Antimicrobial resistance (AMR) is a leading cause of death globally. It is estimated to be associated with nearly 5 million deaths in 2019,1 and projected to contribute to as many as 10 million deaths annually by 2050.2 Although enterococci, specifically Enterococcus faecalis and E faecium, are listed among the pathogens of concern in the Lancet Global Burden of Disease AMR report,1 considerably more resources have been allocated to investigating AMR and new drug development for gram-negative bacteria.
One of the few agents developed to target gram-positive bacteria in the past 2 decades is daptomycin, a parenteral lipopeptide active against a broad range of gram positives, first approved by the US Food and Drug Administration (FDA) in 2003 for skin and soft tissue infections with Staphylococcus aureus, β-hemolytic streptococci, and E faecalis, and later expanded to bacteremia and right-sided endocarditis with S aureus in 2006.3 Given the paucity of therapeutic options for vancomycin-resistant enterococci (VRE) and significant toxicities associated with alternatives (eg, linezolid), daptomycin came to serve as a frontline agent for serious nonpulmonary infections with ampicillin- and vancomycin-resistant enterococci. Unfortunately, as experience with daptomycin has matured, new questions have been raised, such as daptomycin efficacy against isolates with elevated minimum inhibitory concentrations (MICs) and what to do when resistance occurs. Herein, we briefly discuss daptomycin resistance mechanisms, antimicrobial susceptibility testing controversies, daptomycin-resistant enterococci (DRE) epidemiology, and current and future therapeutic options for DRE.
Daptomycin resistance mechanisms in enterococci
Daptomycin is an anionic lipopeptide with a mechanism of action that is not fully elucidated.4 It is thought to exhibit bactericidal killing primarily by binding to cell membrane phospholipids in a calcium-dependent manner, leading to the formation of pores via oligomerization with resultant membrane depolarization, ion leakage, and cell death. Similar to Staphylococcus aureus, initial daptomycin resistance for E faecium is likely due to electrostatic repulsion of the positively charged daptomycin-Ca2+ complex from the cell membrane.5 Enterococci also develop resistance against daptomycin via mutations in genes that encode regulatory pathways involved in the cell envelope stress response (eg, LiaFSR and YycFG) and metabolism of cell membrane phospholipids (eg, gdpD and cls). Mutations in these pathways lead to the thickening and resilience of the cell wall. To date, most described mutations have occurred in LiaFSR, which is sufficient to limit the bactericidal activity of daptomycin; however, additional mutations in other genes can lead to increased resistance.4,5 These mutations are typically acquired under selective pressure with daptomycin exposure,6 but E faecium often reverts to wild-type LiaFSR once pressure is removed.7,8
Daptomycin breakpoint and efficacy controversies in enterococci
Daptomycin use for E faecium remains controversial and is illustrated by the conflicting susceptibility breakpoint positions of the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). In 2019, CLSI updated E faecium daptomycin breakpoints to susceptible dose dependent at 4 µg/mL or less and resistant at 8 µg/mL or greater,9 noting that pharmacokinetic-pharmacodynamic (PK-PD) modeling support higher dosing (10-12 mg/kg) than that approved by the FDA (6 mg/kg) for enterococci with MICs of 2 µg/mL to 4 µg/mL and the imprecision of susceptibility testing for MICs in the range of 1 µg/mL to 4 µg/mL.10 In contrast, EUCAST notes insufficient evidence for the Enterococcus genus, expressing concern that daptomycin dosed at 10 mg/kg to 12 mg/kg is insufficient to treat the wild-type distribution of E faecium isolates, with an epidemiological cutoff value at 8 µg/mL, which is in contrast to CLSI’s estimate of 4 µg/mL and underscores the imprecision of daptomycin in in vitro testing.11 The best evidence to highlight issues with daptomycin susceptibility testing comes from Campeau et al in 2018,12 who described the lack of reproducibility of even the reference method (ie, broth dilution) and the frequent discrepancy between phenotypic susceptibility results and the presence of the most common resistance mutations in LiaFSR.13 Some of the testing imprecision originates from the calcium dependence of daptomycin, thus requiring a fixed concentration in vitro for reliable susceptibility results. Ultimately, neither CLSI nor EUCAST have updated their positions on daptomycin since 2019-2020, and lingering concerns about therapeutic efficacy and testing reliability in the upper range of wild-type MICs remain an important consideration for clinicians using daptomycin to treat serious VRE infections.
Prevalence of daptomycin resistance in enterococci
The increasing prevalence of DRE, particularly among E faecium, is worrisome. A worldwide survey of daptomycin activity against bacterial isolates in hospitalized patients from 2005 to 2012 reported a greater than 99% susceptibility of E faecium (MIC, ≤ 4 μg/mL) within all global regions. However, patterns of higher resistance with daptomycin and E faecium emerged in that same period, with Memorial Sloan Kettering Cancer Center (New York, New York) reporting daptomycin resistance among VRE bloodstream isolates increasing from 3.4% to 15.2% from 2007 to 2009.14 A recent systematic review and meta-analysis including data from 2000 to 2020 estimated the global prevalence of daptomycin resistance among E faecium to be 9.0%.15 At our center, historically, daptomycin susceptibility in enterococci approached 100%, but since late 2023, that susceptibility has abruptly fallen to approximately 80% despite no changes in methodology. To understand whether similar centers in the US were experiencing such a shift we informally surveyed members of 2 email list servs including clinical microbiologists and cancer center antimicrobial stewardship programs in July 2024. We received 10 responses, mostly from large US medical centers, with reports of daptomycin resistance among nonduplicate E faecium isolates at a median of 8.5% (range, 1%-16%). Notably, 5 (50%) centers reported daptomycin resistance of 10% or greater, which included all 3 large cancer centers that responded, and 2 (20%) centers reported an increase in daptomycin resistance of 10% or greater over any 1-year period since 2020.
Therapeutic options for DRE and other difficult-to-treat enterococci
For the DRE era, several potential therapeutic options exist for serious infections. Linezolid, an oxazolidinone with broad gram-positive bacterial activity and an FDA indication for VRE including bloodstream infection (BSI), unfortunately carries considerable potential toxicity, particularly via myelosuppression or peripheral neuropathy with prolonged durations of therapy.16
Although the prospect of therapeutic drug monitoring to minimize toxicity has offered some hope of safe, prolonged use,17,18 reports of coexistent linezolid and daptomycin resistance in VRE are also emerging.19 Tedizolid, a newer oxazolidinone, FDA approved in 2014 for skin and soft tissue infection, may be effective for other indications such as enterococcal BSI,20 but also carries a risk of myelosuppression and other presumptive class toxicities.21,22
Newer tetracycline derivatives are another antimicrobial group of interest for multidrug-resistant E faecium. Tigecycline, a glycylcycline 30S bacterial ribosomal subunit inhibitor, has excellent retained activity against E faecium,23 but suffers from a large volume of distribution, high rates of gastrointestinal adverse effects, and a possible association with increased all-cause mortality (refuted by evidence from a 2019 meta-analysis).24 Nonetheless, data support tigecycline for intra-abdominal infection with E faecium, notably at higher dosing than that indicated on the package insert.25,26 Omadacycline and eravacycline are more recent tetracycline derivatives with promising in vitro activity against E faecium,27-31 but in vivo data against E faecium are limited,32-35 and both agents also suffer from the same pharmacodynamic challenges as tigecycline.36,37
Combination therapy has been an important topic in enterococci, such as with infective endocarditis (IE), where combinations such as ampicillin and gentamicin or ceftriaxone are already well established.38 VRE, and now DRE, poses a unique challenge, as BSIs or IE can be difficult to clear, even with susceptible agents. Limited data suggest that daptomycin combined with β-lactams may be synergistic or improve bacterial killing compared with daptomycin alone in the case of VRE,39-43 and the addition of ceftaroline may even restore daptomycin susceptibility in DRE.44 Other combinations of interest for VRE or DRE, best summarized by Yim et al,45 include linezolid with gentamicin and/or rifampin46-49 and tigecycline with daptomycin.50,51 A final group of antimicrobials with potential use in DRE include novel lipoglycopeptides: oritavancin, dalbavancin, and telavancin.52-54 Although each has promising data against E faecium,55-60 there is still much to learn about PK-PD relationships with limited data on MICs, effective dosing strategies given the prolonged half-lives of oritavancin and dalbavancin, and concerns with cross-reduced susceptibility in the setting of daptomycin resistance.
To date, we have been fortunate regarding our clinical experience with DRE in terms of our patients’ outcomes; most isolates originated from uncomplicated BSIs or the urinary tract, requiring 14 or fewer days of linezolid, for which susceptibility remains near 100%, and some urinary or wound isolates required no therapy. Like other institutions, however, we have faced difficult-to-clear VRE infections on numerous occasions, in some cases resorting to daptomycin-ceftaroline combination therapy and, in at least 1 case, using omadacycline as an adjunct with apparent success.
Conclusion
As DRE becomes a more significant public health threat, considerable work must be done to better understand daptomycin resistance among enterococci, including appropriate susceptibility breakpoints and dosing, and establish evidence-based and tolerable therapeutic regimens for such infections. With our own recent experience with DRE and the described challenges in mind, we call on clinicians, researchers, and policy makers to further elevate and urgently commit resources to the problem of enterococcal drug resistance.
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