidemiol. 2003;24(4):251-256. doi: 10.1086/502196.
- Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010. Infect Control Hosp Epidemiol. 2013;34(1):1-14. doi:10.1086/668770.
- O’Driscoll T, Crank CW. Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management. Infect Drug Resist. 2015;8:217-230. doi: 10.2147/IDR.S54125.
- Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132(15):1435-1486. doi: 10.1161/CIR.0000000000000296.
- Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1-45. doi: 10.1086/599376.
- Zyvox (linezolid) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada Inc; February 2018.
- Tsigrelis C, Singh KV, Coutinho TD, Murray BE, Baddour LM. Vancomycinresistant Enterococcus faecalis endocarditis: linezolid failure and strain characterization of virulence factors. J Clin Microbiol. 2007;45(2):631-635.
- Wilcox MH, Tack KJ, Bouza E, et al. Complicated skin and skin-structure infections and catheter-related bloodstream infections: noninferiority of linezolid in a phase 3 study. Clin Infect Dis. 2009;48(2):203-212. doi: 10.1086/595686.
- Hall AD, Steed ME, Arias CA, Murray BE, Rybak MJ. Evaluation of standard-and high-dose daptomycin versus linezolid against vancomycin-resistant enterococcus isolates in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents Chemother. 2012;56(6):3174-3180. doi: 10.1128/AAC.06439-11.
- Levine DP, Lamp KC. Daptomycin in the treatment of patients with infective endocarditis: experience from a registry. Am J Med. 2007;120(10 suppl 1):S28-33.
- Shukla BS, Shelburne S, Reyes K, et al. Influence of minimum inhibitory concentration in clinical outcomes of enterococcus faecium bacteremia treated with daptomycin: is it time to change the breakpoint? Clin Infect Dis. 2016;62(12):1514-1520. doi: 10.1093/cid/ciw173.
- Moise PA, Sakoulas G, McKinnell JA, et al. Clinical outcomes of daptomycin for vancomycin-resistant enterococcus bacteremia. Clin Ther. 2015;37(7):1443- 1453.e1442. doi: 10.1016/j.clinthera.2015.04.008.
- CLSI. Daptomycin breakpoint revision. Revision memo to CLSI supplement M100, 29th ed. Wayne, PA: Clinical and Laboratory Standards Institute; 2019. clsi.org/media/2663/m100ed29_sample.pdf. Accessed February 6, 2020.
- Moise PA, Hershberger E, Amodio-Groton MI, Lamp KC. Safety and clinical outcomes when utilizing high-dose (> or =8 mg/kg) daptomycin therapy. Ann Pharmacother. 2009;43(7):1211-1219. doi: 10.1345/aph.1M085.
- 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. doi: 10.1093/cid/ciw815.
- Chuang YC, Lin HY, Chen PY, Lin CY, Wang JT, Chang SC. Daptomycin versus linezolid for the treatment of vancomycin-resistant enterococcal bacteraemia: implications of daptomycin dose. Clin Microbiol Infect. 2016;22(10):890. e891-890.e897. doi: 10.1016/j.cmi.2016.07.018.
- Chuang YC, Lin HY, Chen PY, et al. Effect of daptomycin dose on the outcome of vancomycin-resistant, daptomycin-susceptible enterococcus faecium bacteremia. Clin Infect Dis. 2017;64(8):1026-1034. doi: 10.1093/cid/cix024.
- Werth BJ, Steed ME, Ireland CE, et al. Defining daptomycin resistance prevention exposures in vancomycin-resistant Enterococcus faecium and E. faecalis. Antimicrob Agents Chemother. 2014;58(9):5253-5261. doi: 10.1128/AAC.00098-14.
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- Whang DW, Miller LG, Partain NM, McKinnell JA. Systematic review and meta-analysis of linezolid and daptomycin for treatment of vancomycin-resistant enterococcal bloodstream infections. Antimicrob Agents Chemother. 2013;57(10):5013-5018. doi: 10.1128/AAC.00714-13.
- Balli EP, Venetis CA, Miyakis S. Systematic review and meta-analysis of linezolid versus daptomycin for treatment of vancomycin-resistant enterococcal bacteremia. Antimicrob Agents Chemother. 2014;58(2):734-739. doi: 10.1128/AAC.01289-13.
- Chuang YC, Wang JT, Lin HY, Chang SC. Daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bacteremia: systematic review and meta-analysis. BMC Infect Dis. 2014;14:687. doi: 10.1186/s12879-014-0687-9.
- Britt NS, Potter EM, Patel N, Steed ME. Comparison of the effectiveness and safety of linezolid and daptomycin in vancomycin-resistant enterococcal bloodstream infection: a national cohort study of Veterans Affairs patients. Clin Infect Dis. 2015;61(6):871-878. doi: 10.1093/cid/civ444.
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