It Is a "VRE" Serious Controversy

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

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

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.

Literature Review

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.

Conclusion

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.

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